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Chen C, Li Y, Gu Y, Zhai Q, Guo S, Xiang J, Xie Y, An M, Li C, Qin N, Shi Y, Yang L, Zhou J, Xu X, Xu Z, Wang K, Zhu M, Jiang Y, He Y, Xu J, Yin R, Chen L, Xu L, Dai J, Jin G, Hu Z, Wang C, Ma H, Shen H. Massively parallel variant-to-function mapping determines functional regulatory variants of non-small cell lung cancer. Nat Commun 2025; 16:1391. [PMID: 39910069 PMCID: PMC11799298 DOI: 10.1038/s41467-025-56725-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 01/28/2025] [Indexed: 02/07/2025] Open
Abstract
Genome-wide association studies have identified thousands of genetic variants associated with non-small cell lung cancer (NSCLC), however, it is still challenging to determine the causal variants and to improve disease risk prediction. Here, we applied massively parallel reporter assays to perform NSCLC variant-to-function mapping at scale. A total of 1249 candidate variants were evaluated, and 30 potential causal variants within 12 loci were identified. Accordingly, we proposed three genetic architectures underlying NSCLC susceptibility: multiple causal variants in a single haplotype block (e.g. 4q22.1), multiple causal variants in multiple haplotype blocks (e.g. 5p15.33), and a single causal variant (e.g. 20q11.23). We developed a modified polygenic risk score using the potential causal variants from Chinese populations, improving the performance of risk prediction in 450,821 Europeans from the UK Biobank. Our findings not only augment the understanding of the genetic architecture underlying NSCLC susceptibility but also provide strategy to advance NSCLC risk stratification.
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Affiliation(s)
- Congcong Chen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
- The Second People's Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China
| | - Yang Li
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Yayun Gu
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Qiqi Zhai
- Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, 211116, Jiangsu, China
| | - Songwei Guo
- Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, 211116, Jiangsu, China
| | - Jun Xiang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Yuan Xie
- Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, 211116, Jiangsu, China
| | - Mingxing An
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Chenmeijie Li
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Na Qin
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Yanan Shi
- Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, 211116, Jiangsu, China
| | - Liu Yang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Jun Zhou
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Xianfeng Xu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Ziye Xu
- Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, 211116, Jiangsu, China
| | - Kai Wang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Meng Zhu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Yue Jiang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Yuanlin He
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Jing Xu
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Rong Yin
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Department of Thoracic Surgery Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, 210029, Jiangsu, China
| | - Liang Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Lin Xu
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Department of Thoracic Surgery Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, 210029, Jiangsu, China
| | - Juncheng Dai
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Guangfu Jin
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
| | - Zhibin Hu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
- State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China
- State Key Laboratory of Reproductive Medicine (Suzhou Centre), The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215002, Jiangsu, China
| | - Cheng Wang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
- The Second People's Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
| | - Hongxia Ma
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
- Research Units of Cohort Study on Cardiovascular Diseases and Cancers, Chinese Academy of Medical Sciences, Beijing, 100730, China.
| | - Hongbing Shen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
- Research Units of Cohort Study on Cardiovascular Diseases and Cancers, Chinese Academy of Medical Sciences, Beijing, 100730, China.
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Blechter B, Wang X, Shi J, Shiraishi K, Choi J, Matsuo K, Chen TY, Dai J, Hung RJ, Chen K, Shu XO, Kim YT, Choudhury PP, Williams J, Landi MT, Lin D, Zheng W, Yin Z, Zhou B, Wang J, Seow WJ, Song L, Chang IS, Hu W, Chien LH, Cai Q, Hong YC, Kim HN, Wu YL, Wong MP, Richardson BD, Li S, Zhang T, Breeze C, Wang Z, Bassig BA, Kim JH, Albanes D, Wong JY, Shin MH, Chung LP, Yang Y, An SJ, Zheng H, Yatabe Y, Zhang XC, Kim YC, Caporaso NE, Chang J, Man Ho JC, Kubo M, Daigo Y, Song M, Momozawa Y, Kamatani Y, Kobayashi M, Okubo K, Honda T, Hosgood HD, Kunitoh H, Watanabe SI, Miyagi Y, Nakayama H, Matsumoto S, Horinouchi H, Tsuboi M, Hamamoto R, Goto K, Ohe Y, Takahashi A, Goto A, Minamiya Y, Hara M, Nishida Y, Takeuchi K, Wakai K, Matsuda K, Murakami Y, Shimizu K, Suzuki H, Saito M, Ohtaki Y, Tanaka K, Wu T, Wei F, Dai H, Machiela MJ, Su J, Kim YH, Oh IJ, Fun Lee VH, Chang GC, Tsai YH, Che KY, Huang MS, Su WC, Chen YM, Seow A, Park JY, Kweon SS, et alBlechter B, Wang X, Shi J, Shiraishi K, Choi J, Matsuo K, Chen TY, Dai J, Hung RJ, Chen K, Shu XO, Kim YT, Choudhury PP, Williams J, Landi MT, Lin D, Zheng W, Yin Z, Zhou B, Wang J, Seow WJ, Song L, Chang IS, Hu W, Chien LH, Cai Q, Hong YC, Kim HN, Wu YL, Wong MP, Richardson BD, Li S, Zhang T, Breeze C, Wang Z, Bassig BA, Kim JH, Albanes D, Wong JY, Shin MH, Chung LP, Yang Y, An SJ, Zheng H, Yatabe Y, Zhang XC, Kim YC, Caporaso NE, Chang J, Man Ho JC, Kubo M, Daigo Y, Song M, Momozawa Y, Kamatani Y, Kobayashi M, Okubo K, Honda T, Hosgood HD, Kunitoh H, Watanabe SI, Miyagi Y, Nakayama H, Matsumoto S, Horinouchi H, Tsuboi M, Hamamoto R, Goto K, Ohe Y, Takahashi A, Goto A, Minamiya Y, Hara M, Nishida Y, Takeuchi K, Wakai K, Matsuda K, Murakami Y, Shimizu K, Suzuki H, Saito M, Ohtaki Y, Tanaka K, Wu T, Wei F, Dai H, Machiela MJ, Su J, Kim YH, Oh IJ, Fun Lee VH, Chang GC, Tsai YH, Che KY, Huang MS, Su WC, Chen YM, Seow A, Park JY, Kweon SS, Chen KC, Gao YT, Qian B, Wu C, Lu D, Liu J, Schwartz AG, Houlston R, Spitz MR, Gorlov IP, Wu X, Yang P, Lam S, Tardon A, Chen C, Bojesen SE, Johansson M, Risch A, Bickeböller H, Ji BT, Wichmann HE, Christiani DC, Rennert G, Arnold S, Brennan P, McKay J, Field JK, Davies MPA, Shete SS, Le Marchand L, Liu G, Andrew A, Kiemeney LA, Zienolddiny-Narui S, Grankvist K, Johansson M, Cox A, Taylor F, Yuan JM, Lazarus P, Schabath MB, Aldrich MC, Jeon HS, Jiang SS, Sung JS, Chen CH, Hsiao CF, Jung YJ, Guo H, Hu Z, Burdett L, Yeager M, Hutchinson A, Hicks B, Liu J, Zhu B, Berndt SI, Wu W, Wang J, Li Y, Choi JE, Park KH, Sung SW, Liu L, Kang CH, Wang WC, Xu J, Guan P, Tan W, Yu CJ, Yang G, Loon Sihoe AD, Chen Y, Choi YY, Kim JS, Yoon HI, Park IK, Xu P, He Q, Wang CL, Hung HH, Vermeulen RCH, Cheng I, Wu J, Lim WY, Tsai FY, Chan JKC, Li J, Chen H, Lin HC, Jin L, Liu J, Sawada N, Yamaji T, Wyatt K, Li SA, Ma H, Zhu M, Wang Z, Cheng S, Li X, Ren Y, Chao A, Iwasaki M, Zhu J, Jiang G, Fei K, Wu G, Chen CY, Chen CJ, Yang PC, Yu J, Stevens VL, Fraumeni JF, Chatterjee N, Gorlova OY, Amos CI, Shen H, Hsiung CA, Chanock SJ, Rothman N, Kohno T, Lan Q, Zhang H. Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.06.26.24309127. [PMID: 38978671 PMCID: PMC11230324 DOI: 10.1101/2024.06.26.24309127] [Show More Authors] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Polygenic risk scores (PRSs) are promising for risk stratification but have mainly been developed in European populations. This study developed single- and multi-ancestry PRSs for lung adenocarcinoma (LUAD) in East Asian (EAS) never-smokers using genome-wide association study summary statistics from EAS (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. A multi-ancestry PRS, developed using CT-SLEB, was strongly associated with LUAD risk (odds ratio=1.71, 95% confidence interval (CI):1.61,1.82), with an area under the receiver operating curve value of 0.640 (95% CI:0.629,0.653). Individuals in the highest 20% of the PRS had nearly four times the risk compared to the lowest 20%. Individuals in the 95 th percentile of the PRS had an estimated 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41. Our study underscores the potential of multi-ancestry PRS approaches to enhance LUAD risk stratification in EAS never-smokers.
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Serio VB, Rosati D, Maffeo D, Rina A, Ghisalberti M, Bellan C, Spiga O, Mari F, Palmieri M, Frullanti E. The Personalized Inherited Signature Predisposing to Non-Small-Cell Lung Cancer in Non-Smokers. Cancers (Basel) 2024; 16:2887. [PMID: 39199663 PMCID: PMC11352340 DOI: 10.3390/cancers16162887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 08/14/2024] [Accepted: 08/19/2024] [Indexed: 09/01/2024] Open
Abstract
Lung cancer (LC) continues to be an important public health problem, being the most common form of cancer and a major cause of cancer deaths worldwide. Despite the great bulk of research to identify genetic susceptibility genes by genome-wide association studies, only few loci associated to nicotine dependence have been consistently replicated. Our previously published study in few phenotypically discordant sib-pairs identified a combination of germline truncating mutations in known cancer susceptibility genes in never-smoker early-onset LC patients, which does not present in their healthy sib. These results firstly demonstrated the presence of an oligogenic combination of disrupted cancer-predisposing genes in non-smokers patients, giving experimental support to a model of a "private genetic epidemiology". Here, we used a combination of whole-exome and RNA sequencing coupled with a discordant sib's model in a novel cohort of pairs of never-smokers early-onset LC patients and in their healthy sibs used as controls. We selected rare germline variants predicted as deleterious by CADD and SVM bioinformatics tools and absent in the healthy sib. Overall, we identified an average of 200 variants per patient, about 10 of which in cancer-predisposing genes. In most of them, RNA sequencing data reinforced the pathogenic role of the identified variants showing: (i) downregulation in LC tissue (indicating a "second hit" in tumor suppressor genes); (ii) upregulation in cancer tissue (likely oncogene); and (iii) downregulation in both normal and cancer tissue (indicating transcript instability). The combination of the two techniques demonstrates that each patient has an average of six (with a range from four to eight) private mutations with a functional effect in tumor-predisposing genes. The presence of a unique combination of disrupting events in the affected subjects may explain the absence of the familial clustering of non-small-cell lung cancer. In conclusion, these findings indicate that each patient has his/her own "predisposing signature" to cancer development and suggest the use of personalized therapeutic strategies in lung cancer.
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Affiliation(s)
- Viola Bianca Serio
- Cancer Genomics & Systems Biology Laboratory, University of Siena, 53100 Siena, Italy; (V.B.S.); (D.R.); (D.M.); (M.P.)
- Med Biotech Hub and Competence Centre, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy; (A.R.); (F.M.)
| | - Diletta Rosati
- Cancer Genomics & Systems Biology Laboratory, University of Siena, 53100 Siena, Italy; (V.B.S.); (D.R.); (D.M.); (M.P.)
- Med Biotech Hub and Competence Centre, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy; (A.R.); (F.M.)
| | - Debora Maffeo
- Cancer Genomics & Systems Biology Laboratory, University of Siena, 53100 Siena, Italy; (V.B.S.); (D.R.); (D.M.); (M.P.)
- Med Biotech Hub and Competence Centre, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy; (A.R.); (F.M.)
| | - Angela Rina
- Med Biotech Hub and Competence Centre, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy; (A.R.); (F.M.)
| | - Marco Ghisalberti
- Thoracic Surgery Unit, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy;
| | - Cristiana Bellan
- Department of Medical Biotechnology, Section of Pathology, University of Siena, 53100 Siena, Italy;
| | - Ottavia Spiga
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy;
| | - Francesca Mari
- Med Biotech Hub and Competence Centre, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy; (A.R.); (F.M.)
- UOC Laboratorio di Assistenza e Ricerca Traslazionale, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy
| | - Maria Palmieri
- Cancer Genomics & Systems Biology Laboratory, University of Siena, 53100 Siena, Italy; (V.B.S.); (D.R.); (D.M.); (M.P.)
- Med Biotech Hub and Competence Centre, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy; (A.R.); (F.M.)
| | - Elisa Frullanti
- Cancer Genomics & Systems Biology Laboratory, University of Siena, 53100 Siena, Italy; (V.B.S.); (D.R.); (D.M.); (M.P.)
- Med Biotech Hub and Competence Centre, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy; (A.R.); (F.M.)
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Xie Y, Huang C, Zhou X, Wu H, Li A, Zhang X. CD147 TagSNP is associated with the vulnerability to lung cancer in the Chinese population: a case-control study. Discov Oncol 2024; 15:281. [PMID: 39007938 PMCID: PMC11250716 DOI: 10.1007/s12672-024-01155-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Accepted: 07/11/2024] [Indexed: 07/16/2024] Open
Abstract
BACKGROUND Lung cancer, with its high morbidity and mortality, presents a major significant public health challenge. CD147, linked to cancer progression and metastasis, is a promising therapeutic target, including for lung cancer. The genetic variation may influence the expression of the gene and consequently the risk of lung cancer. This study aims to investigate single nucleotide polymorphisms (SNPs) in CD147 to understand their association with the risk of developing lung cancer in the Han Chinese population. METHODS A hospital-based case-control investigation was conducted, enrolling 700 lung cancer patients and 700 cancer-free controls. TagSNPs were selected using Haploview v4.2, and genotype data from the 1000 Genomes Project database were utilized. The selected SNPs (rs28992491, rs67945626, and rs79361899) within the CD147 gene were evaluated using the improved multiple ligation detection reaction method. Statistical analysis included chi-square tests, logistic regression models, and interaction analyses. RESULTS Baseline characteristics of the study population showed no significant differences in gender distribution between cases and controls, but there was a notable difference in smoking rates. No significant associations were found between the three TagSNPs and lung cancer susceptibility in the codominant model. However, stratification analyses revealed interesting findings. Among females, the rs79361899 AA/AG genotype was associated with an increased risk of lung cancer. In individuals aged ≥ 65 years old, the rs28992491 GG and rs79361899 AA genotypes were linked to a higher susceptibility. Furthermore, an interaction analysis demonstrated significant genotype × gender interactions in the rs79361899 recessive model, indicating an increased lung cancer risk in female carriers of the heterozygous or homozygous polymorphic genotype. CONCLUSIONS CD147 polymorphisms play an important role in lung cancer development, particularly in specific subgroup of age and gender. These findings highlight the significance of incorporating genetic variations and their interactions with demographic factors in comprehending the intricate etiology of lung cancer.
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Affiliation(s)
- Yuning Xie
- School of Public Health, North China University of Science and Technology, 21 Bohai Road, Caofeidian Xincheng, Tangshan, 063210, Hebei, China
- College of Life Science, North China University of Science and Technology, Tangshan, China
| | - Chu Huang
- Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xianlei Zhou
- School of Public Health, North China University of Science and Technology, 21 Bohai Road, Caofeidian Xincheng, Tangshan, 063210, Hebei, China
| | - Hongjiao Wu
- School of Public Health, North China University of Science and Technology, 21 Bohai Road, Caofeidian Xincheng, Tangshan, 063210, Hebei, China
- College of Life Science, North China University of Science and Technology, Tangshan, China
| | - Ang Li
- School of Public Health, North China University of Science and Technology, 21 Bohai Road, Caofeidian Xincheng, Tangshan, 063210, Hebei, China
| | - Xuemei Zhang
- School of Public Health, North China University of Science and Technology, 21 Bohai Road, Caofeidian Xincheng, Tangshan, 063210, Hebei, China.
- College of Life Science, North China University of Science and Technology, Tangshan, China.
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Tian X, Liu Z. Single nucleotide variants in lung cancer. CHINESE MEDICAL JOURNAL PULMONARY AND CRITICAL CARE MEDICINE 2024; 2:88-94. [PMID: 39169933 PMCID: PMC11332866 DOI: 10.1016/j.pccm.2024.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Indexed: 08/23/2024]
Abstract
Germline genetic variants, including single-nucleotide variants (SNVs) and copy number variants (CNVs), account for interpatient heterogeneity. In the past several decades, genome-wide association studies (GWAS) have identified multiple lung cancer-associated SNVs in Caucasian and Chinese populations. These variants either reside within coding regions and change the structure and function of cancer-related proteins or reside within non-coding regions and alter the expression level of cancer-related proteins. The variants can be used not only for cancer risk assessment and prevention but also for the development of new therapies. In this review, we discuss the lung cancer-associated SNVs identified to date, their contributions to lung tumorigenesis and prognosis, and their potential use in predicting prognosis and implementing therapeutic strategies.
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Affiliation(s)
- Xiaoling Tian
- Zhejiang Key Laboratory of Medical Epigenetics, Department of Cell Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
| | - Zhe Liu
- Zhejiang Key Laboratory of Medical Epigenetics, Department of Cell Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
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Wen Z, Pei B, Dai L, Lu P, Li X, Zhang C, Ge S. Risk factors analysis and survival prediction model establishment of patients with lung adenocarcinoma based on different pyroptosis-related gene subtypes. Eur J Med Res 2023; 28:601. [PMID: 38111060 PMCID: PMC10726488 DOI: 10.1186/s40001-023-01581-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 12/08/2023] [Indexed: 12/20/2023] Open
Abstract
BACKGROUND Lung adenocarcinoma (LUAD) is a common cancer with a poor prognosis. Pyroptosis is an important process in the development and progression of LUAD. We analyzed the risk factors affecting the prognosis of patients and constructed a nomogram to predict the overall survival of patients based on different pyroptosis-related genes (PRGs) subtypes. METHODS The genomic data of LUAD were downloaded from the TCGA and GEO databases, and all data were filtered and divided into TCGA and GEO cohorts. The process of data analysis and visualization was performed via R software. The data were classified based on different PRGs subtypes using the K-means clustering method. Then, the differentially expressed genes were identified between two different subtypes, and risk factors analysis, survival analysis, functional enrichment analysis, and immune cells infiltration landscape analysis were conducted. The COX regression analysis was used to construct the prediction model. RESULTS Based on the PRGs of LUAD, the patients were divided into two subtypes. We found the survival probability of patients in subtype 1 is higher than that in subtype 2. The results of the logistics analysis showed that gene risk score was closely associated with the prognosis of LUAD patients. The results of GO analysis and KEGG analysis revealed important biological processes and signaling pathways involved in the differentially expressed proteins between the two subtypes. Then we constructed a prediction model of patients' prognosis based on 13 genes, including IL-1A, P2RX1, GSTM2, ESYT3, ZNF682, KCNF1, STK32A, HHIPL2, GDF10, NDC80, GSTA1, BCL2L10, and CCR2. This model was strongly related to the overall survival (OS) and also reflects the immune status in patients with LUAD. CONCLUSION In our study, we examined LUAD heterogeneity with reference to pyroptosis and found different prognoses between the two subtypes. And a novel prediction model was constructed to predict the OS of LUAD patients based on different PRGs signatures. The model has shown excellent predictive efficiency through validation.
