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Zeng F, Chen S, Zhu X, Chen J, Lan M, Chen R, Zhang D, Chen C, Huang S, Li D, Zhang X, Bai F. Analysis of the effect of fecal SDC2, ADHFE1 and PPP2R5C gene methylation test for screening colorectal cancer in the Otog Front Banner. BMC Gastroenterol 2025; 25:324. [PMID: 40307680 PMCID: PMC12042555 DOI: 10.1186/s12876-025-03737-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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 02/26/2025] [Indexed: 05/02/2025] Open
Abstract
OBJECTIVE The incidence of colorectal cancer (CRC) is gradually increasing, making the prevention and early detection of CRC a global priority. The purpose of this study is to evaluate the effect of fecal SDC2, ADHFE1, and PPP2R5C gene methylation on the screening of early CRC in the Otog Front Banner. METHODS This is a retrospective study that collected and analyzed data from the early colorectal cancer screening program conducted in five community health centers in the Otog Front Banner, from January 2023 to October 2023. The study collected stool samples from subjects meeting the inclusion and exclusion criteria, extracted genomic DNA from the feces, and modified it with sulfite. Methylation-specific polymerase chain reaction (MSP) was then used to detect the methylation status of the SDC2, PPP2R5C, and ADHFE1 genes, completing the early screening for colorectalcancer. Individuals with positive screening outcomes were advised to undergo a colonoscopy, and ultimately, all participants completed the questionnaire on high-risk factors for colorectal cancer . The chi-square test was utilized to analyze the positive rates of fecal SDC2, ADHFE1, and PPP2R5C gene methylation screenings, colonoscopy compliance, the positive predictive value of intestinal lesions, and to assess the risk factors associated with cancer. RESULTS A total of 9,135 effective screeners were included in this study, and 636 of them tested positive during the initial screening, yielding a positive rate of 6.9%. The positive predictive value was 50.9% for all intestinal lesions, 1.4% for colorectal cancer , and 9.7% for advanced adenoma. CONCLUSION Fecal SDC2, ADHFE1, and PPP2R5C gene methylation detection methods can serve as primary screening tools, supplemented by colonoscopy, to effectively detect colorectal cancer and precancerous lesions. This strategy may prove to be an effective approach for conducting large-scale colorectal cancer screening in average-risk populations.
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Affiliation(s)
- Fan Zeng
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, 571199, China
| | - Shiiu Chen
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, 571199, China
| | - Xuli Zhu
- Otog Front Banner Peoples Hospital, Inner Mongolia Autonomous Region, China, 016200, Ordos, 016200, China
| | - Jinrun Chen
- Otog Front Banner Peoples Hospital, Inner Mongolia Autonomous Region, China, 016200, Ordos, 016200, China
| | - Maochong Lan
- Graduate School, Jiujiang College, Jiujiang, 332001, China
| | - Runxiang Chen
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, 571199, China
| | - Daya Zhang
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, 571199, China
| | - Chen Chen
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, 571199, China
| | - Shimei Huang
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, 571199, China
| | - Da Li
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, 571199, China
| | - Xiaodong Zhang
- The Second School of Clinical Medicine, Hainan Medical University, Haikou, 571199, China
| | - Feihu Bai
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Yehai Avenue, #368, Longhua District, Haikou, Hainan Province, 570216, China.
- The Gastroenterology Clinical Medical Center of Hainan Province, Haikou, 570216, China.
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Müller D, Győrffy B. EpigenPlot: An interactive web platform for DNA methylation-based biomarker and drug target discovery in colorectal cancer. Br J Pharmacol 2025; 182:1452-1465. [PMID: 39871596 DOI: 10.1111/bph.17455] [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: 09/30/2024] [Revised: 11/15/2024] [Accepted: 12/03/2024] [Indexed: 01/29/2025] Open
Abstract
BACKGROUND AND PURPOSE Genome-wide methylation studies have significantly advanced our understanding of colorectal adenocarcinoma progression and biomarker discovery. Aberrant DNA methylation plays a crucial role in gene expression regulation during cancer transformation, highlighting the need to identify differentially methylated regions (DMRs) as potential diagnostic and therapeutic markers. However, an integrated resource to explore and validate methylation alterations across colorectal cancer stages has been lacking. We aimed to develop a platform that integrates existing methylation data, systematically identifies DMRs and provides a tool for further investigation. EXPERIMENTAL APPROACH We created a database combining Illumina HumanMethylation450K and EPIC data from normal colon, adenoma and adenocarcinoma tissues, comprising 2346 samples from 19 datasets. Methylation levels were analysed in six gene regions, and comparisons between tissue types were made using Mann-Whitney, Kruskal-Wallis and ROC tests. KEY RESULTS Both adenoma and adenocarcinoma samples exhibited a general decrease in methylation compared to healthy tissue. Differential methylation in genes such as ITGA4, NPY, IGFL1 and LRRC4 was validated. The strongest DMRs were observed in the C1orf70 gene's 5'UTR and TSS200 regions, with AUC values of 0.98 in both of the HM450K and EPIC datasets. We established an interactive web-based platform accessible at https://epigenplot.com/ enabling future analysis of individual gene regions. CONCLUSIONS AND IMPLICATIONS Our study provides an integrated database of DNA methylation profiles across normal, adenoma and adenocarcinoma tissues, offering a valuable resource for biomarker discovery. The integrated web platform can serve as a tool for the development of methylation-based therapies in the future.
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Affiliation(s)
- Dalma Müller
- Department of Bioinformatics, Semmelweis University, Budapest, Hungary
| | - Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, Budapest, Hungary
- Department of Biophysics, Medical School, University of Pecs, Pecs, Hungary
- Cancer Biomarker Research Group, Institute of Molecular Life Sciences, Hungarian Research Network, Budapest, Hungary
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Devall MA, Eaton S, Hu G, Sun X, Jakum E, Venkatesh S, Powell SM, Yoshida C, Weisenberger DJ, Cooper GS, Willis J, Ebrahim S, Zoellner J, Casey G, Li L. Association between dietary fructose and human colon DNA methylation: implication for racial disparities in colorectal cancer risk using a cross-sectional study. Am J Clin Nutr 2025; 121:522-534. [PMID: 39788295 PMCID: PMC11923427 DOI: 10.1016/j.ajcnut.2025.01.005] [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: 03/25/2024] [Revised: 12/28/2024] [Accepted: 01/06/2025] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND An increasing body of evidence has linked fructose intake to colorectal cancer (CRC). African-American (AA) adults consume greater quantities of fructose and are more likely to develop right-side colon cancer than European American (EA) adults. OBJECTIVES We examined the hypothesis that fructose consumption leads to epigenomic and transcriptomic differences associated with CRC tumor biology. METHODS Deoxyribonucleic acid methylation data from this cross-sectional study was obtained using the Illumina Infinium MethylationEPIC kit (GSE151732). Right and left colon differentially methylated regions (DMRs) were identified using DMRcate through analysis of Food Frequency Questionnaire data on fructose consumption in normal colon biopsies (n = 79) of AA adults undergoing screening colonoscopy. Secondary analysis of CRC tumors was carried out using data derived from The Cancer Genome Atlas Colon Adenocarcinoma, GSE101764, and GSE193535. Right colon organoids derived from AA (n = 5) and EA (n = 5) adults were exposed to 4.4 mM of fructose for 72 h. Differentially expressed genes (DEGs) were identified using DESeq2. RESULTS We identified 4263 right colon fructose-associated DMRs [false-discovery rates (FDR) < 0.05]. In contrast, only 24 DMRs survived multiple testing corrections (FDR < 0.05) in matched, left colon. Almost 50% of right colon fructose-associated DMRs overlapped regions implicated in CRC in ≥1 of 3 data sets. Highly significant enrichment was also observed between genes corresponding to right colon fructose-associated DMRs and DEGs associated with fructose exposure in right colon organoids of AA individuals (P = 3.28E-30). Overlapping and significant enrichments for fatty acid metabolism, glycolysis, and cell proliferation pathways were also found. Cross-referencing genes within these pathways to DEGs in CRC tumors reveal potential roles for ankyrin repeat domain containing protein 23 and phosphofructokinase, platelet in fructose-mediated CRC risk for AA individuals. CONCLUSIONS Our data support that dietary fructose exerts a greater CRC risk-related effect in the right than left colon among AA adults, alluding to its potential role in contributing to racial disparities in CRC.
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Affiliation(s)
- Matthew A Devall
- Department of Family Medicine, University of Virginia, Charlottesville, VA, United States; University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA, United States
| | - Stephen Eaton
- Department of Family Medicine, University of Virginia, Charlottesville, VA, United States
| | - Gaizun Hu
- Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, United States
| | - Xiangqing Sun
- Department of Family Medicine, University of Virginia, Charlottesville, VA, United States
| | - Ethan Jakum
- Department of Biology, University of Virginia, Charlottesville, VA, United States
| | - Samyukta Venkatesh
- Department of Family Medicine, University of Virginia, Charlottesville, VA, United States
| | - Steven M Powell
- Digestive Health Center, University of Virginia, Charlottesville, VA, United States
| | - Cynthia Yoshida
- Digestive Health Center, University of Virginia, Charlottesville, VA, United States
| | - Daniel J Weisenberger
- Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, United States
| | - Gregory S Cooper
- Department of Medicine, Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Joseph Willis
- Department of Pathology, Case Western Reserve University/University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Seham Ebrahim
- Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, United States
| | - Jamie Zoellner
- University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA, United States; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, United States; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, United States
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, VA, United States; University of Virginia Comprehensive Cancer Center, University of Virginia, Charlottesville, VA, United States.
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Tang X, Guo R, Mo Z, Fu W, Qian X. Causality-driven candidate identification for reliable DNA methylation biomarker discovery. Nat Commun 2025; 16:680. [PMID: 39814752 PMCID: PMC11735613 DOI: 10.1038/s41467-025-56054-y] [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: 06/28/2024] [Accepted: 01/06/2025] [Indexed: 01/18/2025] Open
Abstract
Despite vast data support in DNA methylation (DNAm) biomarker discovery to facilitate health-care research, this field faces huge resource barriers due to preliminary unreliable candidates and the consequent compensations using expensive experiments. The underlying challenges lie in the confounding factors, especially measurement noise and individual characteristics. To achieve reliable identification of a candidate pool for DNAm biomarker discovery, we propose a Causality-driven Deep Regularization framework to reinforce correlations that are suggestive of causality with disease. It integrates causal thinking, deep learning, and biological priors to handle non-causal confounding factors, through a contrastive scheme and a spatial-relation regularization that reduces interferences from individual characteristics and noises, respectively. The comprehensive reliability of the proposed method was verified by simulations and applications involving various human diseases, sample origins, and sequencing technologies, highlighting its universal biomedical significance. Overall, this study offers a causal-deep-learning-based perspective with a compatible tool to identify reliable DNAm biomarker candidates, promoting resource-efficient biomarker discovery.
