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Dupont WD, Jones AL, Smith JR. Coding Variants of the Genitourinary Development Gene WNT9B Carry High Risk for Prostate Cancer. JCO Precis Oncol 2025; 9:e2400569. [PMID: 39874495 PMCID: PMC11980042 DOI: 10.1200/po-24-00569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 10/24/2024] [Accepted: 12/04/2024] [Indexed: 01/30/2025] Open
Abstract
PURPOSE Considerable genetic heterogeneity is currently thought to underlie hereditary prostate cancer (HPC). Most families meeting criteria for HPC cannot be attributed to currently known pathogenic variants. METHODS To discover pathogenic variants predisposing to prostate cancer, we conducted a familial case-control association study using both genome-wide single-allele and identity-by-descent analytic approaches. Sequence of high-risk haplotype carriers was used for variant detection. Candidate pathogenic variants were tested for association with prostate cancer across independent biobanks for replication of observations. RESULTS Pathogenic variants within WNT9B were associated with familial prostate cancer and observations replicated within four of four independent biobanks. WNT9B E152K carried 2.5-fold risk and reached genome-wide significance under meta-analysis, collectively encompassing a half million patients. WNT9B Q47R was also associated with prostate cancer with genome-wide significance among Finns, for which identity-by-descent analyses confirmed a founder effect. WNT9B shares an unexpected commonality with the previously established prostate cancer risk genes HOXB13 and HNF1B: they are each required for embryonic prostate development. With this recognition, we further evaluated two additional genes known to cause Mendelian genitourinary developmental defects, KMT2D and DHCR7. These too were nominally associated with prostate cancer under meta-analyses. CONCLUSION WNT9B and additional genes that are required for early genitourinary development are also involved in the later development of prostate cancer.
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Affiliation(s)
- William D. Dupont
- Medical Research Service, Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - Angela L. Jones
- Vanderbilt Technologies for Advanced Genomics, Vanderbilt University Medical Center, Nashville, TN
| | | | - Jeffrey R. Smith
- Medical Research Service, Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
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Gholami M, Asouri M, Ahmadi AA. Genetic Variants and Haplotype Structures in the CASC Gene Family to Predict Cancer Risk: A Bioinformatics Study. Health Sci Rep 2024; 7:e70228. [PMID: 39640032 PMCID: PMC11618408 DOI: 10.1002/hsr2.70228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 10/01/2024] [Accepted: 11/05/2024] [Indexed: 12/07/2024] Open
Abstract
Background and Aims The cancer susceptibility (CASC) gene family of long noncoding RNAs (lncRNAs) plays an important role in cancer. The aim of this study was to identify genetic variants and haplotype structures of CASC genes associated with cancer risk. Methods Genome-wide association studies (GWAS) significant variants (p ≤ 5 × 10-8) on CASC family genes were identified from the GWAS Catalog-EMBL-EBI, and then cancer-associated variants on CASC genes were extracted. These variants were functionally analyzed, including lncRNA:miRNA binding sites, Regulomedb scores, and eQTL. The 1000 Genome Project genotyping data Phase III were used to identify haplotypic blocks. Finally, the genes associated with them were examined for expression and gene-gene correlation analyses using OncoDB. Results There were six haplotypic blocks in four genes. The GC, TA, and AGAC haplotypes are located in the CASC8 gene and increase the risk of prostate cancer, breast cancer, and colorectal cancer, respectively. The CA haplotype in the CASC15 gene increases the risk of neuroblastoma, AA haplotype in the CASC16 gene increases the risk of breast cancer, and ACGATG haplotype in the CASC17 gene increases the risk of prostate cancer (p ≤ 5 × 10-8). Their genes are interrelated and their expression is increased in these cancers. The rs2294214 is associated with skin cancer and has positive effects on five CASC15:miRNA binding sites. The rs3803662 is located in CASC16:miRNA binding sites, which has positive effects on hsa-miR-4475 and hsa-miR-7845-5p and negative effects on hsa-miR-4524a-3p and hsa-miR-4524b-3p. Conclusion These haplotypic structures and lncRNA:miRNA:SNP interactions on CASC family lncRNAs reveal novel genetic associations between CASC genes and various cancers.