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Affiliation(s)
- Ziang Wen
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Bei Pei
- The Graduated School, Anhui University of Traditonal Chinese Medicine, Hefei, China
| | - Longfei Dai
- The Graduated School, Anhui Medical University, Hefei, China
| | - Peng Lu
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiangyu Li
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chengxin Zhang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shenglin Ge
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
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Huang Y, Bao T, Zhang T, Ji G, Wang Y, Ling Z, Li W. Machine Learning Study of SNPs in Noncoding Regions to Predict Non-small Cell Lung Cancer Susceptibility. Clin Oncol (R Coll Radiol) 2023; 35:701-712. [PMID: 37689528 DOI: 10.1016/j.clon.2023.08.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 07/23/2023] [Accepted: 08/30/2023] [Indexed: 09/11/2023]
Abstract
Non-small cell lung cancer (NSCLC) is the most common pathological subtype of lung cancer. Both environmental and genetic factors have been reported to impact the lung cancer susceptibility. We conducted a genome-wide association study (GWAS) of 287 NSCLC patients and 467 healthy controls in a Chinese population using the Illumina Genome-Wide Asian Screening Array Chip on 712,095 SNPs (single nucleotide polymorphisms). Using logistic regression modeling, GWAS identified 17 new noncoding region SNP loci associated with the NSCLC risk, and the top three (rs80040741, rs9568547, rs6010259) were under a stringent p-value (<3.02e-6). Notably, rs80040741 and rs6010259 were annotated from the intron regions of MUC3A and MLC1, respectively. Together with another five SNPs previously reported in Chinese NSCLC patients and another four covariates (e.g., smoking status, age, low dose CT screening, sex), a predictive model by machine learning methods can separate the NSCLC from healthy controls with an accuracy of 86%. This is the first time to apply machine learning method in predicting the NSCLC susceptibility using both genetic and clinical characteristics. Our findings will provide a promising method in NSCLC early diagnosis and improve our understanding of applying machine learning methods in precision medicine.
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Affiliation(s)
- Y Huang
- Health Management Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Institute of Respiratory Healthy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - T Bao
- Health Management Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Institute of Respiratory Healthy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - T Zhang
- Health Management Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Institute of Respiratory Healthy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - G Ji
- Health Management Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Institute of Respiratory Healthy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Y Wang
- Health Management Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Institute of Respiratory Healthy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Z Ling
- Chengdu Genepre Technology Co., LTD, Chengdu, Sichuan, China
| | - W Li
- Institute of Respiratory Healthy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Department of Respiratory and Critical Care Medicine, Institute of Respiratory Healthy, Precision Medicine Key Laboratory of Sichuan Province, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; The Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, Sichuan 610041, China; State Key Laboratory of Respiratory Health and Multimorbidity, Chengdu, Sichuan 610041, West China Hospital, China.
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8
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Gurav M, Epari S, Gogte P, Pai T, Deshpande G, Karnik N, Shetty O, Desai S. Targeted molecular profiling of solid tumours-Indian tertiary cancer centre experience. J Cancer Res Clin Oncol 2023; 149:7413-7425. [PMID: 36935431 DOI: 10.1007/s00432-023-04693-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 03/12/2023] [Indexed: 03/21/2023]
Abstract
PURPOSE Molecular Profiling of solid tumours is extensively used for prognostic, theranostic, and risk prediction. Next generation sequencing (NGS) has emerged as powerful method for molecular profiling. The present study was performed to identify molecular alterations present in solid tumours in Indian tertiary cancer centre. METHODS Study included 1140 formalin Fixed paraffin embedded samples. NGS was performed using two targeted gene panels viz. Ampliseq Focus panel and Sophia Solid Tumor Plus Solution. Data was analyzed using Illumina's Local Run Manager and SOPHiA DDM software. Variant interpretation and annotations were done as per AMP/ACMG guidelines. RESULTS Total 896 cases were subjected to NGS after excluding cases with suboptimal nucleic acid quality/quantity. DNA alterations were detected in 64.9% and RNA fusions in 6.9% cases. Among detected variants, 86.7% were clinically relevant aberrations. Mutation frequency among different solid tumours was 70.8%, 67.4%, 64.4% in non-small cell lung (NSCLC), lung squamous cell carcinomas and head neck tumours respectively. EGFR, KRAS, BRAF, ALK and ROS1were commonly altered in NSCLC. Gastrointestinal tumours showed mutations in 63.6% with predominant alterations in pancreatic (88.2%), GIST (87.5%), colorectal (78.7%), cholangiocarcinoma (52.9%), neuroendocrine (45.5%), gall bladder (36.7%) and gastric adenocarcinomas (16.7%). The key genes affected were KRAS, NRAS, BRAF and PIK3CA. NGS evaluation identified co-occurring alterations in 37.7% cases otherwise missed by conventional assays. Resistance mutations were detected in progressive lung tumours (39.5%) against EGFR TKIs and ALK/ROS inhibitors. CONCLUSION This is the largest Indian study on molecular profiling of solid tumours providing extensive information about mutational signatures using NGS.
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Affiliation(s)
- Mamta Gurav
- Molecular Pathology laboratory, Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Sridhar Epari
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Prachi Gogte
- Molecular Pathology laboratory, Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Trupti Pai
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Gauri Deshpande
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Nupur Karnik
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Omshree Shetty
- Molecular Pathology laboratory, Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India.
| | - Sangeeta Desai
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
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9
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Lei X, Tian X, Wang H, Xu X, Li G, Liu W, Wang D, Xiao Z, Zhang M, Li MJ, Zhang Z, Ma Z, Liu Z. Noncoding SNP at rs1663689 represses ADGRG6 via interchromosomal interaction and reduces lung cancer progression. EMBO Rep 2023; 24:e56212. [PMID: 37154297 PMCID: PMC10328068 DOI: 10.15252/embr.202256212] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 04/05/2023] [Accepted: 04/18/2023] [Indexed: 05/10/2023] Open
Abstract
A previous genome-wide association study (GWAS) revealed an association of the noncoding SNP rs1663689 with susceptibility to lung cancer in the Chinese population. However, the underlying mechanism is unknown. In this study, using allele-specific 4C-seq in heterozygous lung cancer cells combined with epigenetic information from CRISPR/Cas9-edited cell lines, we show that the rs1663689 C/C variant represses the expression of ADGRG6, a gene located on a separate chromosome, through an interchromosomal interaction of the rs1663689 bearing region with the ADGRG6 promoter. This reduces downstream cAMP-PKA signaling and subsequently tumor growth both in vitro and in xenograft models. Using patient-derived organoids, we show that rs1663689 T/T-but not C/C-bearing lung tumors are sensitive to the PKA inhibitor H89, potentially informing therapeutic strategies. Our study identifies a genetic variant-mediated interchromosomal interaction underlying ADGRG6 regulation and suggests that targeting the cAMP-PKA signaling pathway may be beneficial in lung cancer patients bearing the homozygous risk genotype at rs1663689.
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Affiliation(s)
- Xinyue Lei
- Department of Lung Cancer CenterTianjin Medical University Cancer Institute and HospitalHaihe Laboratory of Cell EcosystemState Key Laboratory of Experimental HematologyDepartment of UrologyThe Second Hospital of Tianjin Medical UniversityKey Laboratory of Immune Microenvironment and Disease of the Ministry of EducationDepartment of ImmunologySchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Xiaoling Tian
- Department of Lung Cancer CenterTianjin Medical University Cancer Institute and HospitalHaihe Laboratory of Cell EcosystemState Key Laboratory of Experimental HematologyDepartment of UrologyThe Second Hospital of Tianjin Medical UniversityKey Laboratory of Immune Microenvironment and Disease of the Ministry of EducationDepartment of ImmunologySchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Hao Wang
- Department of Lung Cancer CenterTianjin Medical University Cancer Institute and HospitalHaihe Laboratory of Cell EcosystemState Key Laboratory of Experimental HematologyDepartment of UrologyThe Second Hospital of Tianjin Medical UniversityKey Laboratory of Immune Microenvironment and Disease of the Ministry of EducationDepartment of ImmunologySchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Xinran Xu
- Department of Pharmacology, School of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Guoli Li
- Department of Lung Cancer CenterTianjin Medical University Cancer Institute and HospitalHaihe Laboratory of Cell EcosystemState Key Laboratory of Experimental HematologyDepartment of UrologyThe Second Hospital of Tianjin Medical UniversityKey Laboratory of Immune Microenvironment and Disease of the Ministry of EducationDepartment of ImmunologySchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Wenxu Liu
- Department of Lung Cancer CenterTianjin Medical University Cancer Institute and HospitalHaihe Laboratory of Cell EcosystemState Key Laboratory of Experimental HematologyDepartment of UrologyThe Second Hospital of Tianjin Medical UniversityKey Laboratory of Immune Microenvironment and Disease of the Ministry of EducationDepartment of ImmunologySchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Dan Wang
- Department of Lung Cancer CenterTianjin Medical University Cancer Institute and HospitalHaihe Laboratory of Cell EcosystemState Key Laboratory of Experimental HematologyDepartment of UrologyThe Second Hospital of Tianjin Medical UniversityKey Laboratory of Immune Microenvironment and Disease of the Ministry of EducationDepartment of ImmunologySchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Zengtuan Xiao
- Department of Lung Cancer CenterTianjin Medical University Cancer Institute and HospitalHaihe Laboratory of Cell EcosystemState Key Laboratory of Experimental HematologyDepartment of UrologyThe Second Hospital of Tianjin Medical UniversityKey Laboratory of Immune Microenvironment and Disease of the Ministry of EducationDepartment of ImmunologySchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Mengzhe Zhang
- Department of Lung Cancer CenterTianjin Medical University Cancer Institute and HospitalHaihe Laboratory of Cell EcosystemState Key Laboratory of Experimental HematologyDepartment of UrologyThe Second Hospital of Tianjin Medical UniversityKey Laboratory of Immune Microenvironment and Disease of the Ministry of EducationDepartment of ImmunologySchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Mulin Jun Li
- Department of Pharmacology, School of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Zhenfa Zhang
- Department of Lung Cancer CenterTianjin Medical University Cancer Institute and HospitalHaihe Laboratory of Cell EcosystemState Key Laboratory of Experimental HematologyDepartment of UrologyThe Second Hospital of Tianjin Medical UniversityKey Laboratory of Immune Microenvironment and Disease of the Ministry of EducationDepartment of ImmunologySchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina
| | - Zhenyi Ma
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Department of Cell Biology, School of Basic Medical SciencesHangzhou Normal UniversityHangzhouChina
| | - Zhe Liu
- Department of Lung Cancer CenterTianjin Medical University Cancer Institute and HospitalHaihe Laboratory of Cell EcosystemState Key Laboratory of Experimental HematologyDepartment of UrologyThe Second Hospital of Tianjin Medical UniversityKey Laboratory of Immune Microenvironment and Disease of the Ministry of EducationDepartment of ImmunologySchool of Basic Medical SciencesTianjin Medical UniversityTianjinChina
- Department of Pharmacology, School of Basic Medical SciencesTianjin Medical UniversityTianjinChina
- Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Department of Cell Biology, School of Basic Medical SciencesHangzhou Normal UniversityHangzhouChina
- Collaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingChina
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10
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Zhang J, Lyu Z, Li B, You Z, Cui N, Li Y, Li Y, Huang B, Chen R, Chen Y, Peng Y, Fang J, Wang Q, Miao Q, Tang R, Gershwin ME, Lian M, Xiao X, Ma X. P4HA2 induces hepatic ductular reaction and biliary fibrosis in chronic cholestatic liver diseases. Hepatology 2023; 78:10-25. [PMID: 36799463 DOI: 10.1097/hep.0000000000000317] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 01/06/2023] [Indexed: 02/18/2023]
Abstract
BACKGROUNDS Prolyl-4-hydroxylases (P4Hs) are key enzymes in collagen synthesis. The P4HA subunit (P4HA1, P4HA2, and P4HA3) contains a substrate binding and catalyzation domain. We postulated that P4HA2 would play a key role in the cholangiocyte pathology of cholestatic liver diseases. METHODS We studied humans with primary biliary cholangitis (PBC) and Primary sclerosing cholangitis (PSC), P4HA2 -/- mice injured by DDC, and P4HA2 -/- /MDR2 -/- double knockout mice. A parallel study was performed in patients with PBC, PSC, and controls using immunohistochemistry and immunofluorescence. In the murine model, the level of ductular reaction and biliary fibrosis were monitored by histology, qPCR, immunohistochemistry, and Western blotting. Expression of Yes1 Associated Transcriptional Regulator (YAP) phosphorylation was measured in isolated mouse cholangiocytes. The mechanism of P4HA2 was explored in RBE and 293T cell lines by using qPCR, Western blot, immunofluorescence, and co-immunoprecipitation. RESULTS The hepatic expression level of P4HA2 was highly elevated in patients with PBC or PSC. Ductular reactive cholangiocytes predominantly expressed P4HA2. Cholestatic patients with more severe liver injury correlated with levels of P4HA2 in the liver. In P4HA2 -/- mice, there was a significantly reduced level of ductular reaction and fibrosis compared with controls in the DDC-induced chronic cholestasis. Decreased liver fibrosis and ductular reaction were observed in P4HA2 -/- /MDR2 -/- mice compared with MDR2 -/- mice. Cholangiocytes isolated from P4HA2 -/- /MDR2 -/- mice displayed a higher level of YAP phosphorylation, resulting in cholangiocytes proliferation inhibition. In vitro studies showed that P4HA2 promotes RBE cell proliferation by inducing SAV1 degradation, eventually resulting in the activation of YAP. CONCLUSIONS P4HA2 promotes hepatic ductular reaction and biliary fibrosis by regulating the SAV1-mediated Hippo signaling pathway. P4HA2 is a potential therapeutic target for PBC and PSC.
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Affiliation(s)
- Jun Zhang
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Zhuwan Lyu
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Bo Li
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Zhengrui You
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Nana Cui
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - You Li
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Yikang Li
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Bingyuan Huang
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Ruiling Chen
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Yong Chen
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Yanshen Peng
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Jingyuan Fang
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Qi Miao
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, California, USA
| | - Min Lian
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, Middle Shandong Road, Shanghai 200001, China
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11
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Yang X, Zhang B. A review on CRISPR/Cas: a versatile tool for cancer screening, diagnosis, and clinic treatment. Funct Integr Genomics 2023; 23:182. [PMID: 37231285 DOI: 10.1007/s10142-023-01117-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/17/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023]
Abstract
Cancer is one of the leading causes of death worldwide and it has the trend of increase incidence. However, in the past decades, as quickly developed new technologies and modified old techniques for cancer screening, diagnosis, and treatment, the cancer-caused mortality rates dropped quickly, and the survival times of cancer patients are enhanced. However, the current death rate is still about 50% and the survival patients always suffer from the side effect of current cancer treatments. Recently developed Nobel Prize-winning CRISPR/Cas technology provides new hope on cancer screening, early diagnosis, and clinic treatment as well as new drug development. Currently, four major CRISPR/Cas9-derived genome editors, CRISPR/Cas9 nucleotide sequence editor, CRISPR/Cas base editor (BE), CRISPR prime editor (PE), and CRISPR interference (CRISPRi) (including both CRISPRa and CRISPRr), were well developed and used to various research and applications, including cancer biology study and cancer screening, diagnosis, and treatment. Additionally, CRISPR/Cas12 and CRISPR/Cas13 genome editors were also widely used in cancer-related basic and applied research as well as treatment. Cancer-associated SNPs and genetic mutations as well as both oncogenes and tumor suppressor genes are perfect targets for CRISPR/Cas-based gene therapy for cancer treatment. CRISPR/Cas is also employed to modify and generate new Chimeric antigen receptor (CAR) T-cells for improving its safety, efficiency, and longer-time last for treating various cancers. Currently, there are many clinic trails of CRISPR-based gene therapy for cancer treatments. Although all CRISPR/Cas-derived genome and epigenome tools are promising methods for cancer biology study and treatment, the efficiency and long term-safety are still the major concerns for CRISPR-based gene therapy. Developing new CRISPR/Cas delivery methods and reducing the potential side effects, including off-target impacts, will enhance CRISPR/Cas application in cancer-related research, diagnosis, and therapeutical treatment.
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Affiliation(s)
- Xianguang Yang
- College of Life Science, Henan Normal University, Xinxiang, 453007, Henan, China.
| | - Baohong Zhang
- Department of Biology, East Carolina University, Greenville, NC, 27858, USA.