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Affiliation(s)
- Xinlu Tang
- The Medical Image and Health Informatics Lab, the School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Rui Guo
- The Medical Image and Health Informatics Lab, the School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Zhanfeng Mo
- College of Computing and Data Science, Nanyang Technological University, Singapore, Singapore
| | - Wenli Fu
- The Medical Image and Health Informatics Lab, the School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaohua Qian
- The Medical Image and Health Informatics Lab, the School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
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Yin J, Liu G, Zhang Y, Zhou Y, Pan Y, Zhang Q, Yu R, Gao S. Gender differences in gliomas: From epidemiological trends to changes at the hormonal and molecular levels. Cancer Lett 2024; 598:217114. [PMID: 38992488 DOI: 10.1016/j.canlet.2024.217114] [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: 05/29/2024] [Revised: 06/28/2024] [Accepted: 07/08/2024] [Indexed: 07/13/2024]
Abstract
Gender plays a crucial role in the occurrence and development of cancer, as well as in the metabolism of nutrients and energy. Men and women display significant differences in the incidence, prognosis, and treatment response across various types of cancer, including certain sex-specific tumors. It has been observed that male glioma patients have a higher incidence and worse prognosis than female patients, but there is currently a limited systematic evaluation of sex differences in gliomas. The purpose of this study is to provide an overview of the association between fluctuations in sex hormone levels and changes in their receptor expression with the incidence, progression, treatment, and prognosis of gliomas. Estrogen may have a protective effect on glioma patients, while exposure to androgens increases the risk of glioma. We also discussed the specific genetic and molecular differences between genders in terms of the malignant nature and prognosis of gliomas. Factors such as TP53, MGMT methylation status may play a crucial role. Therefore, it is essential to consider the gender of patients while treating glioma, particularly the differences at the hormonal and molecular levels. This approach can help in the adoption of an individualized treatment strategy.
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Affiliation(s)
- Jiale Yin
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, 221002, China; Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Gai Liu
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, 221002, China; Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Yue Zhang
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, 221002, China; Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Yu Zhou
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, 221002, China; Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Yuchun Pan
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, 221002, China; Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Qiaoshan Zhang
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, 221002, China; Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Rutong Yu
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, 221002, China; Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Shangfeng Gao
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, 221002, China; Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China.
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Loomans-Kropp HA. The utility of liquid biopsy-based methylation biomarkers for colorectal cancer detection. Front Oncol 2024; 14:1351514. [PMID: 38595823 PMCID: PMC11002156 DOI: 10.3389/fonc.2024.1351514] [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: 12/07/2023] [Accepted: 03/13/2024] [Indexed: 04/11/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent cancers and the second leading cause of cancer-related deaths in the United States. It is also one of the few cancers with established screening guidelines, however these methods have significant patient burden (e.g., time, invasive). In recent years, the development of liquid biopsy-based screening methods for biomarker detection have emerged as alternatives to traditional screening. Methylation biomarkers are of particular interest, and these markers can be identified and measured on circulating tumor and cell-free DNA. This perspective summarizes the current state of CRC screening and the potential integration of DNA methylation markers into liquid biopsy-based techniques. Finally, I discuss limitations to these methods and strategies for improvement. The continued development and implementation of liquid biopsy-based cancer screening approaches may provide an acceptable alternative to individuals unwilling to be screened by traditional methods.
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Affiliation(s)
- Holli A. Loomans-Kropp
- Cancer Control Program, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, United States
- Division of Cancer Prevention and Control, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, United States
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Lu YW, Ding ZL, Mao R, Zhao GG, He YQ, Li XL, Liu J. Early results of the integrative epigenomic-transcriptomic landscape of colorectal adenoma and cancer. World J Gastrointest Oncol 2024; 16:414-435. [PMID: 38425399 PMCID: PMC10900154 DOI: 10.4251/wjgo.v16.i2.414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 11/24/2023] [Accepted: 12/22/2023] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND Aberrant methylation is common during the initiation and progression of colorectal cancer (CRC), and detecting these changes that occur during early adenoma (ADE) formation and CRC progression has clinical value. AIM To identify potential DNA methylation markers specific to ADE and CRC. METHODS Here, we performed SeqCap targeted bisulfite sequencing and RNA-seq analysis of colorectal ADE and CRC samples to profile the epigenomic-transcriptomic landscape. RESULTS Comparing 22 CRC and 25 ADE samples, global methylation was higher in the former, but both showed similar methylation patterns regarding differentially methylated gene positions, chromatin signatures, and repeated elements. High-grade CRC tended to exhibit elevated methylation levels in gene promoter regions compared to those in low-grade CRC. Combined with RNA-seq gene expression data, we identified 14 methylation-regulated differentially expressed genes, of which only AGTR1 and NECAB1 methylation had prognostic significance. CONCLUSION Our results suggest that genome-wide alterations in DNA methylation occur during the early stages of CRC and demonstrate the methylation signatures associated with colorectal ADEs and CRC, suggesting prognostic biomarkers for CRC.
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Affiliation(s)
- You-Wang Lu
- Department of Dermatology and Venereology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Zhao-Li Ding
- Kunming Biological Diversity Regional Center of Large Apparatus and Equipments, Public Technical Service Center, Kunming Institute of Zoology, Kunming 650223, Yunnan Province, China
| | - Rui Mao
- School of Stomatology, Kunming Medical University, Kunming 650500, Yunnan Province, China
| | - Gui-Gang Zhao
- Genome Center of Biodiversity, Kunming Institute of Zoology, Chinese Academy of Science, Kunming 650223, Yunnan Province, China
| | - Yu-Qi He
- Genome Center of Biodiversity, Kunming Institute of Zoology, Chinese Academy of Science, Kunming 650223, Yunnan Province, China
| | - Xiao-Lu Li
- Genome Center of Biodiversity, Kunming Institute of Zoology, Chinese Academy of Science, Kunming 650223, Yunnan Province, China
| | - Jiang Liu
- Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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Zhang F, Zhang X, Zhang H, Lin D, Fan H, Guo S, An F, Zhao Y, Li J, Schrodi SJ, Zhang D. Pan-precancer and cancer DNA methylation profiles revealed significant tissue specificity of interrupted biological processes in tumorigenesis. Epigenetics 2023; 18:2231222. [PMID: 37393582 DOI: 10.1080/15592294.2023.2231222] [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: 03/03/2023] [Revised: 06/13/2023] [Accepted: 06/21/2023] [Indexed: 07/04/2023] Open
Abstract
DNA methylation (DNAme) alterations are known to initiate from the precancerous stage of tumorigenesis. Herein, we investigated the global and local patterns of DNAme perturbations in tumorigenesis by analysing the genome-wide DNAme profiles of the cervix, colorectum, stomach, prostate, and liver at precancerous and cancer stages. We observed global hypomethylation in tissues of both two stages, except for the cervix, whose global DNAme level in normal tissue was lower than that of the other four tumour types. For alterations shared by both stages, there were common hyper-methylation (sHyperMethyl) and hypo-methylation (sHypoMethyl) changes, of which the latter type was more frequently identified in all tissues. Biological pathways interrupted by sHyperMethyl and sHypoMethyl alterations demonstrated significant tissue specificity. DNAme bidirectional chaos indicated by the enrichment of both sHyperMethyl and sHypoMethyl changes in the same pathway was observed in most tissues and was a common phenomenon, particularly in liver lesions. Moreover, for the same enriched pathways, different tissues may be affected by distinct DNAme types. For the PI3K-Akt signalling pathway, sHyperMethyl enrichment was observed in the prostate dataset, but sHypoMethyl enrichment was observed in the colorectum and liver datasets. Nevertheless, they did not show an increased possibility in survival prediction of patients in comparison with other DNAme types. Additionally, our study demonstrated that gene-body DNAme changes of tumour suppressor genes and oncogenes may persist from precancerous lesions to the tumour. Overall, we demonstrate the tissue specificity and commonality of cross-stage alterations in DNA methylation profiles in multi-tissue tumorigenesis.
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Affiliation(s)
- Feifan Zhang
- Key Laboratory of Biomechanics and Mechanobiology, Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine, Beihang University, Beijing, China
| | - Xin Zhang
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Haikun Zhang
- Key Laboratory of Biomechanics and Mechanobiology, Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine, Beihang University, Beijing, China
| | - Dongdong Lin
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Hailang Fan
- Key Laboratory of Biomechanics and Mechanobiology, Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine, Beihang University, Beijing, China
| | - Shicheng Guo
- Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI, USA
| | - Fang An
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, China
| | - Yaqian Zhao
- Key Laboratory of Biomechanics and Mechanobiology, Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine, Beihang University, Beijing, China
| | - Jun Li
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Steven J Schrodi
- Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI, USA
- Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Dake Zhang
- Key Laboratory of Biomechanics and Mechanobiology, Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Engineering Medicine, Beihang University, Beijing, China
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Xie Y, Li P, Sun D, Qi Q, Ma S, Zhao Y, Zhang S, Wang T, Wang J, Li S, Gong T, Xu H, Xiong M, Li G, You C, Luo Z, Li J, Wang C, Du L. DNA Methylation-Based Testing in Peripheral Blood Mononuclear Cells Enables Accurate and Early Detection of Colorectal Cancer. Cancer Res 2023; 83:3636-3649. [PMID: 37602818 PMCID: PMC10618739 DOI: 10.1158/0008-5472.can-22-3402] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 02/15/2023] [Accepted: 08/15/2023] [Indexed: 08/22/2023]
Abstract
An effective blood-based method for the diagnosis of colorectal cancer has not yet been developed. Molecular alterations of immune cells occur early in tumorigenesis, providing the theoretical underpinning for early cancer diagnosis based on immune cell profiling. Therefore, we aimed to develop an effective detection method based on peripheral blood mononuclear cells (PBMC) to improve the diagnosis of colorectal cancer. Analysis of the genome-wide methylation landscape of PBMCs from patients with colorectal cancer and healthy controls by microarray, pyrosequencing, and targeted bisulfite sequencing revealed five DNA methylation markers for colorectal cancer diagnosis, especially early-stage colorectal cancer. A single-tube multiple methylation-specific quantitative PCR assay (multi-msqPCR) for simultaneous detection of five methylation markers was established, which allowed quantitative analysis of samples with as little as 0.1% PBMC DNA and had better discriminative performance than single-molecule detection. Then, a colorectal cancer diagnostic model (CDM) based on methylation markers and the multi-msqPCR method was constructed that achieved high accuracy for early-stage colorectal cancer (AUC = 0.91; sensitivity = 81.18%; specificity = 89.39%), which was improved compared with CEA (AUC = 0.79). The CDM also enabled a high degree of discrimination for advanced adenoma cases (AUC = 0.85; sensitivity = 63.04%). Follow-up data also demonstrated that the CDM could identify colorectal cancer potential up to 2 years before currently used diagnostic methods. In conclusion, the approach constructed in this study based on PBMC-derived DNA methylation markers and a multi-msqPCR method is a promising and easily implementable diagnostic method for early-stage colorectal cancer. SIGNIFICANCE Development of a diagnostic model for early colorectal cancer based on epigenetic analysis of PBMCs supports the utility of altered DNA methylation in immune cells for cancer diagnosis.