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12
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Shi J, Shiraishi K, Choi J, Matsuo K, Chen TY, Dai J, Hung RJ, Chen K, Shu XO, Kim YT, Landi MT, Lin D, Zheng W, Yin Z, Zhou B, Song B, Wang J, Seow WJ, Song L, Chang IS, Hu W, Chien LH, Cai Q, Hong YC, Kim HN, Wu YL, Wong MP, Richardson BD, Funderburk KM, Li S, Zhang T, Breeze C, Wang Z, Blechter B, Bassig BA, Kim JH, Albanes D, Wong JYY, Shin MH, Chung LP, Yang Y, An SJ, Zheng H, Yatabe Y, Zhang XC, Kim YC, Caporaso NE, Chang J, Ho JCM, Kubo M, Daigo Y, Song M, Momozawa Y, Kamatani Y, Kobayashi M, Okubo K, Honda T, Hosgood DH, Kunitoh H, Patel H, Watanabe SI, Miyagi Y, Nakayama H, Matsumoto S, Horinouchi H, Tsuboi M, Hamamoto R, Goto K, Ohe Y, Takahashi A, Goto A, Minamiya Y, Hara M, Nishida Y, Takeuchi K, Wakai K, Matsuda K, Murakami Y, Shimizu K, Suzuki H, Saito M, Ohtaki Y, Tanaka K, Wu T, Wei F, Dai H, Machiela MJ, Su J, Kim YH, Oh IJ, Lee VHF, Chang GC, Tsai YH, Chen KY, Huang MS, Su WC, Chen YM, Seow A, Park JY, Kweon SS, et alShi J, Shiraishi K, Choi J, Matsuo K, Chen TY, Dai J, Hung RJ, Chen K, Shu XO, Kim YT, Landi MT, Lin D, Zheng W, Yin Z, Zhou B, Song B, Wang J, Seow WJ, Song L, Chang IS, Hu W, Chien LH, Cai Q, Hong YC, Kim HN, Wu YL, Wong MP, Richardson BD, Funderburk KM, Li S, Zhang T, Breeze C, Wang Z, Blechter B, Bassig BA, Kim JH, Albanes D, Wong JYY, Shin MH, Chung LP, Yang Y, An SJ, Zheng H, Yatabe Y, Zhang XC, Kim YC, Caporaso NE, Chang J, Ho JCM, Kubo M, Daigo Y, Song M, Momozawa Y, Kamatani Y, Kobayashi M, Okubo K, Honda T, Hosgood DH, Kunitoh H, Patel H, Watanabe SI, Miyagi Y, Nakayama H, Matsumoto S, Horinouchi H, Tsuboi M, Hamamoto R, Goto K, Ohe Y, Takahashi A, Goto A, Minamiya Y, Hara M, Nishida Y, Takeuchi K, Wakai K, Matsuda K, Murakami Y, Shimizu K, Suzuki H, Saito M, Ohtaki Y, Tanaka K, Wu T, Wei F, Dai H, Machiela MJ, Su J, Kim YH, Oh IJ, Lee VHF, Chang GC, Tsai YH, Chen KY, Huang MS, Su WC, Chen YM, Seow A, Park JY, Kweon SS, Chen KC, Gao YT, Qian B, Wu C, Lu D, Liu J, Schwartz AG, Houlston R, Spitz MR, Gorlov IP, Wu X, Yang P, Lam S, Tardon A, Chen C, Bojesen SE, Johansson M, Risch A, Bickeböller H, Ji BT, Wichmann HE, Christiani DC, Rennert G, Arnold S, Brennan P, McKay J, Field JK, Shete SS, Le Marchand L, Liu G, Andrew A, Kiemeney LA, Zienolddiny-Narui S, Grankvist K, Johansson M, Cox A, Taylor F, Yuan JM, Lazarus P, Schabath MB, Aldrich MC, Jeon HS, Jiang SS, Sung JS, Chen CH, Hsiao CF, Jung YJ, Guo H, Hu Z, Burdett L, Yeager M, Hutchinson A, Hicks B, Liu J, Zhu B, Berndt SI, Wu W, Wang J, Li Y, Choi JE, Park KH, Sung SW, Liu L, Kang CH, Wang WC, Xu J, Guan P, Tan W, Yu CJ, Yang G, Sihoe ADL, Chen Y, Choi YY, Kim JS, Yoon HI, Park IK, Xu P, He Q, Wang CL, Hung HH, Vermeulen RCH, Cheng I, Wu J, Lim WY, Tsai FY, Chan JKC, Li J, Chen H, Lin HC, Jin L, Liu J, Sawada N, Yamaji T, Wyatt K, Li SA, Ma H, Zhu M, Wang Z, Cheng S, Li X, Ren Y, Chao A, Iwasaki M, Zhu J, Jiang G, Fei K, Wu G, Chen CY, Chen CJ, Yang PC, Yu J, Stevens VL, Fraumeni JF, Chatterjee N, Gorlova OY, Hsiung CA, Amos CI, Shen H, Chanock SJ, Rothman N, Kohno T, Lan Q. Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population. Nat Commun 2023; 14:3043. [PMID: 37236969 PMCID: PMC10220065 DOI: 10.1038/s41467-023-38196-z] [Show More Authors] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 04/19/2023] [Indexed: 05/28/2023] Open
Abstract
Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.
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Affiliation(s)
- Jianxin Shi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
| | - Kouya Shiraishi
- Division of Genome Biology, National Cancer Research Institute, Tokyo, Japan
| | - Jiyeon Choi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Tzu-Yu Chen
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
| | - Juncheng Dai
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Rayjean J Hung
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada
| | - Kexin Chen
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Young Tae Kim
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Maria Teresa Landi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Dongxin Lin
- Department of Etiology & Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Zhihua Yin
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China
| | - Baosen Zhou
- Department of Clinical Epidemiology and Center of Evidence Based Medicine, The First Hospital of China Medical University, Shenyang, China
| | - Bao Song
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, China
| | - Jiucun Wang
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Wei Jie Seow
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore
| | - Lei Song
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - I-Shou Chang
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan
| | - Wei Hu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Li-Hsin Chien
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
| | - Qiuyin Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Yun-Chul Hong
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hee Nam Kim
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Yi-Long Wu
- Guangdong Lung Cancer Institute, Medical Research Center and Cancer Center of Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Maria Pik Wong
- Department of Pathology, Queen Mary Hospital, Hong Kong, Hong Kong
| | - Brian Douglas Richardson
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
| | - Karen M Funderburk
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Shilan Li
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Department of Biostatistics, Bioinformatics & Biomathematics, Georgetown University Medical Center, Washington, DC, USA
| | - Tongwu Zhang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Charles Breeze
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Zhaoming Wang
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Batel Blechter
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Bryan A Bassig
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Jin Hee Kim
- Department of Environmental Health, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Jason Y Y Wong
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Min-Ho Shin
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Lap Ping Chung
- Department of Pathology, Queen Mary Hospital, Hong Kong, Hong Kong
| | - Yang Yang
- Shanghai Pulmonary Hospital, Shanghai, China
| | - She-Juan An
- Guangdong Lung Cancer Institute, Medical Research Center and Cancer Center of Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Hong Zheng
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Yasushi Yatabe
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Xu-Chao Zhang
- Guangdong Lung Cancer Institute, Medical Research Center and Cancer Center of Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Young-Chul Kim
- Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, Hwasuneup, Republic of Korea
- Department of Internal Medicine, Chonnam National Univerisity Medical School, Gwangju, Republic of Korea
| | - Neil E Caporaso
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Jiang Chang
- Department of Etiology & Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - James Chung Man Ho
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
| | - Michiaki Kubo
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Yataro Daigo
- Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Medical Oncology and Cancer Center, and Center for Advanced Medicine against Cancer, Shiga University of Medical Science, Shiga, Japan
| | - Minsun Song
- Department of Statistics & Research Institute of Natural Sciences, Sookmyung Women's University, Seoul, Republic of Korea
| | - Yukihide Momozawa
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Yoichiro Kamatani
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Masashi Kobayashi
- Department of Thoracic Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kenichi Okubo
- Department of Thoracic Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takayuki Honda
- Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Dean H Hosgood
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA
| | - Hideo Kunitoh
- Department of Medical Oncology, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Harsh Patel
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Shun-Ichi Watanabe
- Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Yohei Miyagi
- Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Haruhiko Nakayama
- Department of Thoracic Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Shingo Matsumoto
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hidehito Horinouchi
- Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Masahiro Tsuboi
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Ryuji Hamamoto
- Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan
| | - Koichi Goto
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yuichiro Ohe
- Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Atsushi Takahashi
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Akiteru Goto
- Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Yoshihiro Minamiya
- Department of Thoracic Surgery, Graduate School of Medicine, Akita University, Akita, Japan
| | - Megumi Hara
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Yuichiro Nishida
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Kenji Takeuchi
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Koichi Matsuda
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Yoshinori Murakami
- Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kimihiro Shimizu
- Department of Surgery, Division of General Thoracic Surgery, Shinshu University School of Medicine Asahi, Nagano, Japan
| | - Hiroyuki Suzuki
- Department of Chest Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Motonobu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yoichi Ohtaki
- Department of Integrative center of General Surgery, Gunma University Hospital, Gunma, Japan
| | - Kazumi Tanaka
- Department of Integrative center of General Surgery, Gunma University Hospital, Gunma, Japan
| | - Tangchun Wu
- Institute of Occupational Medicine and Ministry of Education Key Lab for Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, China
| | - Fusheng Wei
- China National Environmental Monitoring Center, Beijing, China
| | - Hongji Dai
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Mitchell J Machiela
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Jian Su
- Guangdong Lung Cancer Institute, Medical Research Center and Cancer Center of Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yeul Hong Kim
- Department of Internal Medicine, Division of Oncology/Hematology, College of Medicine, Korea University Anam Hospital, Seoul, Republic of Korea
| | - In-Jae Oh
- Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, Hwasuneup, Republic of Korea
- Department of Internal Medicine, Chonnam National Univerisity Medical School, Gwangju, Republic of Korea
| | - Victor Ho Fun Lee
- Department of Clinical Oncology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
| | - Gee-Chen Chang
- School of Medicine and Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Internal Medicine, Division of Pulmonary Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
- Department of Internal Medicine, Division of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ying-Huang Tsai
- Department of Respiratory Therapy, Chang Gung University, Taoyuan, Taiwan
- Department of Pulmonary and Critical Care, Xiamen Chang Gung Hospital, Xiamen, China
| | - Kuan-Yu Chen
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Ming-Shyan Huang
- Department of Internal Medicine, E-Da Cancer Hospital, I-Shou University and Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wu-Chou Su
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yuh-Min Chen
- Department of Chest Medicine, Taipei Veterans General Hospital, and school of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Adeline Seow
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
| | - Jae Yong Park
- Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea
- Jeonnam Regional Cancer Center, Chonnam National University, Hwasun, Republic of Korea
| | - Kun-Chieh Chen
- Department of Internal Medicine, Division of Pulmonary Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yu-Tang Gao
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
| | - Biyun Qian
- Department of Epidemiology and Biostatistics, National Clinical Research Center for Cancer, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Chen Wu
- Department of Etiology & Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Daru Lu
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Jianjun Liu
- Genome Institute of Singapore, Agency of Science, Technology and Research, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | | | - Richard Houlston
- Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK
| | - Margaret R Spitz
- Department of Medicine, Section of Epidemiology and Population Science, Institute for Clinical and Translational Research, Houston, TX, USA
| | - Ivan P Gorlov
- Department of Medicine, Section of Epidemiology and Population Science, Institute for Clinical and Translational Research, Houston, TX, USA
| | - Xifeng Wu
- School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ping Yang
- Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA
| | - Stephen Lam
- British Columbia Cancer Agency, Vancouver, BC, Canada
| | | | - Chu Chen
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Stig E Bojesen
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
| | - Mattias Johansson
- International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - Angela Risch
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
- University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria
| | | | - Bu-Tian Ji
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - H-Erich Wichmann
- Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich, Germany
- Helmholtz Center Munich, Institute of Epidemiology, Munich, Germany
- Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich, Germany
| | | | | | | | - Paul Brennan
- International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | - James McKay
- International Agency for Research on Cancer (IARC/WHO), Lyon, France
| | | | - Sanjay S Shete
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Loic Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Geoffrey Liu
- Princess Margaret Cancer Center, Toronto, ON, Canada
| | | | | | | | - Kjell Grankvist
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | | | | | | | - Jian-Min Yuan
- UPMC Hillman Cancer Center and Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Philip Lazarus
- Washington State University College of Pharmacy, Spokane, WA, USA
| | - Matthew B Schabath
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Melinda C Aldrich
- Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Hyo-Sung Jeon
- Cancer Research Center, Kyungpook National University Medical Center, Daegu, Republic of Korea
| | - Shih Sheng Jiang
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan
| | - Jae Sook Sung
- Department of Internal Medicine, Division of Oncology/Hematology, College of Medicine, Korea University Anam Hospital, Seoul, Republic of Korea
| | - Chung-Hsing Chen
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan
| | - Chin-Fu Hsiao
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
| | - Yoo Jin Jung
- Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Huan Guo
- Department of Occupational and Environmental Health and Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhibin Hu
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Laurie Burdett
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc., Rockville, MD, USA
| | - Meredith Yeager
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc., Rockville, MD, USA
| | - Amy Hutchinson
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc., Rockville, MD, USA
| | - Belynda Hicks
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc., Rockville, MD, USA
| | - Jia Liu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc., Rockville, MD, USA
| | - Bin Zhu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc., Rockville, MD, USA
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Wei Wu
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China
| | - Junwen Wang
- Department of Biochemistry, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Centre for Genomic Sciences, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yuqing Li
- Department of Human Genetics, Genome Institute of Singapore, Singapore, Singapore
| | - Jin Eun Choi
- Cancer Research Center, Kyungpook National University Medical Center, Daegu, Republic of Korea
| | - Kyong Hwa Park
- Department of Internal Medicine, Division of Oncology/Hematology, College of Medicine, Korea University Anam Hospital, Seoul, Republic of Korea
| | - Sook Whan Sung
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Li Liu
- Department of Oncology, Cancer Center, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Chang Hyun Kang
- Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Wen-Chang Wang
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Jun Xu
- School of Public Health, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Peng Guan
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China
- Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, China
| | - Wen Tan
- Department of Etiology & Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chong-Jen Yu
- Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan
| | - Gong Yang
- Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | | | - Ying Chen
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
| | - Yi Young Choi
- Cancer Research Center, Kyungpook National University Medical Center, Daegu, Republic of Korea
| | - Jun Suk Kim
- Department of Internal Medicine, Division of Medical Oncology, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Ho-Il Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - In Kyu Park
- Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ping Xu
- Department of Oncology, Wuhan Iron and Steel (Group) Corporation Staff-Worker Hospital, Wuhan, China
| | - Qincheng He
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China
| | - Chih-Liang Wang
- Department of Pulmonary and Critical Care, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Hsiao-Han Hung
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan
| | - Roel C H Vermeulen
- Division of Environmental Epidemiology, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlands
| | - Iona Cheng
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Junjie Wu
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Wei-Yen Lim
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
| | - Fang-Yu Tsai
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan
| | - John K C Chan
- Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China
| | - Jihua Li
- Qujing Center for Diseases Control and Prevention, Qujing, China
| | - Hongyan Chen
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Hsien-Chih Lin
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
| | - Li Jin
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Jie Liu
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, China
| | - Norie Sawada
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan
| | - Taiki Yamaji
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan
| | - Kathleen Wyatt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc., Rockville, MD, USA
| | - Shengchao A Li
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Cancer Genomics Research Laboratory, Leidos Biomedical Research Inc., Rockville, MD, USA
| | - Hongxia Ma
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Meng Zhu
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Zhehai Wang
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, China
| | - Sensen Cheng
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, China
| | - Xuelian Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China
- Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, China
| | - Yangwu Ren
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China
- Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, China
| | - Ann Chao
- Center for Global Health, National Cancer Institute, Bethesda, MD, USA
| | - Motoki Iwasaki
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan
| | - Junjie Zhu
- Shanghai Pulmonary Hospital, Shanghai, China
| | | | - Ke Fei
- Shanghai Pulmonary Hospital, Shanghai, China
| | - Guoping Wu
- China National Environmental Monitoring Center, Beijing, China
| | - Chih-Yi Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Division of Thoracic Surgery, Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chien-Jen Chen
- Genomic Research Center, Academia Sinica, Taipei, Taiwan
| | - Pan-Chyr Yang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jinming Yu
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, China
| | | | - Joseph F Fraumeni
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Nilanjan Chatterjee
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
- Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Olga Y Gorlova
- Department of Medicine, Section of Epidemiology and Population Science, Institute for Clinical and Translational Research, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Chao Agnes Hsiung
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
| | - Christopher I Amos
- Department of Medicine, Section of Epidemiology and Population Science, Institute for Clinical and Translational Research, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Hongbing Shen
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Nathaniel Rothman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Takashi Kohno
- Division of Genome Biology, National Cancer Research Institute, Tokyo, Japan
| | - Qing Lan
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
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Li L, Shu XS, Geng H, Ying J, Guo L, Luo J, Xiang T, Wu L, Ma BBY, Chan ATC, Zhu X, Ambinder RF, Tao Q. A novel tumor suppressor encoded by a 1p36.3 lncRNA functions as a phosphoinositide-binding protein repressing AKT phosphorylation/activation and promoting autophagy. Cell Death Differ 2023; 30:1166-1183. [PMID: 36813924 PMCID: PMC10154315 DOI: 10.1038/s41418-023-01129-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 01/30/2023] [Accepted: 02/02/2023] [Indexed: 02/24/2023] Open
Abstract
Peptides/small proteins, encoded by noncanonical open reading frames (ORF) of previously claimed non-coding RNAs, have recently been recognized possessing important biological functions, but largely uncharacterized. 1p36 is an important tumor suppressor gene (TSG) locus frequently deleted in multiple cancers, with critical TSGs like TP73, PRDM16, and CHD5 already validated. Our CpG methylome analysis identified a silenced 1p36.3 gene KIAA0495, previously thought coding long non-coding RNA. We found that the open reading frame 2 of KIAA0495 is actually protein-coding and translating, encoding a small protein SP0495. KIAA0495 transcript is broadly expressed in multiple normal tissues, but frequently silenced by promoter CpG methylation in multiple tumor cell lines and primary tumors including colorectal, esophageal and breast cancers. Its downregulation/methylation is associated with poor survival of cancer patients. SP0495 induces tumor cell apoptosis, cell cycle arrest, senescence and autophagy, and inhibits tumor cell growth in vitro and in vivo. Mechanistically, SP0495 binds to phosphoinositides (PtdIns(3)P, PtdIns(3,5)P2) as a lipid-binding protein, inhibits AKT phosphorylation and its downstream signaling, and further represses oncogenic AKT/mTOR, NF-κB, and Wnt/β-catenin signaling. SP0495 also regulates the stability of autophagy regulators BECN1 and SQSTM1/p62 through modulating phosphoinositides turnover and autophagic/proteasomal degradation. Thus, we discovered and validated a 1p36.3 small protein SP0495, functioning as a novel tumor suppressor regulating AKT signaling activation and autophagy as a phosphoinositide-binding protein, being frequently inactivated by promoter methylation in multiple tumors as a potential biomarker.
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Affiliation(s)
- Lili Li
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Xing-Sheng Shu
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
- School of Medicine, Shenzhen University Health Science Center, Shenzhen, China
| | - Hua Geng
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Jianming Ying
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
- Department of Pathology, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Lei Guo
- Department of Pathology, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Jie Luo
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Tingxiu Xiang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing University Cancer Hospital, Chongqing, China
| | - Longtao Wu
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Brigette B Y Ma
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Anthony T C Chan
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Xiaofeng Zhu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Richard F Ambinder
- Johns Hopkins Singapore and Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Qian Tao
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
- Johns Hopkins Singapore and Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
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14
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Durán A, Priestman DA, Las Heras M, Rebolledo-Jaramillo B, Olguín V, Calderón JF, Zanlungo S, Gutiérrez J, Platt FM, Klein AD. A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids. Int J Mol Sci 2023; 24:4915. [PMID: 36902345 PMCID: PMC10002577 DOI: 10.3390/ijms24054915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 02/07/2023] [Accepted: 02/15/2023] [Indexed: 03/08/2023] Open
Abstract
Identification of genetic modulators of lysosomal enzyme activities and glycosphingolipids (GSLs) may facilitate the development of therapeutics for diseases in which they participate, including Lysosomal Storage Disorders (LSDs). To this end, we used a systems genetics approach: we measured 11 hepatic lysosomal enzymes and many of their natural substrates (GSLs), followed by modifier gene mapping by GWAS and transcriptomics associations in a panel of inbred strains. Unexpectedly, most GSLs showed no association between their levels and the enzyme activity that catabolizes them. Genomic mapping identified 30 shared predicted modifier genes between the enzymes and GSLs, which are clustered in three pathways and are associated with other diseases. Surprisingly, they are regulated by ten common transcription factors, and their majority by miRNA-340p. In conclusion, we have identified novel regulators of GSL metabolism, which may serve as therapeutic targets for LSDs and may suggest the involvement of GSL metabolism in other pathologies.
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Affiliation(s)
- Anyelo Durán
- Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7610658, Chile
| | | | - Macarena Las Heras
- Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7610658, Chile
| | - Boris Rebolledo-Jaramillo
- Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7610658, Chile
| | - Valeria Olguín
- Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7610658, Chile
| | - Juan F. Calderón
- Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7610658, Chile
- Research Center for the Development of Novel Therapeutic Alternatives for Alcohol Use Disorders, Santiago 7610658, Chile
| | - Silvana Zanlungo
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330033, Chile
| | - Jaime Gutiérrez
- Cellular Signaling and Differentiation Laboratory, School of Medical Technology, Health Sciences Faculty, Universidad San Sebastian, Santiago 7510602, Chile
| | - Frances M. Platt
- Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK
| | - Andrés D. Klein
- Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7610658, Chile
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15
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Zou K, Sun P, Huang H, Zhuo H, Qie R, Xie Y, Luo J, Li N, Li J, He J, Aschebrook-Kilfoy B, Zhang Y. Etiology of lung cancer: Evidence from epidemiologic studies. JOURNAL OF THE NATIONAL CANCER CENTER 2022; 2:216-225. [PMID: 39036545 PMCID: PMC11256564 DOI: 10.1016/j.jncc.2022.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 09/28/2022] [Accepted: 09/29/2022] [Indexed: 12/05/2022] Open
Abstract
Lung cancer is one of the leading causes of cancer incidence and mortality worldwide. While smoking, radon, air pollution, as well as occupational exposure to asbestos, diesel fumes, arsenic, beryllium, cadmium, chromium, nickel, and silica are well-established risk factors, many lung cancer cases cannot be explained by these known risk factors. Over the last two decades the incidence of adenocarcinoma has risen, and it now surpasses squamous cell carcinoma as the most common histologic subtype. This increase warrants new efforts to identify additional risk factors for specific lung cancer subtypes as well as a comprehensive review of current evidence from epidemiologic studies to inform future studies. Given the myriad exposures individuals experience in real-world settings, it is essential to investigate mixture effects from complex exposures and gene-environment interactions in relation to lung cancer and its subtypes.
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Affiliation(s)
- Kaiyong Zou
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Peiyuan Sun
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huang Huang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haoran Zhuo
- Yale School of Public Health, New Haven, United States of America
| | - Ranran Qie
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuting Xie
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiajun Luo
- Department of Public Health Sciences, the University of Chicago, Chicago, United States of America
| | - Ni Li
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiang Li
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie He
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | | | - Yawei Zhang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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16
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Yang W, Zhang T, Song X, Dong G, Xu L, Jiang F. SNP-Target Genes Interaction Perturbing the Cancer Risk in the Post-GWAS. Cancers (Basel) 2022; 14:5636. [PMID: 36428729 PMCID: PMC9688512 DOI: 10.3390/cancers14225636] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/10/2022] [Accepted: 11/13/2022] [Indexed: 11/18/2022] Open
Abstract
Cancer ranks as the second leading cause of death worldwide, and, being a genetic disease, it is highly heritable. Over the past few decades, genome-wide association studies (GWAS) have identified many risk-associated loci harboring hundreds of single nucleotide polymorphisms (SNPs). Some of these cancer-associated SNPs have been revealed as causal, and the functional characterization of the mechanisms underlying the cancer risk association has been illuminated in some instances. In this review, based on the different positions of SNPs and their modes of action, we discuss the mechanisms underlying how SNPs regulate the expression of target genes to consequently affect tumorigenesis and the development of cancer.
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Affiliation(s)
- Wenmin Yang
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing 210009, China
- The Fourth Clinical College, Nanjing Medical University, Nanjing 210009, China
| | - Te Zhang
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing 210009, China
- The Fourth Clinical College, Nanjing Medical University, Nanjing 210009, China
| | - Xuming Song
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing 210009, China
- The Fourth Clinical College, Nanjing Medical University, Nanjing 210009, China
| | - Gaochao Dong
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing 210009, China
| | - Lin Xu
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing 210009, China
- The Fourth Clinical College, Nanjing Medical University, Nanjing 210009, China
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211116, China
| | - Feng Jiang
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, China
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing 210009, China
- The Fourth Clinical College, Nanjing Medical University, Nanjing 210009, China
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17
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Chen W, Wen MY, Yang KB, Zheng LT, Li X. A pyroptosis expression pattern score predicts prognosis and immune microenvironment of lung squamous cell carcinoma. Front Genet 2022; 13:996444. [PMID: 36437960 PMCID: PMC9685532 DOI: 10.3389/fgene.2022.996444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 10/18/2022] [Indexed: 09/08/2024] Open
Abstract
Pyroptosis has been proved to significantly influence the development of lung squamous cell carcinoma (LUSC). To better predict overall survival (OS) and provide guidance on the selection of therapy for LUSC patients, we constructed a novel prognostic biomarker based on pyroptosis-related genes. The dataset for model construction were obtained from The Cancer Genome Atlas and the validation dataset were obtained from Gene Expression Omnibus. Differential expression genes between different pyroptosis expression patterns were identified. These genes were then used to construct pyroptosis expression pattern score (PEPScore) through weighted gene co-expression network analysis, univariate and multivariate cox regression analysis. Afterward, the differences in molecule and immune characteristics and the effect of different therapies were explored between the subgroups divided by the model. The PEPScore was constructed based on six pyroptosis-related genes (CSF2, FGA, AKAP12, CYP2C18, IRS4, TSLP). Compared with the high-PEPScore subgroup, the low-PEPScore subgroup had significantly better OS, higher TP53 and TTN mutation rate, higher infiltration of T follicular helper cells and CD8 T cells, and may benefit more from chemotherapeutic drugs, immunotherapy and radiotherapy. PEPScore is a prospective prognostic model to differentiate prognosis, molecular and immune microenvironmental features, as well as provide significant guidance for selecting clinical therapies.
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Affiliation(s)
- Wei Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Min-Yu Wen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Kai-Bin Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Li-Tao Zheng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Xuan Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
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18
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Long E, Patel H, Byun J, Amos CI, Choi J. Functional studies of lung cancer GWAS beyond association. Hum Mol Genet 2022; 31:R22-R36. [PMID: 35776125 PMCID: PMC9585683 DOI: 10.1093/hmg/ddac140] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/01/2022] [Accepted: 06/16/2022] [Indexed: 11/14/2022] Open
Abstract
Fourteen years after the first genome-wide association study (GWAS) of lung cancer was published, approximately 45 genomic loci have now been significantly associated with lung cancer risk. While functional characterization was performed for several of these loci, a comprehensive summary of the current molecular understanding of lung cancer risk has been lacking. Further, many novel computational and experimental tools now became available to accelerate the functional assessment of disease-associated variants, moving beyond locus-by-locus approaches. In this review, we first highlight the heterogeneity of lung cancer GWAS findings across histological subtypes, ancestries and smoking status, which poses unique challenges to follow-up studies. We then summarize the published lung cancer post-GWAS studies for each risk-associated locus to assess the current understanding of biological mechanisms beyond the initial statistical association. We further summarize strategies for GWAS functional follow-up studies considering cutting-edge functional genomics tools and providing a catalog of available resources relevant to lung cancer. Overall, we aim to highlight the importance of integrating computational and experimental approaches to draw biological insights from the lung cancer GWAS results beyond association.
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Affiliation(s)
- Erping Long
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Harsh Patel
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jinyoung Byun
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, 77030, USA
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Christopher I Amos
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, 77030, USA
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Jiyeon Choi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
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19
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Wang C, Dai J, Qin N, Fan J, Ma H, Chen C, An M, Zhang J, Yan C, Gu Y, Xie Y, He Y, Jiang Y, Zhu M, Song C, Jiang T, Liu J, Zhou J, Wang N, Hua T, Liang S, Wang L, Xu J, Yin R, Chen L, Xu L, Jin G, Lin D, Hu Z, Shen H. Analyses of rare predisposing variants of lung cancer in 6,004 whole genomes in Chinese. Cancer Cell 2022; 40:1223-1239.e6. [PMID: 36113475 DOI: 10.1016/j.ccell.2022.08.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 07/08/2022] [Accepted: 08/15/2022] [Indexed: 12/24/2022]
Abstract
We present the largest whole-genome sequencing (WGS) study of non-small cell lung cancer (NSCLC) to date among 6,004 individuals of Chinese ancestry, coupled with 23,049 individuals genotyped by SNP array. We construct a high-quality haplotype reference panel for imputation and identify 20 common and low-frequency loci (minor allele frequency [MAF] ≥ 0.5%), including five loci that have never been reported before. For rare loss-of-function (LoF) variants (MAF < 0.5%), we identify BRCA2 and 18 other cancer predisposition genes that affect 5.29% of individuals with NSCLC, and 98.91% (181 of 183) of LoF variants have not been linked previously to NSCLC risk. Promoter variants of BRCA2 also have a substantial effect on NSCLC risk, and their prevalence is comparable with BRCA2 LoF variants. The associations are validated in an independent case-control study including 4,410 individuals and a prospective cohort study including 23,826 individuals. Our findings not only provide a high-quality reference panel for future array-based association studies but depict the whole picture of rare pathogenic variants for NSCLC.
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Affiliation(s)
- Cheng Wang
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Juncheng Dai
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Na Qin
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Jingyi Fan
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Hongxia Ma
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine (Suzhou Centre), Gusu School, Nanjing Medical University, Suzhou 215002, Jiangsu, China; Research Units of Cohort Study on Cardiovascular Diseases and Cancers, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Congcong Chen
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Mingxing An
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Jing Zhang
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Caiwang Yan
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Yayun Gu
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Yuan Xie
- Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Yuanlin He
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Yue Jiang
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Meng Zhu
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Ci Song
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Tao Jiang
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Jia Liu
- Department of Health Promotion & Chronic Non-Communicable Disease Control, Wuxi Center for Disease Control and Prevention, Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi 214145, Jiangsu, China
| | - Jun Zhou
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Nanxi Wang
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Tingting Hua
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Shuang Liang
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Lu Wang
- Department of Health Promotion & Chronic Non-Communicable Disease Control, Wuxi Center for Disease Control and Prevention, Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi 214145, Jiangsu, China
| | - Jing Xu
- Department of Thoracic Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Rong Yin
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Department of Thoracic Surgery Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing 210029, Jiangsu, China
| | - Liang Chen
- Department of Thoracic Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
| | - Lin Xu
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Department of Thoracic Surgery Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing 210029, Jiangsu, China
| | - Guangfu Jin
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China
| | - Dongxin Lin
- Department of Etiology and Carcinogenesis, National Cancer Center and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhibin Hu
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine (Suzhou Centre), Gusu School, Nanjing Medical University, Suzhou 215002, Jiangsu, China.
| | - Hongbing Shen
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, Jiangsu, China; Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China; State Key Laboratory of Reproductive Medicine (Suzhou Centre), Gusu School, Nanjing Medical University, Suzhou 215002, Jiangsu, China; Research Units of Cohort Study on Cardiovascular Diseases and Cancers, Chinese Academy of Medical Sciences, Beijing 100730, China.
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20
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Chen P, Liu Y, Wen Y, Zhou C. Non-small cell lung cancer in China. Cancer Commun (Lond) 2022; 42:937-970. [PMID: 36075878 PMCID: PMC9558689 DOI: 10.1002/cac2.12359] [Citation(s) in RCA: 319] [Impact Index Per Article: 106.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 07/21/2022] [Accepted: 08/24/2022] [Indexed: 04/08/2023] Open
Abstract
In China, lung cancer is a primary cancer type with high incidence and mortality. Risk factors for lung cancer include tobacco use, family history, radiation exposure, and the presence of chronic lung diseases. Most early-stage non-small cell lung cancer (NSCLC) patients miss the optimal timing for treatment due to the lack of clinical presentations. Population-based nationwide screening programs are of significant help in increasing the early detection and survival rates of NSCLC in China. The understanding of molecular carcinogenesis and the identification of oncogenic drivers dramatically facilitate the development of targeted therapy for NSCLC, thus prolonging survival in patients with positive drivers. In the exploration of immune escape mechanisms, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor monotherapy and PD-1/PD-L1 inhibitor plus chemotherapy have become a standard of care for advanced NSCLC in China. In the Chinese Society of Clinical Oncology's guidelines for NSCLC, maintenance immunotherapy is recommended for locally advanced NSCLC after chemoradiotherapy. Adjuvant immunotherapy and neoadjuvant chemoimmunotherapy will be approved for resectable NSCLC. In this review, we summarized recent advances in NSCLC in China in terms of epidemiology, biology, molecular pathology, pathogenesis, screening, diagnosis, targeted therapy, and immunotherapy.
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Affiliation(s)
- Peixin Chen
- School of MedicineTongji UniversityShanghai200092P. R. China
- Department of Medical OncologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433P. R. China
| | - Yunhuan Liu
- Department of Respiratory and Critical Care MedicineHuadong HospitalFudan UniversityShanghai200040P. R. China
| | - Yaokai Wen
- School of MedicineTongji UniversityShanghai200092P. R. China
- Department of Medical OncologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433P. R. China
| | - Caicun Zhou
- School of MedicineTongji UniversityShanghai200092P. R. China
- Department of Medical OncologyShanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghai200433P. R. China
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21
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Zhang P, Chen PL, Li ZH, Zhang A, Zhang XR, Zhang YJ, Liu D, Mao C. Association of smoking and polygenic risk with the incidence of lung cancer: a prospective cohort study. Br J Cancer 2022; 126:1637-1646. [PMID: 35194190 PMCID: PMC9130319 DOI: 10.1038/s41416-022-01736-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 01/23/2022] [Accepted: 02/02/2022] [Indexed: 12/24/2022] Open
Abstract
Background Genetic variation increases the risk of lung cancer, but the extent to which smoking amplifies this effect remains unknown. Therefore, we aimed to investigate the risk of lung cancer in people with different genetic risks and smoking habits. Methods This prospective cohort study included 345,794 European ancestry participants from the UK Biobank and followed up for 7.2 [6.5–7.8] years. Results Overall, 26.2% of the participants were former smokers, and 9.8% were current smokers. During follow-up, 1687 (0.49%) participants developed lung cancer. High genetic risk and smoking were independently associated with an increased risk of incident lung cancer. Compared with never-smokers, HR per standard deviation of the PRS increase was 1.16 (95% CI, 1.11–1.22), and HR of heavy smokers (≥40 pack-years) was 17.89 (95% CI, 15.31–20.91). There were no significant interactions between the PRS and the smoking status or pack-years. Population-attributable fraction analysis showed that smoking cessation might prevent 76.4% of new lung cancers. Conclusions Both high genetic risk and smoking were independently associated with higher lung cancer risk, but the increased risk of smoking was much more significant than heredity. The combination of traditional risk factors and additional PRS provides realistic application prospects for precise prevention.
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Affiliation(s)
- Peidong Zhang
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China.,The Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Pei-Liang Chen
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhi-Hao Li
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - Ao Zhang
- State Key Laboratory of Molecular Neuroscience and Center of Systems Biology and Human Health, Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, China
| | - Xi-Ru Zhang
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - Yu-Jie Zhang
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - Dan Liu
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - Chen Mao
- Department of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China. .,Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
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22
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Profile of Dr. Hong-Bing Shen. SCIENCE CHINA. LIFE SCIENCES 2022; 65:16-18. [PMID: 34455504 DOI: 10.1007/s11427-021-1979-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
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23
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Huang ZY, Shao MM, Zhang JC, Yi FS, Du J, Zhou Q, Wu FY, Li S, Li W, Huang XZ, Zhai K, Shi HZ. Single-cell analysis of diverse immune phenotypes in malignant pleural effusion. Nat Commun 2021; 12:6690. [PMID: 34795282 PMCID: PMC8602344 DOI: 10.1038/s41467-021-27026-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 10/22/2021] [Indexed: 12/25/2022] Open
Abstract
The complex interactions among different immune cells have important functions in the development of malignant pleural effusion (MPE). Here we perform single-cell RNA sequencing on 62,382 cells from MPE patients induced by non-small cell lung cancer to describe the composition, lineage, and functional states of infiltrating immune cells in MPE. Immune cells in MPE display a number of transcriptional signatures enriched for regulatory T cells, B cells, macrophages, and dendritic cells compared to corresponding counterparts in blood. Helper T, cytotoxic T, regulatory T, and T follicular helper cells express multiple immune checkpoints or costimulatory molecules. Cell-cell interaction analysis identifies regulatory B cells with more interactions with CD4+ T cells compared to CD8+ T cells. Macrophages are transcriptionally heterogeneous and conform to M2 polarization characteristics. In addition, immune cells in MPE show the general up-regulation of glycolytic pathways associated with the hypoxic microenvironment. These findings show a detailed atlas of immune cells in human MPE and enhance the understanding of potential diagnostic and therapeutic targets in advanced non-small cell lung cancer.
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Affiliation(s)
- Zhong-Yin Huang
- grid.24696.3f0000 0004 0369 153XDepartment of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, 100020 Beijing, China
| | - Ming-Ming Shao
- grid.24696.3f0000 0004 0369 153XDepartment of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, 100020 Beijing, China
| | - Jian-Chu Zhang
- grid.33199.310000 0004 0368 7223Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China
| | - Feng-Shuang Yi
- grid.24696.3f0000 0004 0369 153XDepartment of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, 100020 Beijing, China
| | - Juan Du
- grid.24696.3f0000 0004 0369 153XDepartment of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, 100020 Beijing, China
| | - Qiong Zhou
- grid.33199.310000 0004 0368 7223Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China
| | - Feng-Yao Wu
- Department of Tuberculosis, Nanning Fourth People’s Hospital, 530022 Nanning, China
| | - Sha Li
- Department of Tuberculosis, Nanning Fourth People’s Hospital, 530022 Nanning, China
| | - Wei Li
- Department of Tuberculosis, Nanning Fourth People’s Hospital, 530022 Nanning, China
| | - Xian-Zhen Huang
- Department of Tuberculosis, Nanning Fourth People’s Hospital, 530022 Nanning, China
| | - Kan Zhai
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, 100020, Beijing, China.
| | - Huan-Zhong Shi
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, 100020, Beijing, China.
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24
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Yang L, Zhao H, Liu K, Wang Y, Liu Q, Sun T, Chen S, Ren L. Smoking behavior and circulating vitamin D levels in adults: A meta-analysis. Food Sci Nutr 2021; 9:5820-5832. [PMID: 34646549 PMCID: PMC8497833 DOI: 10.1002/fsn3.2488] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 06/20/2021] [Accepted: 07/07/2021] [Indexed: 12/16/2022] Open
Abstract
To determine the effect of smoking on circulating vitamin D in adults, we performed a meta-analysis. Literature before 9 May 2021 was retrieved from electronic literature databases such as EMBASE, PubMed, and Cochrane. The quality of the included studies was assessed by two researchers against the Newcastle-Ottawa scale and JBI Evidence-based Health Care Centre criteria. All eligible studies and statistical analyses were performed using STATA 14. Twenty-four studies with 11,340 participants meeting the criteria were included in the meta-analysis. The results of meta-analysis showed that the level of circulating 25(OH)D in smokers was lower than that in nonsmokers. A subgroup analysis based on vitamin D supplement use showed that both smokers who used vitamin D supplements and smokers who did not use vitamin D supplements had lower blood 25(OH)D levels compared with the control group. In addition, subjects were divided into different subgroups according to age for meta-analysis, and the results showed that the serum 25(OH)D level in each subgroup of smokers was lower than that in the control group. This meta-analysis revealed differences in circulating vitamin D levels between smokers and nonsmokers, with smokers likely to have lower circulating vitamin D levels.