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Affiliation(s)
- Yan Xie
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, P.R. China
| | - Peilong Li
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, P.R. China
| | - Dong Sun
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, P.R. China
| | - Qiuchen Qi
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, P.R. China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan, P.R. China
| | - Suhong Ma
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, P.R. China
| | - Yinghui Zhao
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, P.R. China
| | - Shujun Zhang
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, P.R. China
| | - Tiantian Wang
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, P.R. China
| | - Jing Wang
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, P.R. China
| | - Shijun Li
- Department of Clinical Laboratory, The First Hospital of Dalian Medical University, Dalian, P.R. China
| | - Tingting Gong
- Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, P.R. China
| | - Huiting Xu
- Department of Clinical Laboratory Medicine, Affiliated Tumor Hospital of Nantong University, Jiangsu, P.R. China
- Medical School of Nantong University, Nantong, P.R. China
| | - Mengqiu Xiong
- Department of Clinical Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, P.R. China
| | - Guanghua Li
- Department of Clinical Laboratory, Guangdong Provincial People's Hospital/Guangdong Academy of Medical Sciences, Guangzhou, P.R. China
| | - Chongge You
- Laboratory Medicine Center, Lanzhou University Second Hospital, The Second Clinical Medical College of Lanzhou University, Lanzhou, P.R. China
| | - Zhaofan Luo
- Department of Clinical Laboratory, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, P.R. China
| | - Juan Li
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, P.R. China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, P.R. China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan, P.R. China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan, P.R. China
| | - Lutao Du
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, P.R. China
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Shandong Provincial Key Laboratory of Innovation Technology in Laboratory Medicine, Jinan, P.R. China
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10
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Sajibu S, Sonder E, Tiwari A, Orjuela S, Parker HR, Frans OT, Gubler C, Marra G, Robinson MD. Validation of hypermethylated DNA regions found in colorectal cancers as potential aging-independent biomarkers of precancerous colorectal lesions. BMC Cancer 2023; 23:998. [PMID: 37853362 PMCID: PMC10585861 DOI: 10.1186/s12885-023-11487-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: 05/20/2023] [Accepted: 10/06/2023] [Indexed: 10/20/2023] Open
Abstract
BACKGROUND We previously identified 16,772 colorectal cancer-associated hypermethylated DNA regions that were also detectable in precancerous colorectal lesions (preCRCs) and unrelated to normal mucosal aging. We have now conducted a study to validate 990 of these differentially methylated DNA regions (DMRs) in a new series of preCRCs. METHODS We used targeted bisulfite sequencing to validate these 990 potential biomarkers in 59 preCRC tissue samples (41 conventional adenomas, 18 sessile serrated lesions), each with a patient-matched normal mucosal sample. Based on differential DNA methylation tests, a panel of candidate DMRs was chosen on a subset of our cohort and then validated on the remaining part of our cohort and two publicly available datasets with respect to their stratifying potential between preCRCs and normal mucosa. RESULTS Strong statistical significance for the difference in methylation levels was observed across the full set of 990 investigated DMRs. From these, a selected candidate panel of 30 DMRs correctly identified 58/59 tumors (area under the receiver operating curve: 0.998). CONCLUSIONS These validated DNA hypermethylation markers can be exploited to develop more accurate noninvasive colorectal tumor screening assays.
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Affiliation(s)
- Sija Sajibu
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Emanuel Sonder
- Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, Zurich, 8057, Switzerland
- Institute for Neuroscience, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Amit Tiwari
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Stephany Orjuela
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Hannah R Parker
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | | | - Christoph Gubler
- Division of Gastroenterology, Triemli Hospital, Zurich, Switzerland
| | - Giancarlo Marra
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Mark D Robinson
- Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, Zurich, 8057, Switzerland.
- SIB Swiss Institute of Bioinformatics, Vaud, Switzerland.
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11
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Li B, Liu S, Gao Y, Zheng L, Lu Y. Combined detection of SDC2/ADHFE1/PPP2R5C methylation in stool DNA for colorectal cancer screening. J Cancer Res Clin Oncol 2023; 149:10241-10253. [PMID: 37270460 DOI: 10.1007/s00432-023-04943-4] [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: 05/04/2023] [Accepted: 05/26/2023] [Indexed: 06/05/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is a disease of global concern, and its increasing incidence suggests the need for early and accurate diagnosis. The aim of this study was to investigate the value of combined detection of SDC2, ADHFE1 and PPP2R5C gene methylation in stool samples for early CRC screening. METHODS Stool samples from patients with CRC (n = 105), advanced adenoma (AA) (n = 54), non-advanced adenoma (NA) (n = 57), hyperplastic or other polyps (HOP) (n = 47) or no evidence of disease (NED) (n = 100) were collected from September 2021 to September 2022. The methylation levels of SDC2, ADHFE1 and PPP2R5C were quantified by quantitative methylation-specific polymerase chain reaction (qMSP), and faecal immunochemical testing (FIT) was performed. The diagnostic value was assessed using reporter operating characteristic (ROC) curve analysis. RESULTS The sensitivity of combined detection of SDC2/ADHFE1/PPP2R5C methylation in predicting CRC (0-IV) was 84.8%, the specificity was 98.0%, and the AUC was 0.930 (95% CI 0.889-0.970). Compared to FIT and serum tumour biomarkers, it showed better diagnostic performance for different stages of CRC. CONCLUSION The results of this study verified that the methylation levels of SDC2, ADHFE1 and PPP2R5C in stool DNA were significantly increased in CRC patients. Combined detection of SDC2/ADHFE1/PPP2R5C methylation is a potential non-invasive diagnostic method for CRC and precancerous lesion screening. CLINICAL TRIAL REGISTRATION Chinese Clinical Trials Registry, ChiCTR2100046662, registered on 26 May 2021, prospective registration.
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Affiliation(s)
- Ben Li
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shanglong Liu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yuan Gao
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Longbo Zheng
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yun Lu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.
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12
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Janssens K, Neefs I, Ibrahim J, Schepers A, Pauwels P, Peeters M, Van Camp G, Op de Beeck K. Epigenome-wide methylation analysis of colorectal carcinoma, adenoma and normal tissue reveals novel biomarkers addressing unmet clinical needs. Clin Epigenetics 2023; 15:111. [PMID: 37415235 PMCID: PMC10327366 DOI: 10.1186/s13148-023-01516-7] [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: 03/22/2023] [Accepted: 06/01/2023] [Indexed: 07/08/2023] Open
Abstract
BACKGROUND Biomarker discovery in colorectal cancer has mostly focused on methylation patterns in normal and colorectal tumor tissue, but adenomas remain understudied. Therefore, we performed the first epigenome-wide study to profile methylation of all three tissue types combined and to identify discriminatory biomarkers. RESULTS Public methylation array data (Illumina EPIC and 450K) were collected from a total of 1 892 colorectal samples. Pairwise differential methylation analyses between tissue types were performed for both array types to "double evidence" differentially methylated probes (DE DMPs). Subsequently, the identified DMPs were filtered on methylation level and used to build a binary logistic regression prediction model. Focusing on the clinically most interesting group (adenoma vs carcinoma), we identified 13 DE DMPs that could effectively discriminate between them (AUC = 0.996). We validated this model in an in-house experimental methylation dataset of 13 adenomas and 9 carcinomas. It reached a sensitivity and specificity of 96% and 95%, respectively, with an overall accuracy of 96%. Our findings raise the possibility that the 13 DE DMPs identified in this study can be used as molecular biomarkers in the clinic. CONCLUSIONS Our analyses show that methylation biomarkers have the potential to discriminate between normal, precursor and carcinoma tissues of the colorectum. More importantly, we highlight the power of the methylome as a source of markers for discriminating between colorectal adenomas and carcinomas, which currently remains an unmet clinical need.
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Affiliation(s)
- Katleen Janssens
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
- Centre for Oncological Research Antwerp (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Isabelle Neefs
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
- Centre for Oncological Research Antwerp (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Joe Ibrahim
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
- Centre for Oncological Research Antwerp (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Anne Schepers
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
| | - Patrick Pauwels
- Centre for Oncological Research Antwerp (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Marc Peeters
- Centre for Oncological Research Antwerp (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Guy Van Camp
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
- Centre for Oncological Research Antwerp (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Ken Op de Beeck
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium.
- Centre for Oncological Research Antwerp (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium.
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13
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Devall MA, Eaton S, Hu G, Sun X, Jakum E, Venkatesh S, Powell SM, Yoshida C, Weisenberger DJ, Cooper GS, Willis J, Ebrahim S, Zoellner J, Casey G, Li L. Potential role of fructose on human colon DNA methylation in racial disparities observed for colorectal cancer risk. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.05.31.23290777. [PMID: 37398462 PMCID: PMC10312841 DOI: 10.1101/2023.05.31.23290777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Background and aims An increasing body of observational studies has linked fructose intake to colorectal cancer (CRC). African Americans (AAs) are significantly more likely than European Americans to consume greater quantities of fructose and to develop right-side colon cancer. Yet, a mechanistic link between these two associations remains poorly defined. We aimed to identify differentially methylated regions (DMRs) associated with dietary fructose consumption measures obtained from food frequency questionnaires in a cohort of normal colon biopsies derived from AA men and women (n=79). Methods DNA methylation data from this study was obtained using the Illumina Infinium MethylationEPIC kit and is housed under accession GSE151732. DMR analysis was carried out using DMRcate in right and matched left colon, separately. Secondary analysis of CRC tumors was carried out using data derived from TCGA-COAD, GSE101764 and GSE193535. Differential expression analysis was carried out on CRC tumors from TCGA-COAD using DESeq2 . Results We identified 4,263 right-side fructose-DMRs. In contrast, only 24 DMRs survived multiple testing corrections (FDR<0.05) in matched, left colon. To identify targets by which dietary fructose drives CRC risk, we overlaid these findings with data from three CRC tumor datasets. Remarkably, almost 50% of right-side fructose-DMRs overlapped regions associated with CRC in at least one of three datasets. TNXB and CDX2 ranked among the most significant fructose risk DMRs in right and left colon respectively that also displayed altered gene expression in CRC tumors. Conclusions Our mechanistic data support the notion that fructose has a greater CRC-related effect in right than left AA colon, alluding to a potential role for fructose in contributing to racial disparities in CRC.
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14
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Lin R, Qian Y, Zhang J, Xia D, Guo D, Hong L, Qing B, Xu M, Huang Y, Lin W, Chen G, Liu S. Genome-wide DNA methylation profiling of gastric cardia cancer. J Gastroenterol Hepatol 2023; 38:290-300. [PMID: 36342849 DOI: 10.1111/jgh.16054] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 10/25/2022] [Accepted: 11/04/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND AND AIM Aberrant DNA methylation has been found in various cancer types including gastric cancer, yet the genome-wide DNA methylation profile of gastric cardia cancer (GCC) remains unclear. Therefore, we aimed to profile the DNA methylation pattern of GCC and identify promising diagnostic epigenetic biomarkers. METHODS We investigated the genome-wide DNA methylation pattern in eight pairs of GCC and adjacent normal tissues using Illumina 850K microarrays. Subsequently, bisulfite-pyrosequencing and quantitative real-time PCR were performed on eight pairs of GCC-adjacent normal tissues for validation. Finally, we performed immunohistochemistry to examine ADHFE1 expression on 126 pairs of GCC-adjacent normal samples. RESULTS DNA methylome analysis showed global hypomethylation and local hypermethylation of promoter cytosine-phosphate-guanine (CpG) islands (CGIs) in GCC tissues compared with gastric cardia normal mucosa (P < 2.2 × 10-16 ). Differential methylation analysis identified a total of 91 723 differentially-methylated probes (DMPs), and the candidate gene with the largest average DNA methylation difference mapped to ADHFE1 (mean Δβ = 0.53). Subsequently, three DMPs in the ADHFE1 promoter were validated by pyrosequencing. Notably, the mean methylation level of the three candidate DMPs (ADHFE1_cg08090772, ADHFE1_cg19283840, and ADHFE1_cg20295442) was negatively associated with ADHFE1 mRNA expression level (Spearman rho = -0.64, P = 0.01). Moreover, both mRNA (P = 0.0213) and protein (P < 0.0001) expression of ADHFE1 were significantly decreased in GCCs compared with the adjacent normal tissues. CONCLUSIONS Our results reveal DNA methylation aberrations in GCC and that ADHFE1 gene DNA methylation contributes to the risk of GCC, thus providing novel mechanistic insights into gastric cardia cancer carcinogenesis.
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Affiliation(s)
- Runhua Lin
- Department of Pathology, Shantou University Medical College, Shantou, China
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, China
| | - Yanli Qian
- Department of Pathology, Shantou University Medical College, Shantou, China
| | - Jinhai Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Di Xia
- Department of Pathology, Shantou University Medical College, Shantou, China
| | - Dongming Guo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Liangli Hong
- Department of Pathology, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Bojuan Qing
- Department of Pathology, Shantou University Medical College, Shantou, China
| | - Muming Xu
- Department of Abdominal Surgery, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Yiteng Huang
- Health Care Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Wenting Lin
- Department of Pathology, Shantou University Medical College, Shantou, China
| | - Guangcan Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Shuhui Liu
- Department of Pathology, Shantou University Medical College, Shantou, China
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, China
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15
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Huang H, Cao W, Long Z, Kuang L, Li X, Feng Y, Wu Y, Zhao Y, Chen Y, Sun P, Peng P, Zhang J, Yuan L, Li T, Hu H, Li G, Yang L, Zhang X, Hu F, Sun X, Hu D. DNA methylation-based patterns for early diagnostic prediction and prognostic evaluation in colorectal cancer patients with high tumor mutation burden. Front Oncol 2023; 12:1030335. [PMID: 36713578 PMCID: PMC9880489 DOI: 10.3389/fonc.2022.1030335] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 12/28/2022] [Indexed: 01/15/2023] Open
Abstract
Background Immune checkpoint inhibitor (ICI) therapy has proven to be a promising treatment for colorectal cancer (CRC). We aim to investigate the relationship between DNA methylation and tumor mutation burden (TMB) by integrating genomic and epigenetic profiles to precisely identify clinical benefit populations and to evaluate the effect of ICI therapy. Methods A total of 536 CRC tissues from the Cancer Genome Atlas (TCGA) with mutation data were collected and subjected to calculate TMB. 80 CRC patients with high TMB and paired normal tissues were selected as training sets and developed the diagnostic and prognostic methylation models, respectively. In the validation set, the diagnostic model was validated in our in-house 47 CRC tissues and 122 CRC tissues from the Gene Expression Omnibus (GEO) datasets, respectively. And a total of 38 CRC tissues with high TMB from the COLONOMICS dataset verified the prognostic model. Results A positive correlation between differential methylation positions and TMB level was observed in TCGA CRC cohort (r=0.45). The diagnostic score that consisted of methylation levels of four genes (ADHFE1, DOK6, GPR75, and MAP3K14-AS1) showed high diagnostic performance in the discovery (AUC=1.000) and two independent validation (AUC=0.946, AUC=0.857) datasets. Additionally, these four genes showed significant positive correlations with NK cells. The prognostic score containing three genes (POU3F3, SYN2, and TMEM178A) had significantly poorer survival in the high-risk TMB samples than those in the low-risk TMB samples (P=0.016). CRC patients with low-risk scores combined with TMB levels represent a favorable survival. Conclusions By integrating analyses of methylation and mutation data, it is suggested that DNA methylation patterns combined with TMB serve as a novel potential biomarker for early screening in more high-TMB populations and for evaluating the prognostic effect of CRC patients with ICI therapy.
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Affiliation(s)
- Hao Huang
- Department of General Practice, The Affiliated Luohu Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, China
| | - Weifan Cao
- Department of General Practice, The Affiliated Luohu Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, China
| | - Zhiping Long
- Department of Epidemiology, Public Health School of Harbin Medical University, Harbin, China
| | - Lei Kuang
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Center, Shenzhen, China
| | - Xi Li
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Center, Shenzhen, China
| | - Yifei Feng
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Center, Shenzhen, China
| | - Yuying Wu
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Center, Shenzhen, China
| | - Yang Zhao
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Center, Shenzhen, China
| | - Yinggang Chen
- Department of Gastrointestinal Surgery, Shenzhen Hospital, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Peng Sun
- Department of Gastrointestinal Surgery, Shenzhen Hospital, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Panxin Peng
- Department of Gastrointestinal Surgery, Shenzhen Hospital, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Jinli Zhang
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Center, Shenzhen, China
| | - Lijun Yuan
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Center, Shenzhen, China
| | - Tianze Li
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Center, Shenzhen, China
| | - Huifang Hu
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Center, Shenzhen, China
| | - Gairui Li
- Department of Chronic Disease Control and Prevention, Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, China
| | - Longkun Yang
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Xing Zhang
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, China
| | - Fulan Hu
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Center, Shenzhen, China,*Correspondence: Dongsheng Hu, ; Xizhuo Sun, ; Fulan Hu,
| | - Xizhuo Sun
- Department of General Practice, The Affiliated Luohu Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, China,*Correspondence: Dongsheng Hu, ; Xizhuo Sun, ; Fulan Hu,
| | - Dongsheng Hu
- Department of General Practice, The Affiliated Luohu Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, China,Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Center, Shenzhen, China,*Correspondence: Dongsheng Hu, ; Xizhuo Sun, ; Fulan Hu,
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16
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Okada Y, Peng F, Perea J, Corchete L, Bujanda L, Li W, Goel A. Genome-wide methylation profiling identifies a novel gene signature for patients with synchronous colorectal cancer. Br J Cancer 2023; 128:112-120. [PMID: 36319845 PMCID: PMC9814149 DOI: 10.1038/s41416-022-02033-9] [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: 05/24/2022] [Revised: 10/13/2022] [Accepted: 10/17/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND There are no robust tools for the diagnosis of synchronous colorectal cancer (SyCRC). Herein, we developed the first methylation signature to identify and characterise patients with SyCRC. METHODS For biomarker discovery, we analysed the genome-wide methylation profiles of 16 SyCRC and 18 solitary colorectal cancer (SoCRC) specimens. We thereafter established a methylation signature risk-scoring model to identify SyCRC in an independent cohort of 38 SyCRC and 42 SoCRC patients. In addition, we evaluated the prognostic value of the identified methylation profile. RESULTS We identified six differentially methylated CpG probes/sites that distinguished SyCRC from SoCRC. In the validation cohort, we developed a methylation panel that identified patients with SyCRC from not only larger tumour (AUC = 0.91) but also the paired remaining tumour (AUC = 0.93). Moreover, high risk scores of our panel were associated with the development of metachronous CRC among patients with SyCRC (AUC = 0.87) and emerged as an independent predictor for relapse-free survival (hazard ratio = 2.72; 95% CI = 1.12-6.61). Furthermore, the risk stratification model which combined with clinical risk factors was a diagnostic predictor of recurrence (AUC = 0.90). CONCLUSIONS Our novel six-gene methylation panel robustly identifies patients with SyCRC, which has the clinical potential to improve the diagnosis and management of patients with CRC.
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Affiliation(s)
- Yasuyuki Okada
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA, USA
- Department of Gastroenterology and Oncology, Tokushima University Graduate School, Tokushima, Japan
| | - Fuduan Peng
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA
| | - José Perea
- Molecular Medicine Unit. Department of Medicine, Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
- Surgery Department, Vithas Arturo Soria University Hospital and School of Medicine, European University of Madrid, Madrid, Spain
| | - Luis Corchete
- Hematology Department, University Hospital of Salamanca, Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), Cancer Research Center (CiC-IBMCC, CSIC/USAL), Center for Biomedical Research in Network of Cancer (CIBERONC), Salamanca, Spain
| | - Luis Bujanda
- Gastroenterology Department, Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Universidad del País Vasco (UPV/EHU), San Sebastián, Spain
| | - Wei Li
- Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA.
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA, USA.
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
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17
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Nerves in gastrointestinal cancer: from mechanism to modulations. Nat Rev Gastroenterol Hepatol 2022; 19:768-784. [PMID: 36056202 DOI: 10.1038/s41575-022-00669-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/20/2022] [Indexed: 12/08/2022]
Abstract
Maintenance of gastrointestinal health is challenging as it requires balancing multifaceted processes within the highly complex and dynamic ecosystem of the gastrointestinal tract. Disturbances within this vibrant environment can have detrimental consequences, including the onset of gastrointestinal cancers. Globally, gastrointestinal cancers account for ~19% of all cancer cases and ~22.5% of all cancer-related deaths. Developing new ways to more readily detect and more efficiently target these malignancies are urgently needed. Whereas members of the tumour microenvironment, such as immune cells and fibroblasts, have already been in the spotlight as key players of cancer initiation and progression, the importance of the nervous system in gastrointestinal cancers has only been highlighted in the past few years. Although extrinsic innervations modulate gastrointestinal cancers, cells and signals from the gut's intrinsic innervation also have the ability to do so. Here, we shed light on this thriving field and discuss neural influences during gastrointestinal carcinogenesis. We focus on the interactions between neurons and components of the gastrointestinal tract and tumour microenvironment, on the neural signalling pathways involved, and how these factors affect the cancer hallmarks, and discuss the neural signatures in gastrointestinal cancers. Finally, we highlight neural-related therapies that have potential for the management of gastrointestinal cancers.
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18
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Li C, Liu Z, Xu G, Wu S, Peng Y, Wu R, Zhao S, Liao X, Lin R. Aberrant DNA methylation and expression of EYA4 in gastric cardia intestinal metaplasia. Saudi J Gastroenterol 2022; 28:456-465. [PMID: 36453428 PMCID: PMC9843510 DOI: 10.4103/sjg.sjg_228_22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 08/29/2022] [Accepted: 09/05/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Intestinal metaplasia (IM) of the gastric cardia is an important premalignant lesion. However, there is limited information concerning its epidemiological and molecular features. Herein, we aimed to provide an overview of the epidemiological data for gastric cardiac IM and evaluate the role of EYA transcriptional coactivator and phosphatase 4 (EYA4) as an epigenetic biomarker for gastric cardiac IM. METHODS The study was conducted in the context of the gastric cardiac precancerous lesion program in southern China, which included 718 non-cancer participants, who undertook endoscopic biopsy and pathological examination in three endoscopy centers, between November 2018 and November 2021. Pyrosequencing and immunohistochemistry were performed to examine the DNA methylation status and protein expression level of EYA4. RESULTS Gastric cardiac IM presented in 14.1% (101/718) of participants and was more common among older (>50 years; 22.0% [95% CI: 17.8-26.8]) than younger participants (≤50 years; 6.7% [95% CI: 4.5-9.9]; P < 0.001). IM was more common in male participants (16.9% [95% CI: 13.2-21.3] vs. 11.3% [95% CI: 8.3-15.1]; P = 0.04). Pyrosequencing revealed that IM tissues exhibited significantly higher DNA methylation levels in EYA4 gene than normal tissues (P = 0.016). Further, the protein expression level of EYA4 was reduced in IM and absent in intraepithelial neoplasia tissues compared to normal tissues (P < 0.001). CONCLUSIONS Detection rates of gastric cardiac IM increase with age and are higher in men. Our findings highlight the important role of promoter hypermethylation and downregulation of EYA4 in gastric cardiac IM development.