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Affiliation(s)
- Lu Yang
- Hebei General HospitalShijiazhuangChina
| | - Hang Zhao
- Hebei General HospitalShijiazhuangChina
| | - Ke Liu
- Hebei General HospitalShijiazhuangChina
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25
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Sengupta D, Banerjee S, Mukhopadhyay P, Mitra R, Chaudhuri T, Sarkar A, Bhattacharjee G, Nath S, Roychoudhury S, Bhattacharjee S, Sengupta M. A comprehensive meta-analysis and a case-control study give insights into genetic susceptibility of lung cancer and subgroups. Sci Rep 2021; 11:14572. [PMID: 34272429 PMCID: PMC8285487 DOI: 10.1038/s41598-021-92275-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 06/08/2021] [Indexed: 12/17/2022] Open
Abstract
Reports of genetic association of polymorphisms with lung cancer in the Indian subcontinent are often conflicting. To summarise and replicate published evidence for association with lung cancer and its subgroups. We performed a meta-analysis of candidate associations on lung cancer, its histological subtypes and smoking status in the Indian subcontinent following PRISMA guidelines. Multiple testing corrections were done by the Benjamini-Hochberg method through assessment of significance at a false discovery rate of 10%. We genotyped and investigated rs1048943/CYP1A1 in a case-control sample from eastern India, followed by its global meta-analysis using a similar protocol. Meta-analysis of 18 variants of 11 genes reported in 39 studies (7630 cases and 8169 controls) showed significant association of rs1048943/CYP1A1 [2.07(1.49-2.87)] and rs4646903/CYP1A1 [1.48(1.93-1.95)] with overall lung cancer risk at 10% FDR, while nominal association (p < 0.05) was observed for del1/GSTT1, del2/GSTM1, rs1695/GSTP1 and rs17037102/ DKK2. Subtype analysis showed a significant association of del1/GSTT1 with adenocarcinoma, rs4646903/CYP1A1 with squamous carcinoma, and rs1048943/CYP1A1 with both. Association of rs4646903/CYP1A1 in smokers and effect modification by meta-regression analysis was observed. Genotyping of rs1048943/CYP1A1 that presented significant heterogeneity (p < 0.1) revealed an association with adenocarcinoma among eastern Indian smokers, while a global meta-analysis in 10458 cases and 10871 controls showed association with lung cancer and its subgroups. This study identified the susceptibility loci for lung cancer and its covariate-subgroups.
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Affiliation(s)
- Debmalya Sengupta
- Department of Genetics, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, India
| | - Souradeep Banerjee
- Department of Genetics, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, India
| | - Pramiti Mukhopadhyay
- Greehey Children's Cancer Research Institute, UT Health San Antonio, 8403 Floyd Curl Dr., San Antonio, TX-78229, USA
| | - Ritabrata Mitra
- Department of CHEST, IPGME&R, 244 A.J.C. Bose Road, Kolkata, 700020, India
| | - Tamohan Chaudhuri
- Saroj Gupta Cancer Centre and Research Institute, Mahatma Gandhi Road, Thakurpukur, Kolkata, 700063, India
| | - Abhijit Sarkar
- Saroj Gupta Cancer Centre and Research Institute, Mahatma Gandhi Road, Thakurpukur, Kolkata, 700063, India
| | - Gautam Bhattacharjee
- Saroj Gupta Cancer Centre and Research Institute, Mahatma Gandhi Road, Thakurpukur, Kolkata, 700063, India
| | - Somsubhra Nath
- Saroj Gupta Cancer Centre and Research Institute, Mahatma Gandhi Road, Thakurpukur, Kolkata, 700063, India
| | - Susanta Roychoudhury
- CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata, 700032, India
| | - Samsiddhi Bhattacharjee
- National Institute of Biomedical Genomics, Near Netaji Subhas Sanatorium Post Office, Kalyani, West Bengal, 741251, India.
| | - Mainak Sengupta
- Department of Genetics, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, India.
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26
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Ben X, Tian D, Liang J, Wu M, Xie F, Zheng J, Chen J, Fei Q, Guo X, Weng X, Liu S, Xie X, Ying Y, Qiao G, Jing C. APOBEC3B deletion polymorphism and lung cancer risk in the southern Chinese population. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:656. [PMID: 33987354 PMCID: PMC8105993 DOI: 10.21037/atm-21-989] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Background Approximately 80–85% of lung cancer is the non-small cell lung cancer (NSCLC) subtype, which ranks as the leading cause of cancer deaths worldwide. APOBEC3B (A3B) was reported to be a key source of mutations in NSCLC. However, the role of the A3B deletion polymorphism in the etiology of NSCLC has not been well-documented. Methods A case-control study with 317 NSCLC patients and 334 healthy controls was conducted to explore the association between the A3B deletion polymorphism and the risk of NSCLC. The unconditional logistic regression model was performed to calculate the odds ratio (OR) and the 95% confidence interval (CI), and the confounding factors were adjusted, including age, gender, and smoking status, to estimate the risk. An analysis of gene-environment interactions was performed using multifactor dimensionality reduction (MDR) software. Results We found that the del/del genotype of A3B deletion significantly increased NSCLC risk. Compared with individuals carrying the ins/ins genotype of A3B deletion, individuals with the del/del genotype had a 2.36 times increased risk of developing NSCLC after adjusting for confounding factors (OR =2.71, 95% CI: 1.67–4.42, P<0.001). A 3-factor gene-environment (A3B deletion, gender, and smoking) interaction model was found for NSCLC (OR =4.407, 95% CI: 1.174–16.549, P=0.028). Conclusions We propose that the A3B deletion polymorphism can increase the risk of developing NSCLC, and their interactions with gender and smoking may contribute to the risk of NSCLC in the southern Chinese population.
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Affiliation(s)
- Xiaosong Ben
- Department of Thoracic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Dan Tian
- Department of Thoracic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Jiayu Liang
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Min Wu
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Fan Xie
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Jinlong Zheng
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Jingmin Chen
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Qiaoyuan Fei
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Xinrong Guo
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Xueqiong Weng
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Shan Liu
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Xin Xie
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Yuting Ying
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Guibin Qiao
- Department of Thoracic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Chunxia Jing
- Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China.,Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou, China
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27
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Liu Y, Xia J, McKay J, Tsavachidis S, Xiao X, Spitz MR, Cheng C, Byun J, Hong W, Li Y, Zhu D, Song Z, Rosenberg SM, Scheurer ME, Kheradmand F, Pikielny CW, Lusk CM, Schwartz AG, Wistuba II, Cho MH, Silverman EK, Bailey-Wilson J, Pinney SM, Anderson M, Kupert E, Gaba C, Mandal D, You M, de Andrade M, Yang P, Liloglou T, Davies MPA, Lissowska J, Swiatkowska B, Zaridze D, Mukeria A, Janout V, Holcatova I, Mates D, Stojsic J, Scelo G, Brennan P, Liu G, Field JK, Hung RJ, Christiani DC, Amos CI. Rare deleterious germline variants and risk of lung cancer. NPJ Precis Oncol 2021; 5:12. [PMID: 33594163 PMCID: PMC7887261 DOI: 10.1038/s41698-021-00146-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 12/11/2020] [Indexed: 01/19/2023] Open
Abstract
Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial role in the etiology of lung cancers (LC). Whole exome plus targeted sequencing of germline DNA was performed on 1045 LC cases and 885 controls in the discovery set. To unveil the inherited causal variants, we focused on rare and predicted deleterious variants and small indels enriched in cases or controls. Promising candidates were further validated in a series of 26,803 LCs and 555,107 controls. During discovery, we identified 25 rare deleterious variants associated with LC susceptibility, including 13 reported in ClinVar. Of the five validated candidates, we discovered two pathogenic variants in known LC susceptibility loci, ATM p.V2716A (Odds Ratio [OR] 19.55, 95%CI 5.04-75.6) and MPZL2 p.I24M frameshift deletion (OR 3.88, 95%CI 1.71-8.8); and three in novel LC susceptibility genes, POMC c.*28delT at 3' UTR (OR 4.33, 95%CI 2.03-9.24), STAU2 p.N364M frameshift deletion (OR 4.48, 95%CI 1.73-11.55), and MLNR p.Q334V frameshift deletion (OR 2.69, 95%CI 1.33-5.43). The potential cancer-promoting role of selected candidate genes and variants was further supported by endogenous DNA damage assays. Our analyses led to the identification of new rare deleterious variants with LC susceptibility. However, in-depth mechanistic studies are still needed to evaluate the pathogenic effects of these specific alleles.
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Grants
- R01 CA060691 NCI NIH HHS
- U19 CA203654 NCI NIH HHS
- R01 CA084354 NCI NIH HHS
- R01 HL110883 NHLBI NIH HHS
- U01 CA076293 NCI NIH HHS
- R01 CA080127 NCI NIH HHS
- R01 CA141769 NCI NIH HHS
- P30 ES006096 NIEHS NIH HHS
- P50 CA090578 NCI NIH HHS
- P30 CA022453 NCI NIH HHS
- S10 RR024574 NCRR NIH HHS
- HHSN261201300011C NCI NIH HHS
- R01 CA134682 NCI NIH HHS
- R01 CA134433 NCI NIH HHS
- R01 HL113264 NHLBI NIH HHS
- R01 HL082487 NHLBI NIH HHS
- R01 CA250905 NCI NIH HHS
- U19 CA148127 NCI NIH HHS
- P20 GM103534 NIGMS NIH HHS
- R01 CA092824 NCI NIH HHS
- R01 CA087895 NCI NIH HHS
- U01 HL089897 NHLBI NIH HHS
- K07 CA181480 NCI NIH HHS
- HHSN268201100011I NHLBI NIH HHS
- HHSN268201100011C NHLBI NIH HHS
- R01 CA127219 NCI NIH HHS
- R01 CA074386 NCI NIH HHS
- P30 CA023108 NCI NIH HHS
- U01 HL089856 NHLBI NIH HHS
- P30 ES030285 NIEHS NIH HHS
- P30 CA125123 NCI NIH HHS
- DP1 AG072751 NIA NIH HHS
- U01 CA243483 NCI NIH HHS
- HHSN268200782096C NHLBI NIH HHS
- HHSN268201200007C NHLBI NIH HHS
- N01HG65404 NHGRI NIH HHS
- R35 GM122598 NIGMS NIH HHS
- U01 CA209414 NCI NIH HHS
- R03 CA077118 NCI NIH HHS
- 001 World Health Organization
- DP1 CA174424 NCI NIH HHS
- This work was supported by grants from the National Institutes of Health (R01CA127219, R01CA141769, R01CA060691, R01CA87895, R01CA80127, R01CA84354, R01CA134682, R01CA134433, R01CA074386, R01CA092824, R01CA250905, R01HL113264, R01HL082487, R01HL110883, R03CA77118, P20GM103534, P30CA125123, P30CA023108, P30CA022453, P30ES006096, P50CA090578, U01CA243483, U01HL089856, U01HL089897, U01CA76293, U19CA148127, U01CA209414, K07CA181480, N01-HG-65404, HHSN268200782096C, HHSN261201300011I, HHSN268201100011, HHSN268201 200007C, DP1-CA174424, DP1-AG072751, CA125123, RR024574, Intramural Research Program of the National Human Genome Research Institute (JEB-W), and Herrick Foundation. Dr. Amos is an Established Research Scholar of the Cancer Prevention Research Institute of Texas (RR170048). We also want to acknowledge the Cytometry and Cell Sorting Core support by the Cancer Prevention and Research Institute of Texas Core Facility (RP180672). At Toronto, the study is supported by The Canadian Cancer Society Research Institute (# 020214) to R. H., Ontario Institute for Cancer Research to R. H, and the Alan Brown Chair to G. L. and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The Liverpool Lung Project is supported by Roy Castle Lung Cancer Foundation.
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Affiliation(s)
- Yanhong Liu
- Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Jun Xia
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - James McKay
- International Agency for Research on Cancer, Lyon, France
| | - Spiridon Tsavachidis
- Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Xiangjun Xiao
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Margaret R Spitz
- Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Chao Cheng
- Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Jinyoung Byun
- Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Wei Hong
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Yafang Li
- Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Dakai Zhu
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Zhuoyi Song
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA
| | - Susan M Rosenberg
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Michael E Scheurer
- Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Farrah Kheradmand
- Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
| | - Claudio W Pikielny
- Department of Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Lebanon, NH, USA
| | - Christine M Lusk
- Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Ann G Schwartz
- Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael H Cho
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Edwin K Silverman
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | | | - Susan M Pinney
- University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | | | - Elena Kupert
- University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Colette Gaba
- The University of Toledo College of Medicine, Toledo, OH, USA
| | - Diptasri Mandal
- Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Ming You
- Medical College of Wisconsin, Milwaukee, WI, USA
| | | | - Ping Yang
- Mayo Clinic College of Medicine, Scottsdale, AZ, USA
| | - Triantafillos Liloglou
- Roy Castle Lung Cancer Research Programme, The University of Liverpool, Department of Molecular and Clinical Cancer Medicine, Liverpool, UK
| | - Michael P A Davies
- Roy Castle Lung Cancer Research Programme, The University of Liverpool, Department of Molecular and Clinical Cancer Medicine, Liverpool, UK
| | - Jolanta Lissowska
- M. Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Beata Swiatkowska
- Nofer Institute of Occupational Medicine, Department of Environmental Epidemiology, Lodz, Poland
| | - David Zaridze
- Russian N.N. Blokhin Cancer Research Centre, Moscow, Russian Federation
| | - Anush Mukeria
- Russian N.N. Blokhin Cancer Research Centre, Moscow, Russian Federation
| | - Vladimir Janout
- Faculty of Health Sciences, Palacky University, Olomouc, Czech Republic
| | - Ivana Holcatova
- Institute of Public Health and Preventive Medicine, Charles University, 2nd Faculty of Medicine, Prague, Czech Republic
| | - Dana Mates
- National Institute of Public Health, Bucharest, Romania
| | - Jelena Stojsic
- Department of Thoracopulmonary Pathology, Service of Pathology, Clinical Center of Serbia, Belgrade, Serbia
| | | | - Paul Brennan
- International Agency for Research on Cancer, Lyon, France
| | - Geoffrey Liu
- Princess Margaret Cancer Center, Toronto, ON, Canada
| | - John K Field
- Roy Castle Lung Cancer Research Programme, The University of Liverpool, Department of Molecular and Clinical Cancer Medicine, Liverpool, UK
| | - Rayjean J Hung
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | | | - Christopher I Amos
- Dan L. Duncan Comprehensive Cancer Center, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA.
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Corlin L, Liu C, Lin H, Leone D, Yang Q, Ngo D, Levy D, Cupples LA, Gerszten RE, Larson MG, Vasan RS. Proteomic Signatures of Lifestyle Risk Factors for Cardiovascular Disease: A Cross-Sectional Analysis of the Plasma Proteome in the Framingham Heart Study. J Am Heart Assoc 2021; 10:e018020. [PMID: 33372532 PMCID: PMC7955453 DOI: 10.1161/jaha.120.018020] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023]
Abstract
Background Proteomic biomarkers related to cardiovascular disease risk factors may offer insights into the pathogenesis of cardiovascular disease. We investigated whether modifiable lifestyle risk factors for cardiovascular disease are associated with distinctive proteomic signatures. Methods and Results We analyzed 1305 circulating plasma proteomic biomarkers (assayed using the SomaLogic platform) in 897 FHS (Framingham Heart Study) Generation 3 participants (mean age 46±8 years; 56% women; discovery sample) and 1121 FOS (Framingham Offspring Study) participants (mean age 52 years; 54% women; validation sample). Participants were free of hypertension, diabetes mellitus, and clinical cardiovascular disease. We used linear mixed effects models (adjusting for age, sex, body mass index, and family structure) to relate levels of each inverse-log transformed protein to 3 lifestyle factors (ie, smoking, alcohol consumption, and physical activity). A Bonferroni-adjusted P value indicated statistical significance (based on number of proteins and traits tested, P<4.2×10-6 in the discovery sample; P<6.85×10-4 in the validation sample). We observed statistically significant associations of 60 proteins with smoking (37/40 top proteins validated in FOS), 30 proteins with alcohol consumption (23/30 proteins validated), and 5 proteins with physical activity (2/3 proteins associated with the physical activity index validated). We assessed the associations of protein concentrations with previously identified genetic variants (protein quantitative trait loci) linked to lifestyle-related disease traits in the genome-wide-association study catalogue. The protein quantitative trait loci were associated with coronary artery disease, inflammation, and age-related mortality. Conclusions Our cross-sectional study from a community-based sample elucidated distinctive sets of proteins associated with 3 key lifestyle factors.
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Affiliation(s)
- Laura Corlin
- Boston University Department of MedicineBostonMA
- Department of Public Health and Community MedicineTufts University School of MedicineBostonMA
- Department of Civil and Environmental EngineeringTufts University School of EngineeringMedfordMA
| | - Chunyu Liu
- Boston University School of Public HealthBostonMA
| | | | | | - Qiong Yang
- Boston University School of Public HealthBostonMA
| | - Debby Ngo
- Department of MedicineBeth Israel Deaconess Medical CenterBostonMA
- Harvard Medical SchoolBostonMA
| | - Daniel Levy
- Population Sciences BranchNational Heart, Lung, and Blood Institute, National Institutes of HealthBethesdaMD
- Framingham Heart StudyFraminghamMA
| | - L. Adrienne Cupples
- Boston University School of Public HealthBostonMA
- Framingham Heart StudyFraminghamMA
| | - Robert E. Gerszten
- Department of MedicineBeth Israel Deaconess Medical CenterBostonMA
- Harvard Medical SchoolBostonMA
| | - Martin G. Larson
- Boston University School of Public HealthBostonMA
- Framingham Heart StudyFraminghamMA
| | - Ramachandran S. Vasan
- Boston University Department of MedicineBostonMA
- Boston University School of Public HealthBostonMA
- Framingham Heart StudyFraminghamMA
- Boston University Center for Computing and Data SciencesBostonMA
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29
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Association between rs1800796 polymorphism in the IL-6 gene and the risk of lung cancer: An updated meta-analysis. Meta Gene 2020. [DOI: 10.1016/j.mgene.2020.100729] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
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30
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Ma H, Shen H. From human genome epidemiology to systems epidemiology: current progress and future perspective. J Biomed Res 2020; 34:323-327. [PMID: 32648851 PMCID: PMC7540239 DOI: 10.7555/jbr.34.20200027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
The recent progress in human genome epidemiology (HuGE) is already having a profound impact on the practice of medicine and public health. First, the success of genome-wide association studies has greatly expanded the direction and content of epidemiological researches, including revealing new genetic mechanisms of complex diseases, identifying new targets for therapeutic interventions, and improving application in early screening of high-risk populations. At the same time, large-scale genomic studies make it possible to efficiently explore the gene-environment interactions, which will help better understand the biological pathways of complex diseases and identify individuals who may be more susceptible to diseases. Additionally, the emergence of systems epidemiology aims to integrate multi-omics together with epidemiological data to create a systems network that can comprehensively characterize the diverse range of factors contributing to disease development. These progress will help to apply HuGE findings into practice to improve the health of individuals and populations.