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Affiliation(s)
- Chenxi Li
- Department of Pathology, Shantou University Medical College, Shantou, P.R. China
| | - Zhaohui Liu
- Department of Gastroenterology, Shenzhen Second People's Hospital/The First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, P.R. China
| | - Guohua Xu
- Department of Gastroenterology, Huiyang Sanhe Hospital, Huizhou, P.R. China
| | - Shibin Wu
- Department of Gastroenterology, Huiyang Sanhe Hospital, Huizhou, P.R. China
| | - Yunhui Peng
- Department of Gastroenterology, Huiyang Sanhe Hospital, Huizhou, P.R. China
| | - Ruinuan Wu
- Department of Pathology, Shenzhen Second People's Hospital/The First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, P.R. China
| | - Shukun Zhao
- Department of Pathology, Shantou University Medical College, Shantou, P.R. China
| | - Xiaoqi Liao
- Department of Pathology, Shantou University Medical College, Shantou, P.R. China
| | - Runhua Lin
- Department of Pathology, Shantou University Medical College, Shantou, P.R. China
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou, P.R. China
- Address for correspondence: Dr. Runhua Lin, Department of Pathology, Shantou University Medical College, No. 22, Xinling Road, Shantou 515041, P.R. China. E-mail:
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Qian S, Lin S, Xu X, Bai H, Yeerken A, Ying X, Li Z, Fei X, Yang J, Tang M, Wang J, Jin M, Chen K. Hypermethylation of tumor suppressor lncRNA MEF2C-AS1 frequently happened in patients at all stages of colorectal carcinogenesis. Clin Epigenetics 2022; 14:111. [PMID: 36064442 PMCID: PMC9446566 DOI: 10.1186/s13148-022-01328-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 08/23/2022] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND The novel long noncoding RNA MEF2C-AS1 has been identified to play suppressor roles during tumorigenesis. DNA methylation has a regulatory effect on gene expression in cancer initiation and progression. However, the methylation status of MEF2C-AS1 and its role in colorectal cancer (CRC) development remain unclear. METHODS The expression and methylation levels of MEF2C-AS1 were systematically analyzed among 31 cancers with available qualified data in GEPIA and UCSC Xena databases. Then, the MEF2C-AS1 methylation status was firstly examined among 12 CRCs by Illumina Infinium MethylationEPIC BeadChip in in-house step 1 and further quantified among 48 CRCs by the MassARRAY method in in-house step 2. Subsequently, its methylation and expression levels were quantified among 81 non-advanced adenomas (NAAs), 81 advanced adenomas (AAs), and 286 CRCs using the MassARRAY method, and among 34 NAAs, 45 AAs, and 75 CRCs by qRT-PCR, in in-house step 3, respectively. The effect of MEF2C-AS1 methylation on CRC survival was analyzed by the Kaplan-Meier method. Additionally, in vitro cell proliferation, migration and invasion assays, and bioinformatics analysis were performed to explore the role of MEF2C-AS1 in colorectal carcinogenesis. RESULTS Lower expression and higher methylation of MEF2C-AS1 were found in CRC by online databases. In the comparisons of lesion tissues with adjacent normal tissues, MEF2C-AS1 hypermethylation of each individual site and mean level was found among CRC patients in in-house step 1 and step 2, more meaningfully, among NAA patients, AA patients, and CRC patients at all stages during colorectal carcinogenesis in in-house step 3 (all p < 0.05). Further comparisons demonstrated significant differences between CRC and NAA (p = 0.025), AA and NAA (p = 0.020). Moreover, MEF2C-AS1 hypermethylation was associated with poorer disease-specific survival of CRC patients (p = 0.044). In addition, hypermethylation and lower expression of MEF2C-AS1 were verified in RKO cells, and the MEF2C-AS1 overexpression significantly suppressed RKO cell proliferation, migration, and invasion. CONCLUSIONS The findings reveal that MEF2C-AS1 hypermethylation might be an early driven event during colorectal carcinogenesis. It might serve as a promising prognostic biomarker for CRC survival. Our study also indicates the potential tumor-suppressing role of MEF2C-AS1 in CRC.
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Affiliation(s)
- Sangni Qian
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Shujuan Lin
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Xin Xu
- Department of Public Health, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Hao Bai
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Aibuta Yeerken
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Xiaojiang Ying
- Department of Anorectal Surgery, Shaoxing People's Hospital, Shaoxing, 312000, China
| | - Zhenjun Li
- Department of Anorectal Surgery, Shaoxing People's Hospital, Shaoxing, 312000, China
| | - Xinglin Fei
- Jiashan Institute of Cancer Prevention and Treatment, Jiaxing, 314100, China
| | - Jinhua Yang
- Jiashan Institute of Cancer Prevention and Treatment, Jiaxing, 314100, China
| | - Mengling Tang
- Department of Public Health, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Jianbing Wang
- Department of Public Health, National Clinical Research Center for Child Health of the Children's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Mingjuan Jin
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
| | - Kun Chen
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
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20
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Zhan L, Sun C, Zhang Y, Zhang Y, Jia Y, Wang X, Li F, Li D, Wang S, Yu T, Zhang J, Li D. Four methylation-driven genes detected by linear discriminant analysis model from early-stage colorectal cancer and their methylation levels in cell-free DNA. Front Oncol 2022; 12:949244. [PMID: 36158666 PMCID: PMC9491101 DOI: 10.3389/fonc.2022.949244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 08/12/2022] [Indexed: 12/24/2022] Open
Abstract
The process of colorectal cancer (CRC) formation is considered a typical model of multistage carcinogenesis in which aberrant DNA methylation plays an important role. In this study, 752 methylation-driven genes (MDGs) were identified by the MethylMix package based on methylation and gene expression data of CRC in The Cancer Genome Atlas (TCGA). Iterative recursive feature elimination (iRFE) based on linear discriminant analysis (LDA) was used to determine the minimum MDGs (iRFE MDGs), which could distinguish between cancer and cancer-adjacent tissues. Further analysis indicated that the changes in methylation levels of the four iRFE MDGs, ADHFE1-Cluster1, CNRIP1-Cluster1, MAFB, and TNS4, occurred in adenoma tissues, while changes did not occur until stage IV in cell-free DNA. Furthermore, the methylation levels of iRFE MDGs were correlated with the genes involved in the reprogramming process of somatic cells to pluripotent stem cells, which is considered the common signature of cancer cells and embryonic stem cells. The above results indicated that the four iRFE MDGs may play roles in the early stage of colorectal carcinogenesis and highlighted the complicated relationship between tissue DNA and cell-free DNA (cfDNA).
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Affiliation(s)
- Lei Zhan
- Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Changjian Sun
- Clinical Laboratory, Air Force Hospital of Northern Theater, PLA, Shenyang, China
| | - Yu Zhang
- Clinical Laboratory, Air Force Hospital of Northern Theater, PLA, Shenyang, China
| | - Yue Zhang
- Clinical Laboratory, Air Force Hospital of Northern Theater, PLA, Shenyang, China
| | - Yuzhe Jia
- Clinical Laboratory, Air Force Hospital of Northern Theater, PLA, Shenyang, China
| | - Xiaoyan Wang
- Clinical Laboratory, Air Force Hospital of Northern Theater, PLA, Shenyang, China
| | - Feifei Li
- Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Donglin Li
- Orthopedics Department, Air Force Hospital of Northern Theater, PLA, Shenyang, China
| | - Shen Wang
- Department of Ultrasound and Special Diagnosis, Air Force Hospital of Northern Theater, PLA, Shenyang, China
| | - Tao Yu
- Nursing Department, Air Force Medical Center, PLA, Beijing, China
| | - Jingdong Zhang
- Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Deyang Li
- Clinical Laboratory, Air Force Hospital of Northern Theater, PLA, Shenyang, China
- *Correspondence: Deyang Li,
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21
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Devall MA, Eaton S, Ali MW, Powell SM, Li L, Casey G. Insights into Early Onset Colorectal Cancer through Analysis of Normal Colon Organoids of Familial Adenomatous Polyposis Patients. Cancers (Basel) 2022; 14:4138. [PMID: 36077675 PMCID: PMC9454756 DOI: 10.3390/cancers14174138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/22/2022] [Accepted: 08/25/2022] [Indexed: 01/07/2023] Open
Abstract
Early onset colorectal cancer (EOCRC) rates have increased in recent decades. While lowering the recommended age for routine colonoscopies to 45 may reduce this burden, such measures do not address those who develop CRC before that age. Additional measures are needed to identify individuals at-risk for CRC. To better define transcriptomic events that precede the development of CRC, we performed RNA-sequencing analysis in colon organoids derived from seven healthy and six familial adenomatous polyposis (FAP) patients. This led to the identification of 2635 significant differentially expressed genes (FDR < 0.05). Through secondary analysis of publicly available datasets, we found that these genes were enriched for significant genes also present in FAP CRC and non-hereditary CRC datasets, including a subset that were unique to EOCRC. By exposing FAP colon organoids to a three-day ethanol treatment, we found that two EOCRC-relevant genes were also targets of CRC related lifestyle factors. Our data provides unique insight into the potential, early mechanisms of CRC development in colon epithelial cells, which may provide biomarkers for patient monitoring. We also show how modifiable lifestyle factors may further alter genes relevant to EOCRC, adding weight to the hypothesis that such factors represent an important contributor to increased EOCRC incidence.
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Affiliation(s)
- Matthew A. Devall
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
- Department of Family Medicine, University of Virginia, Charlottesville, VA 22903, USA
| | - Stephen Eaton
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
- Department of Family Medicine, University of Virginia, Charlottesville, VA 22903, USA
| | - Mourad W. Ali
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
| | - Steven M. Powell
- Digestive Health Center, University of Virginia, Charlottesville, VA 22903, USA
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, VA 22903, USA
- Comprehensive Cancer Center, University of Virginia, Charlottesville, VA 22911, USA
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA
- Comprehensive Cancer Center, University of Virginia, Charlottesville, VA 22911, USA
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA
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22
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Caruso FP, D'Andrea MR, Coppola L, Landriscina M, Condelli V, Cerulo L, Giordano G, Porras A, Pancione M. Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer. Cancer Cell Int 2022; 22:253. [PMID: 35953834 PMCID: PMC9373545 DOI: 10.1186/s12935-022-02672-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 06/27/2022] [Indexed: 12/24/2022] Open
Abstract
In addition to being novel biomarkers for poor cancer prognosis, members of Lymphocyte antigen-6 (Ly6) gene family also play a crucial role in avoiding immune responses to tumors. However, it has not been possible to identify the underlying mechanism of how Ly6 gene regulation operates in human cancers. Transcriptome, epigenome and proteomic data from independent cancer databases were analyzed in silico and validated independently in 334 colorectal cancer tissues (CRC). RNA mediated gene silencing of regulatory genes, and treatment with MEK and p38 MAPK inhibitors were also tested in vitro. We report here that the Lymphocyte antigen 6G6D is universally downregulated in mucinous CRC, while its activation progresses through the classical adenoma-carcinoma sequence. The DNA methylation changes in LY6G6D promoter are intimately related to its transcript regulation, epigenomic and histological subtypes. Depletion of DNA methyltransferase 1 (DNMT1), which maintains DNA methylation, results in the derepression of LY6G6D expression. RNA-mediated gene silencing of p38α MAPK or its selective chemical inhibition, however, reduces LY6G6D expression, reducing trametinib's anti-inflammatory effects. Patients treated with FOLFOX-based first-line therapy experienced decreased survival due to hypermethylation of the LY6G6D promoter and decreased p38α MAPK signaling. We found that cancer-specific immunodominant epitopes are controlled by p38α MAPKs signaling and suppressed by DNA methylation in histological variants with Mucinous differentiation. This work provides a promising prospective for clinical application in diagnosis and personalized therapeutic strategies of colorectal cancer.
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Affiliation(s)
| | | | - Luigi Coppola
- UOC Anatomia ed Istologia Patologica e Citologia Diagnostica, Dipartimento dei Servizi Diagnostici e della Farmaceutica, Ospedale Sandro Pertini, ASL Roma 2, 00157, Rome, Italy
| | - Matteo Landriscina
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata (CROB), Rionero in Vulture, Potenza, Italy
| | - Valentina Condelli
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata (CROB), Rionero in Vulture, Potenza, Italy
| | - Luigi Cerulo
- Bioinformatics Laboratory, BIOGEM scrl, Ariano Irpino, Avellino, Italy
| | - Guido Giordano
- Unit of Medical Oncology and Biomolecular Therapy, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122, Foggia, Italy.
| | - Almudena Porras
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University Madrid, 28040, Madrid, Spain.
- Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040, Madrid, Spain.
| | - Massimo Pancione
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy.
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23
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Zhang L, Li D, Gao L, Fu J, Sun S, Huang H, Zhang D, Jia C, Zheng T, Cui B, Liu Y, Zhao Y. Promoter Methylation of QKI as a Potential Specific Biomarker for Early Detection of Colorectal Cancer. Front Genet 2022; 13:928150. [PMID: 36017498 PMCID: PMC9395658 DOI: 10.3389/fgene.2022.928150] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 06/24/2022] [Indexed: 11/16/2022] Open
Abstract
Early and specific detection of cancer provides an opportunity for appropriate treatment. Although studies have suggested that QKI is a tumor suppressor gene, no studies have evaluated the diagnostic utility of QKI methylation in colorectal cancer (CRC). Here, we evaluated the methylation status of QKI by integrating the methylation data of tissues and cell lines of multiple cancer types. The diagnostic performance of QKI was analyzed in the discovery dataset from the TCGA CRC 450K array (n = 440) and tested in the test sets (n = 845) from the GEO. The methylation level of QKI was further validated in our independent dataset (n = 388) using targeted bisulfite sequencing. All detected CpG sites in the QKI promoter showed CRC-specific hypermethylation in 31 types of tumor tissues. In the discovery dataset, six consecutive CpG sites achieved high diagnostic performances, with AUCs ranging from 0.821 to 0.930. In the test set, a region (chr6: 163,834,452–163,834,924) including four consecutive CpG sites had robust diagnostic ability in distinguishing CRC and adenoma from normal samples. In the validation dataset, similar robust results were observed in both early- and advanced-stage CRC patients. In addition, QKI exhibited hypermethylation in the cfDNA of patients with CRC (n = 14). Collectively, the QKI promoter is a CRC-specific methylation biomarker and holds great promise for improving the diagnosis using minimally invasive biopsy.
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Affiliation(s)
- Lei Zhang
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Dapeng Li
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Lijing Gao
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Jinming Fu
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Simin Sun
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Hao Huang
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Ding Zhang
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Chenyang Jia
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Ting Zheng
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
| | - Binbin Cui
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
- *Correspondence: Yashuang Zhao, ; Yanlong Liu, ; Binbin Cui,
| | - Yanlong Liu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
- *Correspondence: Yashuang Zhao, ; Yanlong Liu, ; Binbin Cui,
| | - Yashuang Zhao
- Department of Epidemiology, College of Public Health, Harbin Medical University, Harbin, China
- *Correspondence: Yashuang Zhao, ; Yanlong Liu, ; Binbin Cui,
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24
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Yao Z, Zhu G, Too J, Duan M, Wang Z. Feature Selection of OMIC Data by Ensemble Swarm Intelligence Based Approaches. Front Genet 2022; 12:793629. [PMID: 35350819 PMCID: PMC8957794 DOI: 10.3389/fgene.2021.793629] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 12/22/2021] [Indexed: 12/28/2022] Open
Abstract
OMIC datasets have high dimensions, and the connection among OMIC features is very complicated. It is difficult to establish linkages among these features and certain biological traits of significance. The proposed ensemble swarm intelligence-based approaches can identify key biomarkers and reduce feature dimension efficiently. It is an end-to-end method that only relies on the rules of the algorithm itself, without presets such as the number of filtering features. Additionally, this method achieves good classification accuracy without excessive consumption of computing resources.
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Affiliation(s)
- Zhaomin Yao
- Department of Nuclear Medicine, General Hospital of Northern Theater Command, Shenyang, China.,College of Medicine and Biological Information Engineering, Northeastern University, Shenyang, China
| | - Gancheng Zhu
- Key Laboratory of Symbolic Computation, College of Computer Science and Technology, Knowledge Engineering of Ministry of Education, Jilin University, Changchun, China
| | - Jingwei Too
- Faculty of Electrical Engineering, Universiti Teknikal Malaysia Melaka, Hang Tuah Jaya, Melaka, Malaysia
| | - Meiyu Duan
- Key Laboratory of Symbolic Computation, College of Computer Science and Technology, Knowledge Engineering of Ministry of Education, Jilin University, Changchun, China
| | - Zhiguo Wang
- Department of Nuclear Medicine, General Hospital of Northern Theater Command, Shenyang, China.,College of Medicine and Biological Information Engineering, Northeastern University, Shenyang, China
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25
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Müller D, Győrffy B. DNA methylation-based diagnostic, prognostic, and predictive biomarkers in colorectal cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188722. [PMID: 35307512 DOI: 10.1016/j.bbcan.2022.188722] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/21/2022] [Accepted: 03/13/2022] [Indexed: 12/12/2022]
Abstract
DNA methylation is an epigenetic mechanism regulating gene expression. Changes in DNA methylation were suggested to be useful biomarkers for diagnosis, and for the determination of prognosis and treatment response. Here, we provide an overview of methylation-based biomarkers in colorectal cancer. First, we start with the two methylation-based diagnostic biomarkers already approved for colorectal cancer, SEPT9 and the combination of NDRG4 and BMP3. Then, we provide a list-based overview of new biomarker candidates depending on the sample source including plasma, stool, urine, and surgically removed tumor tissues. The most often identified markers like SDC2, VIM, APC, MGMT, SFRP1, SFRP2, and NDRG4 have distinct functions previously linked to tumor progression. Although numerous studies have identified tumor-specific methylation changes, most of these alterations were observed in a single study only. The lack of validation in independent samples means low reproducibility and is a major limitation. The genome-wide determination of methylation status (methylome) can provide data to solve these issues. In the third section of the review, methylome studies focusing on different aspects related to CRC, including precancerous lesions, CRC-specific changes, molecular subtypes, aging, and chemotherapy response are summarized. Notably, techniques simultaneously analyzing a large set of regions can also uncover epigenetic regulation of genes which have not yet been associated with tumorigenesis previously. A remaining constraint of studies published to date is the low patient number utilized in these preventing the identification of clinically valuable biomarker candidates. Either future large-scale studies or the integration of already available methylome-level data will be necessary to uncover biomarkers sufficiently robust for clinical application.
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Affiliation(s)
- Dalma Müller
- Dept. of Bioinformatics, Semmelweis University, Budapest, Hungary; Cancer Biomarker Research Group, RCNS, Budapest, Hungary
| | - Balázs Győrffy
- Dept. of Bioinformatics, Semmelweis University, Budapest, Hungary; Cancer Biomarker Research Group, RCNS, Budapest, Hungary.
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26
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Lin S, Gu S, Qian S, Liu Y, Sheng J, Li Q, Yang J, Ying X, Li Z, Tang M, Wang J, Chen K, Jin M. Genome-Wide Methylation Profiling of lncRNAs Reveals a Novel Progression-Related and Prognostic Marker for Colorectal Cancer. Front Oncol 2022; 11:782077. [PMID: 35127488 PMCID: PMC8811200 DOI: 10.3389/fonc.2021.782077] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 12/29/2021] [Indexed: 01/05/2023] Open
Abstract
Sporadic colorectal cancer (CRC) develops principally through the adenoma-carcinoma sequence. Previous studies revealed that DNA methylation alterations play a significant role in colorectal neoplastic transformation. On the other hand, long noncoding RNAs (lncRNAs) have been identified to be associated with some critical tumorigenic processes of CRC. Accumulating evidence indicates more intricate regulatory relationships between DNA methylation and lncRNAs in CRC. Nevertheless, the methylation alterations of lncRNAs at different stages of colorectal carcinogenesis based on a genome-wide scale remain elusive. Therefore, in this study, we first used an Illumina MethylationEPIC BeadChip (850K array) to identify the methylation status of lncRNAs in 12 pairs of colorectal cancerous and adjacent normal tissues from cohort I, followed by cross-validation with The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. Then, the abnormal hypermethylation of candidate genes in colorectal lesions was successfully confirmed by MassARRAY EpiTYPER in cohort II including 48 CRC patients, and cohort III including 286 CRC patients, 81 advanced adenoma (AA) patients and 81 nonadvanced adenoma (NAA) patients. DLX6-AS1 hypermethylation was detected at all stages of colorectal neoplasms and occurred as early as the NAA stage during colorectal neoplastic progression. The methylation levels were significantly higher in the comparisons of CRC vs. NAA (P < 0.001) and AA vs. NAA (P = 0.004). Moreover, the hypermethylation of DLX6-AS1 promoter was also found in cell-free DNA samples collected from CRC patients as compared to healthy controls (P adj = 0.003). Multivariate Cox proportional hazards regression analysis revealed DLX6-AS1 promoter hypermethylation was independently associated with poorer disease-specific survival (HR = 2.52, 95% CI: 1.35-4.69, P = 0.004) and overall survival (HR = 1.64, 95% CI: 1.02-2.64, P = 0.042) in CRC patients. Finally, a nomogram was constructed and verified by a calibration curve to predict the survival probability of individual CRC patients (C-index: 0.789). Our findings indicate DLX6-AS1 hypermethylation might be an early event during colorectal carcinogenesis and has the potential to be a novel biomarker for CRC progression and prognosis.
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Affiliation(s)
- Shujuan Lin
- Department of Epidemiology and Biostatistics at School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Simeng Gu
- Department of Epidemiology and Biostatistics at School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Environmental Health, Institute of Endemic Diseases, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China
| | - Sangni Qian
- Department of Epidemiology and Biostatistics at School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yaxin Liu
- Institute of Environmental Medicine, and Cancer Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jinghao Sheng
- Institute of Environmental Medicine, and Cancer Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qilong Li
- Department of Screening, Jiashan Institute of Cancer Prevention and Treatment, Jiashan, China
| | - Jinhua Yang
- Department of Screening, Jiashan Institute of Cancer Prevention and Treatment, Jiashan, China
| | - Xiaojiang Ying
- Department of Anorectal Surgery, Shaoxing People’s Hospital, Shaoxing, China
| | - Zhenjun Li
- Department of Anorectal Surgery, Shaoxing People’s Hospital, Shaoxing, China
| | - Mengling Tang
- Department of Epidemiology and Biostatistics at School Public Health and the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianbing Wang
- Department of Epidemiology and Biostatistics at School of Public Health and National Clinical Research Center for Child Health of the Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kun Chen
- Department of Epidemiology and Biostatistics at School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mingjuan Jin
- Department of Epidemiology and Biostatistics at School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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27
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Epigenome-Wide DNA Methylation Profiling in Colorectal Cancer and Normal Adjacent Colon Using Infinium Human Methylation 450K. Diagnostics (Basel) 2022; 12:diagnostics12010198. [PMID: 35054365 PMCID: PMC8775085 DOI: 10.3390/diagnostics12010198] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/31/2021] [Accepted: 01/03/2022] [Indexed: 01/20/2023] Open
Abstract
The aims were to profile the DNA methylation in colorectal cancer (CRC) and to explore cancer-specific methylation biomarkers. Fifty-four pairs of CRCs and the adjacent normal tissues were subjected to Infinium Human Methylation 450K assay and analysed using ChAMP R package. A total of 26,093 differentially methylated probes were identified, which represent 6156 genes; 650 probes were hypermethylated, and 25,443 were hypomethylated. Hypermethylated sites were common in CpG islands, while hypomethylated sites were in open sea. Most of the hypermethylated genes were associated with pathways in cancer, while the hypomethylated genes were involved in the PI3K-AKT signalling pathway. Among the identified differentially methylated probes, we found evidence of four potential probes in CRCs versus adjacent normal; HOXA2 cg06786372, OPLAH cg17301223, cg15638338, and TRIM31 cg02583465 that could serve as a new biomarker in CRC since these probes were aberrantly methylated in CRC as well as involved in the progression of CRC. Furthermore, we revealed the potential of promoter methylation ADHFE1 cg18065361 in differentiating the CRC from normal colonic tissue from the integrated analysis. In conclusion, aberrant DNA methylation is significantly involved in CRC pathogenesis and is associated with gene silencing. This study reports several potential important methylated genes in CRC and, therefore, merit further validation as novel candidate biomarker genes in CRC.