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Affiliation(s)
- Hongxia Ma
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Hongbing Shen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China
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31
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Ma F, Xie Y, Lei Y, Kuang Z, Liu X. The microRNA-130a-5p/RUNX2/STK32A network modulates tumor invasive and metastatic potential in non-small cell lung cancer. BMC Cancer 2020; 20:580. [PMID: 32571328 PMCID: PMC7310151 DOI: 10.1186/s12885-020-07056-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 06/09/2020] [Indexed: 12/18/2022] Open
Abstract
Background Non-small cell lung cancer (NSCLC) remains a huge health burden for human health and life worldwide. Our study here was to illuminate the relevance of microRNA-130a-5p (miR-130a-5p) on growth and epithelial mesenchymal transition (EMT) in NSCLC cells along with metastasis in vivo, and to explore the underlying mechanism. Methods RT-qPCR was carried out for miR-130a-5p expression determination in NSCLC cells and tissue samples. Dual-luciferase reporter gene assay, RT-qPCR and western blot were carried out to study the potential targets of miR-130a-5p. Effects of miR-130a-5p, runt-related transcription factor 2 (RUNX2) and encoding serine/threonine kinase 32A (STK32A) on NSCLC proliferation, migration, invasion as well as EMT processes were assessed by cell counting kits-8, colony formation, Transwell and western blot assays. Results miR-130a-5p was diminished in NSCLC tissues and cells versus their counterparts. miR-130a-5p exerted its repressive role in NSCLC by curtailing cell viability, migration, invasion as well as EMT, while facilitating apoptosis. miR-130a-5p directly targeted RUNX2, a transcription factor, and conversely regulated its expression. RUNX2 was found to interact with STK32A to promote its expression. Following the validation of the supporting role of STK32A in NSCLC cells and NF-κB p65 phosphorylation, RUNX2 overexpression was monitored to reverse miR-130a-5p-inhibited NSCLC tumor volume and weight through enhancing STK32A expression in vivo. Conclusions miR-130a-5p diminished the growth and EMT of NSCLC cells by regulating the RUNX2/STK32A/NF-κB p65 axis, offering possible targets for the treatment for NSCLC.
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Affiliation(s)
- Fang Ma
- Department of Oncology, the Second Xiangya Hospital of Central South University, No. 139, Renmin Middle Road, Furong District, Changsha, 410000, Hunan, P.R. China
| | - Yangchun Xie
- Department of Oncology, the Second Xiangya Hospital of Central South University, No. 139, Renmin Middle Road, Furong District, Changsha, 410000, Hunan, P.R. China
| | - Yiyu Lei
- Department of Oncology, the Second Xiangya Hospital of Central South University, No. 139, Renmin Middle Road, Furong District, Changsha, 410000, Hunan, P.R. China
| | - Zengshuyu Kuang
- Department of Oncology, Zhuzhou 331 Hospital, Zhuzhou, 412000, Hunan, P.R. China
| | - Xianling Liu
- Department of Oncology, the Second Xiangya Hospital of Central South University, No. 139, Renmin Middle Road, Furong District, Changsha, 410000, Hunan, P.R. China.
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32
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Zhou W, Zhu W, Tong X, Ming S, Ding Y, Li Y, Li Y. CHRNA5 rs16969968 polymorphism is associated with lung cancer risk: A meta-analysis. CLINICAL RESPIRATORY JOURNAL 2020; 14:505-513. [PMID: 32049419 DOI: 10.1111/crj.13165] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 02/08/2020] [Indexed: 12/28/2022]
Abstract
OBJECTIVE To evaluate the genetic association between rs16969968 and lung cancer risk by meta-analysis. DATA SOURCE We searched eligible studies from MEDLINE, Web of Science and EMBASE up to Dec, 2017. STUDY SELECTION Association studies concerning rs16969968 and lung cancer risk were included. We assessed the association strength between this polymorphism and risk of lung cancer by calculating odds ratios (OR) and 95% confidence interval (95%CI). RESULTS A total of 26 data sets comprising 30 772 lung cancers and 90 954 controls were included. rs16969968 was found to be associated with lung cancer risk in population of European ancestry in all models (A vs. G: OR = 1.30, 95%CI 1.27-1.33, P < 0.001; AA + GA vs. GG: OR = 1.38, 95%CI 1.33-1.43, P < 0.001; AA vs. GG + GA: OR = 1.45, 95%CI 1.38-1.53, P < 0.001), consistent with previous genome-wide association study (GWAS). However, no association was observed in Asians (A vs. G: OR = 1.19. 95%CI 0.95-1.49, P = 0.131). The minor allele A may increase the risk of lung cancer in both smokers (OR = 1.33, 95%CI 1.29-1.39, P < 0.001) and nonsmokers (OR = 1.25, 95%CI 1.12-1.39, P < 0.001). There was no obvious publication bias in all analyses. CONCLUSIONS Our analysis provided more evidence that rs16969968 is a susceptibility locus of lung cancer in the Caucasians and that it may be not associated with the risk in the Asians.
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Affiliation(s)
- Wei Zhou
- Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Wenjie Zhu
- Department of Integrative Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xunliang Tong
- Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Shuhong Ming
- Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Yong Ding
- Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Yi Li
- Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Yanming Li
- Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Beijing, China
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33
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Kong J, Chen X, Wang J, Li J, Xu F, Gao S, Yu H, Qian B. Genetic Polymorphisms in the Vitamin D Pathway and Non-small Cell Lung Cancer Survival. Pathol Oncol Res 2019; 26:1709-1715. [PMID: 31625015 PMCID: PMC7297819 DOI: 10.1007/s12253-019-00702-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 07/19/2019] [Indexed: 01/08/2023]
Abstract
Various genetic polymorphisms have been linked to lung cancer susceptibility and survival outcomes. Vitamin D (VD) regulates cell proliferation and differentiation, inhibits tumor growth and induces apoptosis. Observations from several previous studies including our own suggest that genetic polymorphisms in the VD pathway may be associated with lung cancer risk. The aim of this study is to assess if genetic polymorphisms in the VD pathway are associated with the prognosis of non-small cell lung cancer (NSCLC). Nine single nucleotide polymorphisms (SNPs) in five genes in the VD pathway were genotyped with the TaqMan assays in 542 patients with primary NSCLC, and the relationships between these SNPs and overall survival were evaluated. We found that SNP rs10741657 in the CYP2R1 gene was associated with the prognosis of NSCLC, especially in elderly patients and not being treated with chemotherapy. Some of the VD pathway-related genetic polymorphisms may influence the prognosis of NSCLC. More research is needed to further confirm the finding and test if VD supplements can be used for NSCLC treatment.
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Affiliation(s)
- Jinyu Kong
- Henan Key Laboratory of Cancer Epigenetics; Cancer Institute, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China.,Department of Cancer Epidemiology and Biostatistics, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.,Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai, 200025, China
| | - Xiaojie Chen
- Medical College, Henan University of Science and Technology, Luoyang, 471003, Henan, China
| | - Jian Wang
- Department of Image Diagnoses, The First Affiliated Hospital, and College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471003, China
| | - Jingxin Li
- Department of Cancer Epidemiology and Biostatistics, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Fangxiu Xu
- Department of Cancer Epidemiology and Biostatistics, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
| | - Shegan Gao
- Henan Key Laboratory of Cancer Epigenetics; Cancer Institute, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Herbert Yu
- Epidemiology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA
| | - Biyun Qian
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Faculty of Public Health, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai, 200025, China.
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34
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Cao X, Huang M, Zhu M, Fang R, Ma Z, Jiang T, Dai J, Ma H, Jin G, Shen H, Du J, Xu L, Hu Z. Mendelian randomization study of telomere length and lung cancer risk in East Asian population. Cancer Med 2019; 8:7469-7476. [PMID: 31605466 PMCID: PMC6885879 DOI: 10.1002/cam4.2590] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/04/2019] [Accepted: 09/14/2019] [Indexed: 12/11/2022] Open
Abstract
Associations between telomere length and cancer risk have been investigated in many epidemiological studies, but the results are controversial. These associations may be biased by reverse causation or confounded by environmental exposures. To avoid potential biases, we used Mendelian randomization method to evaluate whether TL is the causal risk factor for lung cancer. We conducted Mendelian randomization analysis in two published East Asian GWAS studies (7127 cases and 6818 controls). We used both weighted genetic risk score and inverse‐variance weighting method to estimate the relationship between TL and lung cancer risk. Nonlinear test also used to detect potential association trends. We observed that increased weight GRS was associated with increased risk of lung cancer (OR = 2.25, 95%CI: 1.81‐2.78, P = 1.18 × 10−13). In different subtypes, weight GRS was significantly associated with lung adenocarcinoma risk (OR = 2.69, 95% CI: 2.11‐3.42, P = 7.20 × 10−16); while lung squamous cell carcinoma showed a marginal association (OR = 1.45, 95% CI = 1.01‐2.10, P = .047). Nonlinear analysis suggested a log‐linear dose‐response relationship between increased weight GRS and lung cancer risk. Our results indicated that longer TL increases lung cancer risk. Those biological mechanisms changes caused by long TL may play an important role in lung carcinogenesis.
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Affiliation(s)
- Xuguang Cao
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.,Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Department of Thoracic and Cardiovascular Surgery, First People's Hospital of Yancheng, Yancheng, China
| | - Mingtao Huang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.,Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Meng Zhu
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.,Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Rui Fang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.,Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Zijian Ma
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.,Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Tao Jiang
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.,Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Juncheng Dai
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.,Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Hongxia Ma
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.,Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Guangfu Jin
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.,Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Hongbing Shen
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.,Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Jiangbo Du
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Lin Xu
- Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Zhibin Hu
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.,Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
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Wei Y, Wang X, Zhang Z, Xie M, Li Y, Cao H, Zhao X. Role of Polymorphisms of FAM13A, PHLDB1, and CYP24A1 in Breast Cancer Risk. Curr Mol Med 2019; 19:579-588. [PMID: 31215377 DOI: 10.2174/1566524019666190619125109] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 05/30/2019] [Accepted: 05/30/2019] [Indexed: 01/08/2023]
Abstract
Background:
Single-nucleotide polymorphisms (SNPs) are important
indicators of susceptibility to breast cancer.
Objective:
To assess the associations between SNPs in the FAM13A, PHLDB1, and
CYP24A1 gene and breast cancer risk in the Chinese Han population.
Methods:
We performed a case-control study including 379 female breast cancer
patients and 407 female healthy controls. The three SNPs were genotyped using Agena
MassARRAY platform. The χ2 test was used to compare alleles and genotypes
frequencies of polymorphisms between case and control groups. Genetic models
analyses to assess the associations between SNPs and breast cancer risk by computing
odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression.
RegulomeDB and HaploReg databases were used to calculate possible functional
effects of polymorphisms.
Results:
Overall analysis results showed that rs4809957 was associated with an
increased risk of breast cancer (allele A: OR = 1.27, 95% CI: 1.03-1.55, p = 0.024; AA
vs. GG: OR = 1.80, 95% CI: 1.15–2.82, p = 0.010; recessive model: OR = 1.70, 95% CI:
1.12–2.58, p = 0.012); and rs1059122 was found to be associated with a reduced breast
cancer risk in the recessive model (OR = 0.71, 95% CI: 0.51–0.98, p = 0.039).
Stratification analysis found significant associations between the three SNPs
(rs1059122, rs17748, and rs4809957) and breast cancer risk.
Conclusion:
Our results suggested that rs1059122 (FAM13A), rs17748 (PHLDB1), and
rs4809957 (CYP24A1) might contribute to breast cancer susceptibility in the Chinese
Han population. Future studies with large samples are required to confirm our findings,
as well as functional studies are needed to explore their function in the breast cancer
development.
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Affiliation(s)
- Ying Wei
- Department of Internal Medicine Oncology, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, China
| | - Xiaolin Wang
- Department of General Surgery, The Second Hospital of Yulin City Shaanxi Province, Yulin, Shaanxi 719000, China
| | - Zhe Zhang
- Department of General Surgery, The Second Hospital of Yulin City Shaanxi Province, Yulin, Shaanxi 719000, China
| | - Mingrui Xie
- Department of Internal Medicine Oncology, The Second Hospital of Yulin City Shaanxi Province, Yulin, Shaanxi 719000, China
| | - Yuyao Li
- Department of Internal Medicine Oncology, The Second Hospital of Yulin City Shaanxi Province, Yulin, Shaanxi 719000, China
| | - Hongxin Cao
- Department of Internal Medicine Oncology, The Second Hospital of Yulin City Shaanxi Province, Yulin, Shaanxi 719000, China
| | - Xinhan Zhao
- Department of Internal Medicine Oncology, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, China
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Sun D, Ren X, Ari E, Korcsmaros T, Csermely P, Wu LY. Discovering cooperative biomarkers for heterogeneous complex disease diagnoses. Brief Bioinform 2019; 20:89-101. [PMID: 28968712 DOI: 10.1093/bib/bbx090] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Indexed: 12/13/2022] Open
Abstract
Biomarkers with high reproducibility and accurate prediction performance can contribute to comprehending the underlying pathogenesis of related complex diseases and further facilitate disease diagnosis and therapy. Techniques integrating gene expression profiles and biological networks for the identification of network-based disease biomarkers are receiving increasing interest. The biomarkers for heterogeneous diseases often exhibit strong cooperative effects, which implies that a set of genes may achieve more accurate outcome prediction than any single gene. In this study, we evaluated various biomarker identification methods that consider gene cooperative effects implicitly or explicitly, and proposed the gene cooperation network to explicitly model the cooperative effects of gene combinations. The gene cooperation network-enhanced method, named as MarkRank, achieves superior performance compared with traditional biomarker identification methods in both simulation studies and real data sets. The biomarkers identified by MarkRank not only have a better prediction accuracy but also have stronger topological relationships in the biological network and exhibit high specificity associated with the related diseases. Furthermore, the top genes identified by MarkRank involve crucial biological processes of related diseases and give a good prioritization for known disease genes. In conclusion, MarkRank suggests that explicit modeling of gene cooperative effects can greatly improve biomarker identification for complex diseases, especially for diseases with high heterogeneity.
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Affiliation(s)
- Duanchen Sun
- Academy of Mathematics and Systems Science, Chinese Academy of Sciences, and School of Mathematical Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Xianwen Ren
- Biodynamic Optical Imaging Center, Peking University, Beijing, China
| | - Eszter Ari
- Department of Genetics, Eötvös Loránd University, Budapest
| | - Tamas Korcsmaros
- Institute of Food Research and the Earlham Institute, Norwich, UK
| | - Peter Csermely
- Department of Medical Chemistry, Semmelweis University, Budapest, Hungary
| | - Ling-Yun Wu
- Academy of Mathematics and Systems Science, Chinese Academy of Sciences, and School of Mathematical Sciences, University of Chinese Academy of Sciences, Beijing, China
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37
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Sen A, Stark H. Role of cytochrome P450 polymorphisms and functions in development of ulcerative colitis. World J Gastroenterol 2019; 25:2846-2862. [PMID: 31249444 PMCID: PMC6589734 DOI: 10.3748/wjg.v25.i23.2846] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/26/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
Cytochromes P450s (CYPs) are terminal enzymes in CYP dependent monooxygenases, which constitute a superfamily of enzymes catalysing the metabolism of both endogenous and exogenous substances. One of their main tasks is to facilitate the excretion of these substances and eliminate their toxicities in most phase 1 reactions. Endogenous substrates of CYPs include steroids, bile acids, eicosanoids, cholesterol, vitamin D and neurotransmitters. About 80% of currently used drugs and environmental chemicals comprise exogenous substrates for CYPs. Genetic polymorphisms of CYPs may affect the enzyme functions and have been reported to be associated with various diseases and adverse drug reactions among different populations. In this review, we discuss the role of some critical CYP isoforms (CYP1A1, CYP2D6, CYP2J2, CYP2R1, CYP3A5, CYP3A7, CYP4F3, CYP24A1, CYP26B1 and CYP27B1) in the pathogenesis or aetiology of ulcerative colitis concerning gene polymorphisms. In addition, their significance in metabolism concerning ulcerative colitis in patients is also discussed showing a clear underestimation in genetic studies performed so far.
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Affiliation(s)
- Alaattin Sen
- Department of Molecular Biology and Genetics, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri 38080, Turkey
- Biology Department, Faculty of Arts and Sciences, Pamukkale University, Denizli 20070, Turkey
| | - Holger Stark
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Duesseldorf 40225, Germany
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38
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Wen Y, Zhu C, Li N, Li Z, Cheng Y, Dong J, Zhu M, Wang Y, Dai J, Ma H, Jin G, Dai M, Hu Z, Shen H. Fine Mapping in Chromosome 3q28 Identified Two Variants Associated with Lung Cancer Risk in Asian Population. J Cancer 2019; 10:1862-1869. [PMID: 31205543 PMCID: PMC6547980 DOI: 10.7150/jca.28379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Accepted: 01/20/2019] [Indexed: 11/23/2022] Open
Abstract
Genome-wide association studies (GWASs) have consistently identified chromosome 3q28 as a lung cancer susceptibility region. To further characterize the potential genetic mechanism of the variants in this region, we conducted a fine-mapping study on chromosome 3q28 region. We performed a target resequencing in 200 lung cancer cases and 300 controls in the screening and followed by validation in multi-ethnic lung cancer GWASs with 12,843 cases and 12,639 controls. For our identified novel variants, we conducted expression quantitative trait loci (eQTL) analysis to reveal the potential target genes. Two susceptibility variants were identified (rs4396880: G>A, OR = 0.35, 95%CI: 0.20-0.62, P = 3.01×10-4; and rs3856776: C>T, OR = 2.05, 95%CI: 1.32-3.18, P = 1.49×10-3) and further supported in Asian population (rs4396880: OR = 0.88, P = 7.43×10-6; and rs3856776: OR =1.17, P = 1.64×10-4). The eQTL analysis showed the A allele of rs4396880 was significantly associated with higher mRNA expression of TP63 (P = 1.70×10-4) in lung tissues, while rs3856776 showed significant association with the expression of LEPREL1-AS1 (P = 6.90×10-3), which was the antisense RNA of LEPREL1 and could suppress the translation of LEPREL1. Notably, LEPREL1 was aberrantly downregulated (P = 2.54×10-18) in lung tumor tissues based on TCGA database. In conclusion, this is the first fine-mapping analysis of 3q28 region in Han Chinese, and we found two variants associated with lung cancer susceptibility in Asian population. What's more, rs3856776 was newly identified and might modulate lung cancer susceptibility by suppressing the function of LEPREL1.