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Wang A, Ma Q, Gong B, Sun L, Afrim FK, Sun R, He T, Huang H, Zhu J, Zhou G, Ba Y. DNA methylation and fluoride exposure in school-age children: Epigenome-wide screening and population-based validation. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 223:112612. [PMID: 34371455 DOI: 10.1016/j.ecoenv.2021.112612] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/02/2021] [Accepted: 08/04/2021] [Indexed: 06/13/2023]
Abstract
Excessive fluoride exposure and epigenetic change can induce numerous adverse health outcomes, but the role of epigenetics underneath the harmful health effects induced by fluoride exposure is unclear. In such gap, we evaluated the associations between fluoride exposure and genome-wide DNA methylation, and identified that novel candidate genes associated with fluoride exposure. A total of 931 school-age children (8-12 years) in Tongxu County of Henan Province (China) were recruited in 2017. Urinary fluoride (UF) concentrations were measured using the national standardized ion selective electrode method. Participants were divided into a high fluoride-exposure group (HFG) and control group (CG) according to the UF concentrations. Candidate differentially methylated regions (DMRs) were screened by Infinium-Methylation EPIC BeadChip of DNA samples collected from 16 participants (eight each from each group). Differentially methylated genes (DMGs) containing DMRs associated with skeletal and neuronal development influenced by fluoride exposure were confirmed using MethylTarget™ technology from 100 participants (fifty each from each group). DMGs were verified by quantitative methylation specific PCR from 815 participants. Serum levels of hormones were measured by auto biochemical analyzer. The mediation analysis of methylation in the effect of fluoride exposure on hormone levels was also performed. A total of 237 differentially methylated sites (DMSs) and 212 DMRs were found in different fluoride-exposure groups in the epigenome-wide phase. Methylation of the target sequences of neuronatin (NNAT), calcitonin-related polypeptide alpha (CALCA) and methylenetetrahydrofolate dehydrogenase 1 showed significant difference between the HFG and CG. Each 0.06% (95% CI: -0.11%, -0.01%) decreased in NNAT methylation status correlated with each increase of 1.0 mg/L in UF concentration in 815 school-age children using QMSP. Also, each 1.88% (95% CI: 0.04%, 3.72%) increase in CALCA methylation status correlated with each increase of 1.0 mg/L in UF concentration. The mediating effect of NNAT methylation was found in alterations of ACTH levels influenced by fluoride exposure, with a β value of 11.7% (95% CI: 3.4%, 33.4%). In conclusion, long-term fluoride exposure affected the methylation pattern of genomic DNA. NNAT and CALCA as DMGs might be susceptible to fluoride exposure in school-age children.
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Affiliation(s)
- Anqi Wang
- Department of Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, PR China; Environment and Health Innovation Team, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Qiang Ma
- Teaching and Research Office, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
| | - Biao Gong
- Department of Endemic Disease, Kaifeng Center for Disease Prevention and Control, Kaifeng, Henan 475004, PR China
| | - Long Sun
- Department of Endemic Disease, Kaifeng Center for Disease Prevention and Control, Kaifeng, Henan 475004, PR China
| | - Francis-Kojo Afrim
- Department of Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Renjie Sun
- Department of Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Tongkun He
- Department of Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Hui Huang
- Department of Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, PR China; Environment and Health Innovation Team, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Jingyuan Zhu
- Department of Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Guoyu Zhou
- Department of Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, PR China; Environment and Health Innovation Team, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, PR China
| | - Yue Ba
- Department of Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, PR China; Environment and Health Innovation Team, School of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, PR China.
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Anghel SA, Ioniță-Mîndrican CB, Luca I, Pop AL. Promising Epigenetic Biomarkers for the Early Detection of Colorectal Cancer: A Systematic Review. Cancers (Basel) 2021; 13:4965. [PMID: 34638449 PMCID: PMC8508438 DOI: 10.3390/cancers13194965] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 09/22/2021] [Accepted: 09/29/2021] [Indexed: 12/12/2022] Open
Abstract
In CRC, screening compliance is decreased due to the experienced discomfort associated with colonoscopy, although this method is the gold standard in terms of sensitivity and specificity. Promoter DNA methylation (hypomethylation or hypermethylation) has been linked to all CRC stages. Study objectives: to systematically review the current knowledge on approved biomarkers, reveal new potential ones, and inspect tactics that can improve performance. This research was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines; the risk of bias was evaluated using the revised Quality Assessment of Diagnostic Accuracy Studies criteria (QUADAS-2). The Web of Science® Core Collection, MEDLINE® and Scopus® databases were searched for original articles published in peer-reviewed journals with the specific keywords "colorectal cancer", "early detection", "early-stage colorectal cancer", "epigenetics", "biomarkers", "DNA methylation biomarkers", "stool or blood or tissue or biopsy", "NDRG4", "BMP3", "SEPT9", and "SDC2". Based on eligibility criteria, 74 articles were accepted for analysis. mSDC2 and mSEPT9 were frequently assessed in studies, alone or together as part of the ColoDefense panel test-the latter with the greatest performance. mBMP3 may not be an appropriate marker for detecting CRC. A panel of five methylated binding sites of the CTCF gene holds the promise for early-stage specific detection of CRC. CRC screening compliance and accuracy can be enhanced by employing a stool mt-DNA methylation test.
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Affiliation(s)
- Sorina Andreea Anghel
- Department of Clinical Laboratory, Food Safety, "Carol Davila" University of Medicine and Pharmacy, 6 Traian Vuia Street, 020945 Bucharest, Romania
- Department of Molecular Cell Biology, Institute of Biochemistry, Splaiul Independentei 296, 060031 Bucharest, Romania
| | - Corina-Bianca Ioniță-Mîndrican
- Department of Clinical Laboratory, Food Safety, "Carol Davila" University of Medicine and Pharmacy, 6 Traian Vuia Street, 020945 Bucharest, Romania
- Department of Toxicology, Faculty of Pharmacy, "Carol Davila" University of Medicine and Pharmacy, 020945 Bucharest, Romania
| | - Ioana Luca
- Department of Clinical Laboratory, Food Safety, "Carol Davila" University of Medicine and Pharmacy, 6 Traian Vuia Street, 020945 Bucharest, Romania
| | - Anca Lucia Pop
- Department of Clinical Laboratory, Food Safety, "Carol Davila" University of Medicine and Pharmacy, 6 Traian Vuia Street, 020945 Bucharest, Romania
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30
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Haskins IN, Wang BD, Bernot JP, Cauley E, Horvath A, Marks JH, Lee NH, Agarwal S. Genomics of Black American colon cancer disparities: An RNA sequencing (RNA-Seq) study from an academic, tertiary referral center. Surgery 2021; 170:1160-1167. [PMID: 34016457 PMCID: PMC8490290 DOI: 10.1016/j.surg.2021.03.031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 02/10/2021] [Accepted: 03/11/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Black Americans have a higher incidence and mortality rate from colorectal cancer compared to their non-Hispanic White American counterparts. Even when controlling for sociodemographic differences between these 2 populations, Black Americans remain disproportionately affected by colorectal cancer. The purpose of our study was to determine if differences in gene expression between Black American and non-Hispanic White American colon cancer specimens could help explain differences in the incidence and mortality rate between these 2 populations. METHODS Black Americans and non-Hispanic White Americans undergoing colon resection for stages I, II, or III colon cancer at a single institution were identified. Black American and non-Hispanic White American patients were matched for age, sex, and colon cancer stage to minimize the risk of confounding variables. Tissue samples were obtained at the time of colon resection and were analyzed using RNA sequencing to determine if there were differences in the expression of genes and biologic processes between the 2 groups. RESULTS A total of 17 colon cancer specimens were analyzed; 8 (47.1%) patients were Black Americans. A total of 456 genes were identified as being expressed differently (ie, up or downregulated) in Black American compared to non-Hispanic White American colon cancer specimens. Moreover, 500 different genetic pathways were noted to be significantly over-represented with differentially expressed genes in our comparison of Black American and non-Hispanic White American colon cancer specimens, the majority of which plays a role in inflammation and immune cell function. CONCLUSION Significant differences in gene expression and genetic pathways exist between Black Americans and non-Hispanic White Americans. Additional and multi-institutional and registry-based studies are needed to validate our findings and to further elucidate the contribution that these differences have to the overall incidence and mortality rate from colon cancer in these 2 patient populations.
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Affiliation(s)
- Ivy N Haskins
- Department of Surgery, George Washington University, Washington, DC; Department of Surgery, University of Nebraska Medical Center, Omaha, NE. https://twitter.com/IvyNHaskinsMD
| | - Bi-Dar Wang
- Department of Pharmacology & Physiology, School of Medicine and Health Sciences, GW Cancer Center, George Washington University, Washington, DC
| | - James P Bernot
- Department of Pharmacology & Physiology, School of Medicine and Health Sciences, GW Cancer Center, George Washington University, Washington, DC
| | - Edmund Cauley
- Department of Pharmacology & Physiology, School of Medicine and Health Sciences, GW Cancer Center, George Washington University, Washington, DC
| | - Anelia Horvath
- Department of Pharmacology & Physiology, School of Medicine and Health Sciences, GW Cancer Center, George Washington University, Washington, DC
| | - John H Marks
- Division of Colorectal Surgery, Lankenau Medical Center, Wynnewood, PA. https://twitter.com/JohnMarksMD
| | - Norman H Lee
- Department of Pharmacology & Physiology, School of Medicine and Health Sciences, GW Cancer Center, George Washington University, Washington, DC.
| | - Samir Agarwal
- Department of Surgery, George Washington University, Washington, DC; Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, FL.
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Cheng YC, Wu PH, Chen YJ, Yang CH, Huang JL, Chou YC, Chang PK, Wen CC, Jao SW, Huang HH, Tsai YH, Pai TW. Using Comorbidity Pattern Analysis to Detect Reliable Methylated Genes in Colorectal Cancer Verified by Stool DNA Test. Genes (Basel) 2021; 12:1539. [PMID: 34680934 PMCID: PMC8535797 DOI: 10.3390/genes12101539] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/26/2021] [Accepted: 09/27/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide in 2020. Colonoscopy and the fecal immunochemical test (FIT) are commonly used as CRC screening tests, but both types of tests possess different limitations. Recently, liquid biopsy-based DNA methylation test has become a powerful tool for cancer screening, and the detection of abnormal DNA methylation in stool specimens is considered as an effective approach for CRC screening. The aim of this study was to develop a novel approach in biomarker selection based on integrating primary biomarkers from genome-wide methylation profiles and secondary biomarkers from CRC comorbidity analytics. A total of 125 differential methylated probes (DMPs) were identified as primary biomarkers from 352 genome-wide methylation profiles. Among them, 51 biomarkers, including 48 hypermethylated DMPs and 3 hypomethylated DMPs, were considered as suitable DMP candidates for CRC screening tests. After comparing with commercial kits, three genes (ADHFE1, SDC2, and PPP2R5C) were selected as candidate epigenetic biomarkers for CRC screening tests. Methylation levels of these three biomarkers were significantly higher for patients with CRC than normal subjects. The sensitivity and specificity of integrating methylated ADHFE1, SDC2, and PPP2R5C for CRC detection achieved 84.6% and 92.3%, respectively. Through an integrated approach using genome-wide DNA methylation profiles and electronic medical records, we could design a biomarker panel that allows for early and accurate noninvasive detection of CRC using stool samples.
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Affiliation(s)
- Yi-Chiao Cheng
- Division of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (Y.-C.C.); (P.-H.W.); (P.-K.C.); (C.-C.W.); (S.-W.J.)
| | - Po-Hsien Wu
- Division of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (Y.-C.C.); (P.-H.W.); (P.-K.C.); (C.-C.W.); (S.-W.J.)
| | - Yen-Ju Chen
- Department of Computer Science and Information Engineering, National Taipei University of Technology, Taipei 10608, Taiwan; (Y.-J.C.); (Y.-H.T.)
| | - Cing-Han Yang
- Department of Computer Science and Engineering, National Taiwan Ocean University, Keelung 20224, Taiwan; (C.-H.Y.); (J.-L.H.)
| | - Jhen-Li Huang
- Department of Computer Science and Engineering, National Taiwan Ocean University, Keelung 20224, Taiwan; (C.-H.Y.); (J.-L.H.)
| | - Yu-Ching Chou
- School of Public Health, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Pi-Kai Chang
- Division of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (Y.-C.C.); (P.-H.W.); (P.-K.C.); (C.-C.W.); (S.-W.J.)
| | - Chia-Cheng Wen
- Division of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (Y.-C.C.); (P.-H.W.); (P.-K.C.); (C.-C.W.); (S.-W.J.)
| | - Shu-Wen Jao
- Division of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; (Y.-C.C.); (P.-H.W.); (P.-K.C.); (C.-C.W.); (S.-W.J.)
| | - Hsin-Hui Huang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, Taipei Medical University, Taipei 11042, Taiwan;
| | - Yi-Hsuan Tsai
- Department of Computer Science and Information Engineering, National Taipei University of Technology, Taipei 10608, Taiwan; (Y.-J.C.); (Y.-H.T.)
| | - Tun-Wen Pai
- Department of Computer Science and Information Engineering, National Taipei University of Technology, Taipei 10608, Taiwan; (Y.-J.C.); (Y.-H.T.)
- Department of Computer Science and Engineering, National Taiwan Ocean University, Keelung 20224, Taiwan; (C.-H.Y.); (J.-L.H.)
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32
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Genome-wide DNA methylation profiling and gut flora analysis in intestinal polyps patients. Eur J Gastroenterol Hepatol 2021; 33:1071-1081. [PMID: 34213504 DOI: 10.1097/meg.0000000000002181] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The intestinal polyp is the precancerous lesion of colorectal cancer. DNA methylation and intestinal microbiota may play an important role in the development of intestinal polyp. MATERIALS AND METHODS In this study, we included 10 patients with intestinal polyps who received the colonoscopy examination. We applied the Illumina Human Methylation 850K array to investigate the epigenome-wide DNA methylation patterns. Then, we filtered out the hub genes in the protein-protein interaction networks using functional epigenetic modules analysis. We also analyzed the colonizing bacteria on the surface of polyps compared with those in normal colonic mucosal epithelium with 16S ribosomal DNA sequencing. RESULTS We identified 323 hypermethylated sites and 7992 hypomethylated sites between intestinal polyps and normal samples. Five hub genes, including CREB1, LPA, SVIL and KRT18, were identified in five modules. Hypomethylation of CREB1 is a candidate marker of colorectal adenoma. Gut microbiota analysis showed that Butyricicoccus was significantly decreased in the intestinal polyp groups. CONCLUSION In conclusion, we identified DNA methylation disparities in intestinal polyps compared with normal tissue, of which methylation of CREB1 may hold clinical significance in colorectal cancer progress. Colonizing bacteria in the colonic epithelium might be related to the formation of intestinal polyps.
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Chen Q, Wu Q, Peng Y. ADHFE1 is a correlative factor of patient survival in cancer. Open Life Sci 2021; 16:571-582. [PMID: 34179501 PMCID: PMC8216228 DOI: 10.1515/biol-2021-0065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/10/2021] [Accepted: 05/13/2021] [Indexed: 12/23/2022] Open
Abstract
Alcohol dehydrogenase iron containing 1 (ADHFE1) encodes a hydroxyacid-oxoacid transhydrogenase participating in multiple biological processes. The role of ADHFE1 in cancer has not been fully uncovered. Herein, we performed data analysis to investigate the expression of ADHFE1 and the underlying regulatory mechanisms, its relationship with cancer patients’ survival, and the relevant pathways in cancer. A range of recognized, web-available databases and bioinformatics tools were used in this in silico study. We found that ADHFE1 was frequently downregulated and hypermethylated in various cancer cell lines and tissue samples. High expression of ADHFE1 was positively associated with favorable patient prognosis in breast, colon, and gastric cancers. Pathway analysis revealed its potential role in cancer-related biological processes, including energy metabolism, DNA replication, and cell cycle regulation. AHDFE1 mRNA expression and DNA methylation can potentially be used as diagnostic markers in cancer and might be of great value in predicting the survival of patients with cancer.
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Affiliation(s)
- Qi Chen
- Department of Traditional Chinese Medicine, The First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Qiyan Wu
- Cancer Center Key Lab, The First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Yaojun Peng
- Department of Emergency, The First Medical Centre, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China
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Huang W, Weng W, Wu B, Ye T, Lin Z, Zhang Z, Shi K. Development and validation of the trans-omics model for pancreatic adenocarcinoma. Epigenomics 2021; 13:15-30. [PMID: 33356543 DOI: 10.2217/epi-2020-0184] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Aim: To develop a trans-omics-based molecular clinicopathological algorithm for predicting pancreatic adenocarcinoma prognosis, we performed a comprehensive analysis of the expression levels of mRNA, DNA methylation and DNA copy number in The Cancer Genome Atlas dataset. Materials & methods: Based on the least absolute shrinkage and selection operator method - COX regression analysis, a trans-omics-based classifier was established to predict overall survival. Nomogram was constructed by combining the classifier band clinical pathological characterization. Results: Based on trans-omics, we developed a 10-gene-based classifier and a molecular-clinicopathologic nomogram for predicting overall survival with satisfactory accuracy. Conclusion: Trans-omics-based classifier and molecule-clinicopathological nomogram based on the classifier can accurately predict the prognosis of pancreatic adenocarcinoma patients.
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Affiliation(s)
- Weiguo Huang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang Province, PR China
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang Province, PR China
| | - Wanqing Weng
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang Province, PR China
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang Province, PR China
| | - Boda Wu
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang Province, PR China
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang Province, PR China
| | - Tingbo Ye
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang Province, PR China
| | - Zhuo Lin
- Department of Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, PR China
| | - Zhongjing Zhang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang Province, PR China
| | - Keqing Shi
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang Province, PR China
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Li D, Zhang L, Fu J, Huang H, Sun S, Zhang D, Zhao L, Ucheojor Onwuka J, Zhao Y, Cui B. SCTR hypermethylation is a diagnostic biomarker in colorectal cancer. Cancer Sci 2020; 111:4558-4566. [PMID: 32970347 PMCID: PMC7734158 DOI: 10.1111/cas.14661] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 07/12/2020] [Accepted: 09/12/2020] [Indexed: 12/12/2022] Open
Abstract
Diagnostic markers for both colorectal cancer (CRC) and its precursor lesions are lacking. Although aberrant methylation of the secretin receptor (SCTR) gene was observed in CRC, the diagnostic performance has not been evaluated. Therefore, this study aimed to assess and verify the diagnostic value of SCTR methylation of CRC and its precursor lesions through integrating the largest methylation data. The diagnostic performance of SCTR methylation was analyzed in the discovery set from The Cancer Genome Atlas (TCGA) CRC methylation data (N = 440), and verified in a large-scale test set (N = 938) from the Gene Expression Omnibus (GEO). Targeted bisulfite sequencing analysis was developed and applied to detect the methylation status of SCTR in our independent validation set (N = 374). Our findings revealed that the SCTR gene was frequently hypermethylated at its CpG islands in CRC. In the TCGA discovery set, the diagnostic score was constructed using 4 CpG sites (cg01013590, cg20505223, cg07176264, and cg26009192) and achieved high diagnostic performance (area under the ROC curve [AUC] = 0.964). In the GEO test set, the diagnostic score had robust diagnostic ability to distinguish CRC (AUC = 0.948) and its precursor lesions (AUC = 0.954) from normal samples. Moreover, hypermethylation of the SCTR gene was also found in cell-free DNA samples collected from CRC patients, but not in those from healthy controls. In the validation set, consistent results were observed using the targeted bisulfite sequencing array. Our study highlights that hypermethylation at CpG islands of the SCTR gene is a potential diagnostic biomarker in CRCs and its precursor lesions.
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Affiliation(s)
- DaPeng Li
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Lei Zhang
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - JinMing Fu
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Hao Huang
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - SiMin Sun
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Ding Zhang
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - LiYuan Zhao
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Justina Ucheojor Onwuka
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - YaShuang Zhao
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - BinBin Cui
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin, China
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36
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Johnstone SE, Reyes A, Qi Y, Adriaens C, Hegazi E, Pelka K, Chen JH, Zou LS, Drier Y, Hecht V, Shoresh N, Selig MK, Lareau CA, Iyer S, Nguyen SC, Joyce EF, Hacohen N, Irizarry RA, Zhang B, Aryee MJ, Bernstein BE. Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer. Cell 2020; 182:1474-1489.e23. [PMID: 32841603 PMCID: PMC7575124 DOI: 10.1016/j.cell.2020.07.030] [Citation(s) in RCA: 140] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 05/04/2020] [Accepted: 07/20/2020] [Indexed: 02/06/2023]
Abstract
Widespread changes to DNA methylation and chromatin are well documented in cancer, but the fate of higher-order chromosomal structure remains obscure. Here we integrated topological maps for colon tumors and normal colons with epigenetic, transcriptional, and imaging data to characterize alterations to chromatin loops, topologically associated domains, and large-scale compartments. We found that spatial partitioning of the open and closed genome compartments is profoundly compromised in tumors. This reorganization is accompanied by compartment-specific hypomethylation and chromatin changes. Additionally, we identify a compartment at the interface between the canonical A and B compartments that is reorganized in tumors. Remarkably, similar shifts were evident in non-malignant cells that have accumulated excess divisions. Our analyses suggest that these topological changes repress stemness and invasion programs while inducing anti-tumor immunity genes and may therefore restrain malignant progression. Our findings call into question the conventional view that tumor-associated epigenomic alterations are primarily oncogenic.
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Affiliation(s)
- Sarah E Johnstone
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA
| | - Alejandro Reyes
- Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Data Sciences, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02215, USA
| | - Yifeng Qi
- Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Carmen Adriaens
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA
| | - Esmat Hegazi
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA
| | - Karin Pelka
- Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA
| | - Jonathan H Chen
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA
| | - Luli S Zou
- Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Data Sciences, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02215, USA
| | - Yotam Drier
- The Lautenberg Center for Immunology and Cancer Research, The Hebrew University, Jerusalem, Israel
| | - Vivian Hecht
- Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA
| | - Noam Shoresh
- Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA
| | - Martin K Selig
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Caleb A Lareau
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02215, USA
| | - Sowmya Iyer
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Son C Nguyen
- Department of Genetics, Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Eric F Joyce
- Department of Genetics, Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nir Hacohen
- Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA
| | - Rafael A Irizarry
- Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Data Sciences, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02215, USA
| | - Bin Zhang
- Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Martin J Aryee
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02215, USA.
| | - Bradley E Bernstein
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02129, USA.
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