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Affiliation(s)
- Yang Wen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chen Zhu
- Zhejiang Provincial Office for Cancer Prevention and Control, Zhejiang Cancer Center/Zhejiang Cancer Hospital, Hangzhou 310004, China
| | - Ni Li
- National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhihua Li
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yang Cheng
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jing Dong
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Meng Zhu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuzhuo Wang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Juncheng Dai
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center of Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Hongxia Ma
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center of Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Guangfu Jin
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center of Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Min Dai
- National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhibin Hu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center of Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Hongbing Shen
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center of Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China
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ZCCHC10 suppresses lung cancer progression and cisplatin resistance by attenuating MDM2-mediated p53 ubiquitination and degradation. Cell Death Dis 2019; 10:414. [PMID: 31138778 PMCID: PMC6538723 DOI: 10.1038/s41419-019-1635-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 05/04/2019] [Accepted: 05/13/2019] [Indexed: 02/08/2023]
Abstract
The activation of p53 tumor suppressor is essential for preventing abnormal cell proliferation and carcinogenesis. ZCCHC10 was previously identified as a potential p53-interacting partner in a yeast two-hybrid screen, but the interaction in cells and its subsequent influence on p53 activity and cancer development have not been investigated. In this paper, we demonstrate that ZCCHC10 expression levels are statistically lower in lung adenocarcinoma tissues than the corresponding adjacent noncancerous tissues, and decreased expression of ZCCHC10 mRNA predicts poorer survival of the patients. Ectopic expression of ZCCHC10 in lung cancer cells harboring wild-type p53 dramatically suppresses cell proliferation, colony formation, migration, invasion and cisplatin resistance in vitro, as well as tumor growth and metastasis in vivo. Conversely, knockdown of ZCCHC10 exerts opposite effects in the normal lung cell Beas-2b. However, ZCCHC10 has no influence on the biological behaviors of p53-null (H358) or p53-mutant (H1437) lung cancer cells. Mechanistically, ZCCHC10 binds and stabilizes p53 by disrupting the interaction between p53 and MDM2. The p53 inhibitor pifithrin-α attenuated the influences of ZCCHC10 overexpression on p53 pathway, cell cycle, apoptosis, and epithelial-mesenchymal transition, whereas the p53 activator Nutlin3 could reverse the effects of ZCCHC10 knockdown. Collectively, our results indicate that ZCCHC10 exerts its tumor-suppressive effects by stabilizing the p53 protein and can be used a potential prognostic marker and therapeutic target in lung adenocarcinoma.
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Shao L, Zuo X, Yang Y, Zhang Y, Yang N, Shen B, Wang J, Wang X, Li R, Jin G, Yu D, Chen Y, Sun L, Li Z, Fu Q, Hu Z, Han X, Song X, Shen H, Sun Y. The inherited variations of a p53-responsive enhancer in 13q12.12 confer lung cancer risk by attenuating TNFRSF19 expression. Genome Biol 2019; 20:103. [PMID: 31126313 PMCID: PMC6533720 DOI: 10.1186/s13059-019-1696-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Accepted: 04/22/2019] [Indexed: 12/20/2022] Open
Abstract
Background Inherited factors contribute to lung cancer risk, but the mechanism is not well understood. Defining the biological consequence of GWAS hits in cancers is a promising strategy to elucidate the inherited mechanisms of cancers. The tag-SNP rs753955 (A>G) in 13q12.12 is highly associated with lung cancer risk in the Chinese population. Here, we systematically investigate the biological significance and the underlying mechanism behind 13q12.12 risk locus in vitro and in vivo. Results We characterize a novel p53-responsive enhancer with lung tissue cell specificity in a 49-kb high linkage disequilibrium block of rs753955. This enhancer harbors 3 highly linked common inherited variations (rs17336602, rs4770489, and rs34354770) and six p53 binding sequences either close to or located between the variations. The enhancer effectively protects normal lung cell lines against pulmonary carcinogen NNK-induced DNA damages and malignant transformation by upregulating TNFRSF19 through chromatin looping. These variations significantly weaken the enhancer activity by affecting its p53 response, especially when cells are exposed to NNK. The effect of the mutant enhancer alleles on TNFRSF19 target gene in vivo is supported by expression quantitative trait loci analysis of 117 Chinese NSCLC samples and GTEx data. Differentiated expression of TNFRSF19 and its statistical significant correlation with tumor TNM staging and patient survival indicate a suppressor role of TNFRSF19 in lung cancer. Conclusion This study provides evidence of how the inherited variations in 13q12.12 contribute to lung cancer risk, highlighting the protective roles of the p53-responsive enhancer-mediated TNFRSF19 activation in lung cells under carcinogen stress. Electronic supplementary material The online version of this article (10.1186/s13059-019-1696-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Lipei Shao
- Key laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211126, China.,Department of Cell Biology, Nanjing Medical University, Nanjing, 211126, China
| | - Xianglin Zuo
- Key laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211126, China.,Department of Cell Biology, Nanjing Medical University, Nanjing, 211126, China
| | - Yin Yang
- Key laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211126, China.,Department of Cell Biology, Nanjing Medical University, Nanjing, 211126, China
| | - Yu Zhang
- Key laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211126, China.,Department of Cell Biology, Nanjing Medical University, Nanjing, 211126, China
| | - Nan Yang
- Key laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211126, China
| | - Bin Shen
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211126, China
| | - Jianying Wang
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211126, China
| | - Xuchun Wang
- Key laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211126, China.,Department of Cell Biology, Nanjing Medical University, Nanjing, 211126, China
| | - Ruilei Li
- Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650000, Yunnan, China
| | - Guangfu Jin
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211126, China.,Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center, Nanjing Medical University, Nanjing, 211126, China
| | - Dawei Yu
- Key laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211126, China.,Department of Cell Biology, Nanjing Medical University, Nanjing, 211126, China
| | - Yuan Chen
- Key laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211126, China.,Department of Cell Biology, Nanjing Medical University, Nanjing, 211126, China
| | - Luan Sun
- Key laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211126, China.,Department of Cell Biology, Nanjing Medical University, Nanjing, 211126, China
| | - Zhen Li
- Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650000, Yunnan, China
| | - Qiaofen Fu
- Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650000, Yunnan, China
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211126, China.,Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center, Nanjing Medical University, Nanjing, 211126, China
| | - Xiao Han
- Key laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211126, China
| | - Xin Song
- Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650000, Yunnan, China.
| | - Hongbin Shen
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211126, China. .,Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center, Nanjing Medical University, Nanjing, 211126, China.
| | - Yujie Sun
- Key laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211126, China. .,Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center, Nanjing Medical University, Nanjing, 211126, China. .,Department of Cell Biology, Nanjing Medical University, Nanjing, 211126, China.
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Precision oncology of lung cancer: genetic and genomic differences in Chinese population. NPJ Precis Oncol 2019; 3:14. [PMID: 31069257 PMCID: PMC6499836 DOI: 10.1038/s41698-019-0086-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 03/15/2019] [Indexed: 02/07/2023] Open
Abstract
Knowledge of the lung cancer genome has experienced rapid growth over the past decade. Genome-wide association studies and sequencing studies have identified dozens of genetic variants and somatic mutations implicated in the development of lung cancer in both Chinese and Caucasian populations. With the accumulating evidence, heterogeneities in lung cancer susceptibility were observed in different ethnicities. In this review, the progress on germline-based genetic variants and somatic-based genomic mutations associated with lung cancer and the differences between Chinese and Caucasian populations were systematically summarized. In the analysis of the genetic predisposition to lung cancer, 6 susceptibility loci were shared by Chinese and Caucasian populations (3q28, 5p15, 6p21, 9p21.3, 12q13.13 and 15q25), 14 loci were specific to the Chinese population (1p36.32, 5q31.1, 5q32, 6p21.1, 6q22.2, 6p21.32, 7p15.3, 10p14, 10q25.2, 12q23.1, 13q22, 17q24.3, 20q13.2, and 22q12), and 12 loci were specific to the Caucasian population (1p31.1, 2q32.1, 6q27, 8p21.1, 8p12, 10q24.3, 11q23.3, 12p13.33, 13q13.1, 15q21.1, 20q13.33 and 22q12.1). In the analysis of genomic and somatic alterations, different mutation rates were observed for EGFR (Chinese: 39–59% vs. TCGA: 14%), KRAS (Chinese: 7–11% vs. TCGA: 31%), TP53 (Chinese: 44% vs. TCGA: 53%), CDKN2A (Chinese: 22% vs. TCGA: 15%), NFE2L2 (Chinese: 28% vs. TCGA: 17%), STK11 (Chinese: 4–7% vs. TCGA: 16%), KEAP1 (Chinese: 3–5% vs. TCGA: 18%), and NF1 (Chinese: <2% vs. TCGA: 12%). In addition, frequently amplified regions encompassing genes involved in cytoskeletal organization or focal adhesion were identified only in Chinese patients. These results provide a comprehensive description of the genetic and genomic differences in lung cancer susceptibility between Chinese and Caucasian populations and may contribute to the development of precision medicine for lung cancer treatment and prevention.
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42
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Gruzieva O, Xu CJ, Yousefi P, Relton C, Merid SK, Breton CV, Gao L, Volk HE, Feinberg JI, Ladd-Acosta C, Bakulski K, Auffray C, Lemonnier N, Plusquin M, Ghantous A, Herceg Z, Nawrot TS, Pizzi C, Richiardi L, Rusconi F, Vineis P, Kogevinas M, Felix JF, Duijts L, den Dekker HT, Jaddoe VWV, Ruiz JL, Bustamante M, Antó JM, Sunyer J, Vrijheid M, Gutzkow KB, Grazuleviciene R, Hernandez-Ferrer C, Annesi-Maesano I, Lepeule J, Bousquet J, Bergström A, Kull I, Söderhäll C, Kere J, Gehring U, Brunekreef B, Just AC, Wright RJ, Peng C, Gold DR, Kloog I, DeMeo DL, Pershagen G, Koppelman GH, London SJ, Baccarelli AA, Melén E. Prenatal Particulate Air Pollution and DNA Methylation in Newborns: An Epigenome-Wide Meta-Analysis. ENVIRONMENTAL HEALTH PERSPECTIVES 2019; 127:57012. [PMID: 31148503 PMCID: PMC6792178 DOI: 10.1289/ehp4522] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 05/02/2019] [Accepted: 05/06/2019] [Indexed: 05/22/2023]
Abstract
BACKGROUND Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes. OBJECTIVES We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter [Formula: see text] ([Formula: see text]) or [Formula: see text] ([Formula: see text]) and DNA methylation in newborns and children. METHODS We meta-analyzed associations between exposure to [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression. RESULTS Six CpGs were significantly associated [false discovery rate (FDR) [Formula: see text]] with prenatal [Formula: see text] and 14 with [Formula: see text] exposure. Two of the [Formula: see text] CpGs mapped to FAM13A (cg00905156) and NOTCH4 (cg06849931) previously associated with lung function and asthma. Although these associations did not replicate in the smaller newborn sample, both CpGs were significant ([Formula: see text]) in 7- to 9-y-olds. For cg06849931, however, the direction of the association was inconsistent. Concurrent [Formula: see text] exposure was associated with a significantly higher NOTCH4 expression at age 16 y. We also identified several DMRs associated with either prenatal [Formula: see text] and or [Formula: see text] exposure, of which two [Formula: see text] DMRs, including H19 and MARCH11, replicated in newborns. CONCLUSIONS Several differentially methylated CpGs and DMRs associated with prenatal PM exposure were identified in newborns, with annotation to genes previously implicated in lung-related outcomes. https://doi.org/10.1289/EHP4522.
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Affiliation(s)
- Olena Gruzieva
- 1 Institute of Environmental Medicine, Karolinska Institutet , Stockholm, Sweden
- 2 Centre for Occupational and Environmental Medicine, Stockholm County Council , Stockholm, Sweden
| | - Cheng-Jian Xu
- 3 Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen , Netherlands
- 4 Department of Pediatric Pulmonology and Pediatric Allergology, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Netherlands
- 5 Department of Genetics, University Medical Center Groningen, University of Groningen , Netherlands
| | - Paul Yousefi
- 6 MRC Integrative Epidemiology Unit, University of Bristol , Bristol, UK
- 7 Population Health Sciences, Bristol Medical School, University of Bristol , Bristol, UK
| | - Caroline Relton
- 6 MRC Integrative Epidemiology Unit, University of Bristol , Bristol, UK
- 7 Population Health Sciences, Bristol Medical School, University of Bristol , Bristol, UK
| | - Simon Kebede Merid
- 1 Institute of Environmental Medicine, Karolinska Institutet , Stockholm, Sweden
| | - Carrie V Breton
- 8 Department of Preventive Medicine, University of Southern California Los Angeles , Los Angeles, California, USA
| | - Lu Gao
- 8 Department of Preventive Medicine, University of Southern California Los Angeles , Los Angeles, California, USA
| | - Heather E Volk
- 9 Department of Mental Health, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland, USA
- 10 Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland, USA
| | - Jason I Feinberg
- 9 Department of Mental Health, Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland, USA
| | - Christine Ladd-Acosta
- 11 Department of Epidemiology, School of Public Health, University of Michigan , Ann Arbor, Michigan, USA
| | - Kelly Bakulski
- 11 Department of Epidemiology, School of Public Health, University of Michigan , Ann Arbor, Michigan, USA
| | - Charles Auffray
- 12 European Institute for Systems Biology and Medicine (EISBM), CNRS-ENS-UCBL, Université de Lyon , Lyon, France
| | - Nathanaël Lemonnier
- 12 European Institute for Systems Biology and Medicine (EISBM), CNRS-ENS-UCBL, Université de Lyon , Lyon, France
- 13 Institute for Advanced Biosciences, UGA-Institut national de la santé et de la recherché médicale (Inserm) , La Tronche, France
| | - Michelle Plusquin
- 14 Centre for Environmental Sciences, Hasselt University , Diepenbeek, Belgium
- 15 MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London , London, UK
| | - Akram Ghantous
- 16 Epigenetics Group, International Agency for Research on Cancer, Lyon, France
| | - Zdenko Herceg
- 16 Epigenetics Group, International Agency for Research on Cancer, Lyon, France
| | - Tim S Nawrot
- 14 Centre for Environmental Sciences, Hasselt University , Diepenbeek, Belgium
- 17 Department of Public Health & Primary Care, Leuven University , Leuven, Belgium
| | - Costanza Pizzi
- 18 Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin and CPO-Piemonte , Turin, Italy
| | - Lorenzo Richiardi
- 18 Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin and CPO-Piemonte , Turin, Italy
| | - Franca Rusconi
- 19 Unit of Epidemiology, Meyer Children's University Hospital , Florence, Italy
| | - Paolo Vineis
- 15 MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London , London, UK
| | - Manolis Kogevinas
- 20 Barcelona Institute for Global Health (ISGlobal) , Barcelona, Spain
- 22 CIBER Epidemiología y Salud Pública (CIBERESP) , Madrid, Spain
| | - Janine F Felix
- 23 Generation R Study Group, Erasmus MC (Medical Centre) , University Medical Center Rotterdam , Rotterdam, Netherlands
- 25 Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, Netherlands
| | - Liesbeth Duijts
- 23 Generation R Study Group, Erasmus MC (Medical Centre) , University Medical Center Rotterdam , Rotterdam, Netherlands
- 26 Department of Pediatrics, Divisions of Respiratory Medicine and Allergology, and Neonatology, Erasmus MC, University Medical Center , Rotterdam, Netherlands
| | - Herman T den Dekker
- 23 Generation R Study Group, Erasmus MC (Medical Centre) , University Medical Center Rotterdam , Rotterdam, Netherlands
- 25 Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, Netherlands
| | - Vincent W V Jaddoe
- 23 Generation R Study Group, Erasmus MC (Medical Centre) , University Medical Center Rotterdam , Rotterdam, Netherlands
- 25 Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam , Rotterdam, Netherlands
| | - José L Ruiz
- 27 Center for Genomic Regulation (CRG) , Barcelona, Spain
- 28 Instituto de Parasitología y Biomedicina López-Neyra (IPBLN), Spanish National Research Council (CSIC) , Armilla, Granada, Spain
| | - Mariona Bustamante
- 20 Barcelona Institute for Global Health (ISGlobal) , Barcelona, Spain
- 22 CIBER Epidemiología y Salud Pública (CIBERESP) , Madrid, Spain
- 27 Center for Genomic Regulation (CRG) , Barcelona, Spain
| | - Josep Maria Antó
- 20 Barcelona Institute for Global Health (ISGlobal) , Barcelona, Spain
- 22 CIBER Epidemiología y Salud Pública (CIBERESP) , Madrid, Spain
- 29 Hospital de Mar Medical Research Institute (IMIM) , Barcelona, Spain
| | - Jordi Sunyer
- 20 Barcelona Institute for Global Health (ISGlobal) , Barcelona, Spain
- 22 CIBER Epidemiología y Salud Pública (CIBERESP) , Madrid, Spain
- 29 Hospital de Mar Medical Research Institute (IMIM) , Barcelona, Spain
| | - Martine Vrijheid
- 20 Barcelona Institute for Global Health (ISGlobal) , Barcelona, Spain
- 22 CIBER Epidemiología y Salud Pública (CIBERESP) , Madrid, Spain
| | | | - Regina Grazuleviciene
- 31 Department of Environmental Sciences, Vytauto Didziojo Universitetas , Kaunas, Lithuania
| | - Carles Hernandez-Ferrer
- 20 Barcelona Institute for Global Health (ISGlobal) , Barcelona, Spain
- 32 Computational Health Informatics Program , Boston Children's Hospital , Boston, Massachusetts, USA
| | - Isabella Annesi-Maesano
- 33 Epidemiology of Allergic and Respiratory Diseases Department, IPLESP, Inserm and Sorbonne University Medical School Saint-Antoine , Paris, France
| | - Johanna Lepeule
- 34 Université Grenoble Alpes, Inserm, National Institute of Health & Medical Research, CNRS, IAB , Grenoble, France
| | - Jean Bousquet
- 35 Innovation Partnership on Active and Healthy Ageing Reference Site, MACVIA-France (Contre les Maladies Chroniques pour un Vieillissement Actif en France European) , Montpellier, France
- 36 U 1168, VIMA: Ageing and Chronic Diseases Epidemiological and Public Health Approaches, Inserm Villejuif, Université Versailles St-Quentin-en-Yvelines , Montigny le Bretonneux, France
| | - Anna Bergström
- 1 Institute of Environmental Medicine, Karolinska Institutet , Stockholm, Sweden
- 2 Centre for Occupational and Environmental Medicine, Stockholm County Council , Stockholm, Sweden
| | - Inger Kull
- 1 Institute of Environmental Medicine, Karolinska Institutet , Stockholm, Sweden
- 37 Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet , Stockholm, Sweden
- 38 Sachs Children's Hospital , Stockholm, Sweden
| | - Cilla Söderhäll
- 39 Department of Women's and Children's Health, Karolinska Institutet , Stockholm, Sweden
- 40 Department of Biosciences and Nutrition, Karolinska Institutet , Stockholm, Sweden
| | - Juha Kere
- 40 Department of Biosciences and Nutrition, Karolinska Institutet , Stockholm, Sweden
- 42 School of Basic and Medical Biosciences, King's College London, Guy's Hospital , London, UK
| | - Ulrike Gehring
- 44 Institute for Risk Assessment Sciences, Utrecht University , Utrecht, Netherlands
| | - Bert Brunekreef
- 44 Institute for Risk Assessment Sciences, Utrecht University , Utrecht, Netherlands
- 45 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University , Utrecht, Netherlands
| | - Allan C Just
- 46 Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai , New York, USA
| | - Rosalind J Wright
- 47 Department of Pediatrics, Icahn School of Medicine at Mount Sinai , New York, USA
| | - Cheng Peng
- 48 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts, USA
| | - Diane R Gold
- 48 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts, USA
- 49 Department of Environmental Health, Harvard T.H. Chan School of Public Health , Boston, Massachusetts, USA
| | - Itai Kloog
- 50 Department of Geography and Environmental Development, Ben-Gurion University of the Negev , Beer Sheva, Israel
| | - Dawn L DeMeo
- 48 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts, USA
| | - Göran Pershagen
- 1 Institute of Environmental Medicine, Karolinska Institutet , Stockholm, Sweden
- 2 Centre for Occupational and Environmental Medicine, Stockholm County Council , Stockholm, Sweden
| | - Gerard H Koppelman
- 3 Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen , Netherlands
- 4 Department of Pediatric Pulmonology and Pediatric Allergology, University Medical Center Groningen, Beatrix Children's Hospital, University of Groningen , Netherlands
| | - Stephanie J London
- 51 National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), U.S. Department of Health and Human Services , Research Triangle Park, North Carolina, USA
| | - Andrea A Baccarelli
- 52 Department of Environmental Health Sciences, Columbia University Mailman School of Public Health , New York, USA
| | - Erik Melén
- 1 Institute of Environmental Medicine, Karolinska Institutet , Stockholm, Sweden
- 38 Sachs Children's Hospital , Stockholm, Sweden
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Lorenzo-González M, Fernández-Villar A, Ruano-Ravina A. Disentangling tobacco-related lung cancer-genome-wide interaction study of smoking behavior and non-small cell lung cancer risk. J Thorac Dis 2019; 11:10-13. [PMID: 30863557 DOI: 10.21037/jtd.2018.11.29] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Affiliation(s)
- María Lorenzo-González
- Service of Preventive Medicine, University Hospital Complex of Ourense, Ourense, Spain.,Department of Preventive Medicine and Public Health, University of Santiago de Compostela, A Coruña, Spain
| | - Alberto Fernández-Villar
- Service of Neumology, University Hospital Complex of Vigo, Vigo, Spain.,Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Spain
| | - Alberto Ruano-Ravina
- Department of Preventive Medicine and Public Health, University of Santiago de Compostela, A Coruña, Spain.,CIBER de Epidemiología y Salud Pública CIBERESP, CIBERESP, Spain.,Department of Epidemiology, Brown School of Public Health, Brown University, Providence, Rhode Island, USA
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44
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Wang X, Yang X, Li J, Liu F, Chen J, Liu X, Cao J, Shen C, Yu L, Lu F, Wu X, Zhao L, Wu X, Li Y, Hu D, Huang J, Lu X, Gu D. Impact of healthy lifestyles on cancer risk in the Chinese population. Cancer 2019; 125:2099-2106. [PMID: 30748010 DOI: 10.1002/cncr.31971] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 12/06/2018] [Accepted: 12/17/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Xinyan Wang
- Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Xueli Yang
- Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Jianxin Li
- Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Fangchao Liu
- Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Jichun Chen
- Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Xiaoqing Liu
- Division of Epidemiology Guangdong Provincial People’s Hospital and Cardiovascular Institute Guangzhou China
| | - Jie Cao
- Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Chong Shen
- Department of Epidemiology and Biostatistics, School of Public Health Nanjing Medical University Nanjing China
| | - Ling Yu
- Department of Cardiology Fujian Provincial People’s Hospital Fuzhou China
| | - Fanghong Lu
- Cardio‐Cerebrovascular Control and Research Center Institute of Basic Medicine, Shandong Academy of Medical Sciences Jinan China
| | - Xianping Wu
- Sichuan Center for Disease Control and Prevention Chengdu China
| | - Liancheng Zhao
- Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Xigui Wu
- Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Ying Li
- Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Dongsheng Hu
- Department of Prevention Medicine Shenzhen University School of Medicine Shenzhen China
| | - Jianfeng Huang
- Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Xiangfeng Lu
- Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
| | - Dongfeng Gu
- Key Laboratory of Cardiovascular Epidemiology & Department of Epidemiology Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
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45
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Qu R, Li X, Quan X, Xia L, Fang X, Li H, Zhou B. Polymorphism in CYP24A1 Is Associated with Lung Cancer Risk: A Case-Control Study in Chinese Female Nonsmokers. DNA Cell Biol 2019; 38:243-249. [PMID: 30724597 DOI: 10.1089/dna.2018.4510] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
CYP24A1 plays important roles in antiproliferative effects, which have been proved in many human tumor cells. Polymorphisms in CYP24A1 may affect the risk of lung cancer, but the results remained inconclusive. To enhance the understanding of possible relationship between CYP24A1 polymorphism rs6068816 and lung cancer risks, we first carried out this case-control study among Chinese female nonsmokers, including 345 lung cancer patients and 351 noncancer controls. Our results revealed that individuals carrying CT and CC genotype were associated with decreasing lung cancer risk (adjusted odds ratios were 0.71 and 0.59, and 95% confidence intervals were 0.52-0.97 and 0.35-0.99, p-values were 0.031 and 0.048, respectively). Patients carrying allele-T showed lower hazard risks, especially in adenocarcinoma and advanced stage cancers. We also found that subjects with allele-T showed a relatively low risk of lung cancer when they were exposed to oil fume. But neither additive scale nor multiplicative scale revealed interactions between allele-T and environmental exposures, including oil fume, coal fuel fume, and passive smoking. Overall, these findings indicated that CYP24A1 polymorphism rs6068816 could be significantly associated with susceptibility of lung cancer in Chinese female nonsmokers.
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Affiliation(s)
- Ruoyi Qu
- 1 Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China.,2 Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, P.R. China
| | - Xuelian Li
- 1 Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China.,2 Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, P.R. China
| | - Xiaowei Quan
- 1 Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China.,2 Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, P.R. China
| | - Lingzi Xia
- 1 Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China.,2 Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, P.R. China
| | - Xue Fang
- 1 Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China.,2 Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, P.R. China
| | - Hang Li
- 1 Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China.,2 Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, P.R. China
| | - Baosen Zhou
- 1 Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China.,2 Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, P.R. China
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46
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Mousavi SE, Amini H, Heydarpour P, Amini Chermahini F, Godderis L. Air pollution, environmental chemicals, and smoking may trigger vitamin D deficiency: Evidence and potential mechanisms. ENVIRONMENT INTERNATIONAL 2019; 122:67-90. [PMID: 30509511 DOI: 10.1016/j.envint.2018.11.052] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/20/2018] [Accepted: 11/21/2018] [Indexed: 06/09/2023]
Abstract
Beyond vitamin D (VD) effect on bone homeostasis, numerous physiological functions in human health have been described for this versatile prohormone. In 2016, 95% of the world's population lived in areas where annual mean ambient particulate matter (<2.5 μm) levels exceeded the World Health Organization guideline value (Shaddick et al., 2018). On the other hand, industries disperse thousands of chemicals continually into the environment. Further, considerable fraction of populations are exposed to tobacco smoke. All of these may disrupt biochemical pathways and cause detrimental consequences, such as VD deficiency (VDD). In spite of the remarkable number of studies conducted on the role of some of the above mentioned exposures on VDD, the literature suffers from two main shortcomings: (1) an overview of the impacts of environmental exposures on the levels of main VD metabolites, and (2) credible engaged mechanisms in VDD because of those exposures. To summarize explanations for these unclear topics, we conducted the present review, using relevant keywords in the PubMed database, to investigate the adverse effects of exposure to air pollution, some environmental chemicals, and smoking on the VD metabolism, and incorporate relevant potential pathways disrupting VD endocrine system (VDES) leading to VDD. Air pollution may lead to the reduction of VD cutaneous production either directly by blocking ultraviolet B photons or indirectly by decreasing outdoor activity. Heavy metals may reduce VD serum levels by increasing renal tubular dysfunction, as well as downregulating the transcription of cytochrome P450 mixed-function oxidases (CYPs). Endocrine-disrupting chemicals (EDCs) may inhibit the activity and expression of CYPs, and indirectly cause VDD through weight gain and dysregulation of thyroid hormone, parathyroid hormone, and calcium homeostasis. Smoking through several pathways decreases serum 25(OH)D and 1,25(OH)2D levels, VD intake from diet, and the cutaneous production of VD through skin aging. In summary, disturbance in the cutaneous production of cholecalciferol, decreased intestinal intake of VD, the modulation of genes involved in VD homeostasis, and decreased local production of calcitriol in target tissues are the most likely mechanisms that involve in decreasing the serum VD levels.
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Affiliation(s)
- Sayed Esmaeil Mousavi
- Department of Water and Wastewater Treatment, Water and Wastewater Consulting Engineers (Design & Research), Isfahan, Iran; Social Health Determinants Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran.
| | - Heresh Amini
- Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, United States; Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland
| | - Pouria Heydarpour
- MS Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Amini Chermahini
- Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Lode Godderis
- Centre for Environment and Health, Department of Public Health and Primary Care, University of Leuven (KU, Leuven), Belgium; IDEWE, External Service for Prevention at Protection at Work, Heverlee, Belgium
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47
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Noronha V, Rajendra A, Joshi A, Patil V, Menon N, Prabhash K. Epidermal growth factor receptor-mutated non-small-cell lung cancer: A primer on contemporary management. CANCER RESEARCH, STATISTICS, AND TREATMENT 2019. [DOI: 10.4103/crst.crst_51_19] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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48
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Duan W, Zhang R, Zhao Y, Shen S, Wei Y, Chen F, Christiani DC. Bayesian variable selection for parametric survival model with applications to cancer omics data. Hum Genomics 2018; 12:49. [PMID: 30400837 PMCID: PMC6218990 DOI: 10.1186/s40246-018-0179-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 10/07/2018] [Indexed: 12/15/2022] Open
Abstract
Background Modeling thousands of markers simultaneously has been of great interest in testing association between genetic biomarkers and disease or disease-related quantitative traits. Recently, an expectation-maximization (EM) approach to Bayesian variable selection (EMVS) facilitating the Bayesian computation was developed for continuous or binary outcome using a fast EM algorithm. However, it is not suitable to the analyses of time-to-event outcome in many public databases such as The Cancer Genome Atlas (TCGA). Results We extended the EMVS to high-dimensional parametric survival regression framework (SurvEMVS). A variant of cyclic coordinate descent (CCD) algorithm was used for efficient iteration in M-step, and the extended Bayesian information criteria (EBIC) was employed to make choice on hyperparameter tuning. We evaluated the performance of SurvEMVS using numeric simulations and illustrated the effectiveness on two real datasets. The results of numerical simulations and two real data analyses show the well performance of SurvEMVS in aspects of accuracy and computation. Some potential markers associated with survival of lung or stomach cancer were identified. Conclusions These results suggest that our model is effective and can cope with high-dimensional omics data. Electronic supplementary material The online version of this article (10.1186/s40246-018-0179-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Weiwei Duan
- Department of Biostatistics, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,China International Cooperation Center for Environment and Human Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,Joint Laboratory of Health and Environmental Risk Assessment (HERA), Nanjing Medical University School of Public Health / Harvard School of Public Health, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,Key Laboratory of Biomedical Big Data of Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Ruyang Zhang
- Department of Biostatistics, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,China International Cooperation Center for Environment and Human Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,Joint Laboratory of Health and Environmental Risk Assessment (HERA), Nanjing Medical University School of Public Health / Harvard School of Public Health, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,Key Laboratory of Biomedical Big Data of Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Yang Zhao
- Department of Biostatistics, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,China International Cooperation Center for Environment and Human Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,Joint Laboratory of Health and Environmental Risk Assessment (HERA), Nanjing Medical University School of Public Health / Harvard School of Public Health, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,Key Laboratory of Biomedical Big Data of Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Sipeng Shen
- Department of Biostatistics, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,China International Cooperation Center for Environment and Human Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,Joint Laboratory of Health and Environmental Risk Assessment (HERA), Nanjing Medical University School of Public Health / Harvard School of Public Health, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,Key Laboratory of Biomedical Big Data of Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Yongyue Wei
- Department of Biostatistics, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,China International Cooperation Center for Environment and Human Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,Joint Laboratory of Health and Environmental Risk Assessment (HERA), Nanjing Medical University School of Public Health / Harvard School of Public Health, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,Key Laboratory of Biomedical Big Data of Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China
| | - Feng Chen
- Department of Biostatistics, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China. .,China International Cooperation Center for Environment and Human Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China. .,Joint Laboratory of Health and Environmental Risk Assessment (HERA), Nanjing Medical University School of Public Health / Harvard School of Public Health, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China. .,Key Laboratory of Biomedical Big Data of Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.
| | - David C Christiani
- China International Cooperation Center for Environment and Human Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,Joint Laboratory of Health and Environmental Risk Assessment (HERA), Nanjing Medical University School of Public Health / Harvard School of Public Health, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.,Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA.,Pulmonary and Critical Care Division, Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, MA, 02114, USA
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49
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The forty years of medical genetics in China. J Genet Genomics 2018; 45:569-582. [PMID: 30459119 DOI: 10.1016/j.jgg.2018.10.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 10/31/2018] [Indexed: 02/06/2023]
Abstract
Medical genetics is the newest cutting-edge discipline that focuses on solving medical problems using genetics knowledge and methods. In China, medical genetics research activities initiated from a poor inner basis but a prosperous outer environment. During the 40 years of reform and opening-up policy, Chinese scientists contributed significantly in the field of medical genetics, garnering considerable attention worldwide. In this review, we highlight the significant findings and/or results discovered by Chinese scientists in monogenic diseases, complex diseases, cancer, genetic diagnosis, as well as gene manipulation and gene therapy. Due to these achievements, China is widely recognized to be at the forefront of medical genetics research and development. However, the significant progress and development that has been achieved could not have been accomplished without sufficient funding and a well-constructed logistics network. The successful implementation of translational and precise medicine sourced from medical genetics will depend on an open ethics policy and intellectual property protection, along with strong support at the national industry level.
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50
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Yang C, Stueve TR, Yan C, Rhie SK, Mullen DJ, Luo J, Zhou B, Borok Z, Marconett CN, Offringa IA. Positional integration of lung adenocarcinoma susceptibility loci with primary human alveolar epithelial cell epigenomes. Epigenomics 2018; 10:1167-1187. [PMID: 30212242 PMCID: PMC6391636 DOI: 10.2217/epi-2018-0003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 05/10/2018] [Indexed: 01/12/2023] Open
Abstract
AIM To identify functional lung adenocarcinoma (LUAD) risk SNPs. MATERIALS & METHODS Eighteen validated LUAD risk SNPs (p ≤ 5 × 10-8) and 930 SNPs in high linkage disequilibrium (r2 > 0.5) were integrated with epigenomic information from primary human alveolar epithelial cells. Enhancer-associated SNPs likely affecting transcription factor-binding sites were predicted. Three SNPs were functionally investigated using luciferase assays, expression quantitative trait loci and cancer-specific expression. RESULTS Forty-seven SNPs mapped to putative enhancers; 11 located to open chromatin. Of these, seven altered predicted transcription factor-binding motifs. Rs6942067 showed allele-specific luciferase expression and expression quantitative trait loci analysis indicates that it influences expression of DCBLD1, a gene that encodes an unknown membrane protein and is overexpressed in LUAD. CONCLUSION Integration of candidate LUAD risk SNPS with epigenomic marks from normal alveolar epithelium identified numerous candidate functional LUAD risk SNPs including rs6942067, which appears to affect DCBLD1 expression. Data deposition: Data are provided in GEO record GSE84273.
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Affiliation(s)
- Chenchen Yang
- Department of Surgery, University of Southern California, CA 90089, USA
- Department of Biochemistry & Molecular Medicine, University of Southern California, CA 90089, USA
- Norris Comprehensive Cancer Center, University of Southern California, CA 90089, USA
| | - Theresa Ryan Stueve
- Department of Surgery, University of Southern California, CA 90089, USA
- Department of Biochemistry & Molecular Medicine, University of Southern California, CA 90089, USA
- Norris Comprehensive Cancer Center, University of Southern California, CA 90089, USA
- Department of Preventive Medicine, University of Southern California, CA 90089, USA
| | - Chunli Yan
- Department of Surgery, University of Southern California, CA 90089, USA
- Department of Biochemistry & Molecular Medicine, University of Southern California, CA 90089, USA
- Norris Comprehensive Cancer Center, University of Southern California, CA 90089, USA
| | - Suhn K Rhie
- Department of Surgery, University of Southern California, CA 90089, USA
- Department of Biochemistry & Molecular Medicine, University of Southern California, CA 90089, USA
- Norris Comprehensive Cancer Center, University of Southern California, CA 90089, USA
| | - Daniel J Mullen
- Department of Surgery, University of Southern California, CA 90089, USA
- Department of Biochemistry & Molecular Medicine, University of Southern California, CA 90089, USA
- Norris Comprehensive Cancer Center, University of Southern California, CA 90089, USA
| | - Jiao Luo
- Department of Biochemistry & Molecular Medicine, University of Southern California, CA 90089, USA
- Department of Medicine, Division of Pulmonary & Critical Care & Sleep Medicine, University of Southern California, CA 90089, USA
| | - Beiyun Zhou
- Norris Comprehensive Cancer Center, University of Southern California, CA 90089, USA
- Department of Medicine, Division of Pulmonary & Critical Care & Sleep Medicine, University of Southern California, CA 90089, USA
- Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, CA 90089, USA
| | - Zea Borok
- Department of Biochemistry & Molecular Medicine, University of Southern California, CA 90089, USA
- Norris Comprehensive Cancer Center, University of Southern California, CA 90089, USA
- Department of Medicine, Division of Pulmonary & Critical Care & Sleep Medicine, University of Southern California, CA 90089, USA
- Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, CA 90089, USA
| | - Crystal N Marconett
- Department of Surgery, University of Southern California, CA 90089, USA
- Department of Biochemistry & Molecular Medicine, University of Southern California, CA 90089, USA
- Norris Comprehensive Cancer Center, University of Southern California, CA 90089, USA
| | - Ite A Offringa
- Department of Surgery, University of Southern California, CA 90089, USA
- Department of Biochemistry & Molecular Medicine, University of Southern California, CA 90089, USA
- Norris Comprehensive Cancer Center, University of Southern California, CA 90089, USA
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