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Affiliation(s)
- Morteza Gholami
- Department of ParamedicineAmol School of Paramedicine, Mazandaran University of Medical SciencesSariIran
- Metabolic Disorders Research CenterEndocrinology and Metabolism Molecular‐Cellular Sciences Institute, Tehran University of Medical SciencesTehranIran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences InstituteTehran University of Medical SciencesTehranIran
| | - Mohsen Asouri
- Department of ParamedicineAmol School of Paramedicine, Mazandaran University of Medical SciencesSariIran
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Zhang LX, Luo PQ, Wei ZJ, Xu AM, Guo T. Expression and significant roles of the long non-coding RNA CASC19/miR-491-5p/HMGA2 axis in the development of gastric cancer. World J Gastrointest Oncol 2024; 16:3559-3584. [PMID: 39171190 PMCID: PMC11334029 DOI: 10.4251/wjgo.v16.i8.3559] [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: 12/20/2023] [Revised: 04/25/2024] [Accepted: 06/12/2024] [Indexed: 08/07/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is a common malignant tumor, long non-coding RNA and microRNA (miRNA) are important regulators that affect tumor proliferation, metastasis and chemotherapy resistance, and thus participate in tumor progression. CASC19 is a new bio-marker which can promote tumor invasion and metastasis. However, the mechanism by which CASC19 affects the progression of GC through miRNA is not clear. AIM To explore the role of the CASC19/miR-491-5p/HMGA2 regulatory axis in GC. METHODS To explore the expression and prognosis of CASC19 in GC through clinical samples, and investigate the effects of inhibiting CASC19 on the proliferation, migration, invasion and other functions of GC cells through cell counting Kit-8 (CCK-8), ethynyldeoxyuridine, Wound healing assay, Transwell, Western blot and flow cytometry experiments. The effect of miR-491-5p and HMGA2 in GC were also proved. The regulatory relationship between CASC19 and miR-491-5p, miR-491-5p and HMGA2 were validated through Dual-luciferase reporter gene assay and reverse transcription PCR. Then CCK-8, Transwell, Wound healing assay, flow cytometry and animal experiments verify the role of CASC19/miR-491-5p/HMGA2 regulatory axis. RESULTS The expression level of CASC19 is related to the T stage, N stage, and tumor size of patients. Knockdown of the expression of CASC19 can inhibit the ability of proliferation, migration, invasion and EMT conversion of GC cells, and knocking down the expression of CASC19 can promote the apoptosis of GC cells. Increasing the expression of miR-491-5p can inhibit the proliferation of GC cells, miR-491-5p mimics can inhibit EMT conversion, and promote the apoptosis of GC cells, while decreasing the expression of miR-491-5p can promote the proliferation and EMT conversion and inhibit the apoptosis of GC cells. The expression of HMGA2 in GC tissues is higher than that in adjacent tissues. At the same time, the expression level of HMGA2 is related to the N and T stages of the patients. Reducing the level of HMGA2 can promote cell apoptosis and inhibit the proliferation of GC cells. Cell experiments and animal experiments have proved that CASC19 can regulates the expression of HMGA2 through miR-491-5p, thereby affecting the biological functions of GC. CONCLUSION CASC19 regulates the expression of HMGA2 through miR-491-5p to affect the development of GC. This axis may serve as a potential biomarker and therapeutic target of GC.
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Affiliation(s)
- Li-Xiang Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei 230031, Anhui Province, China
- Anhui Provincial Key Laboratory of Digestive Disease, Hefei 230031, Anhui Province, China
| | - Pan-Quan Luo
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230031, Anhui Province, China
| | - Zhi-Jian Wei
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230031, Anhui Province, China
| | - A-Man Xu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230031, Anhui Province, China
| | - Tao Guo
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230031, Anhui Province, China
- Anhui Public Health Clinical Center, Hefei 230000, Anhui Province, China
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Gholami M. Common and novel haplotype structures between different types of cancer. Cancer Rep (Hoboken) 2024; 7:e2107. [PMID: 39031745 PMCID: PMC11190585 DOI: 10.1002/cnr2.2107] [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: 02/16/2024] [Revised: 04/03/2024] [Accepted: 05/07/2024] [Indexed: 07/22/2024] Open
Abstract
BACKGROUND Background: Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with cancer risk. GWAS data are important for cancer prevention and understanding the underlying mechanisms of cancer. AIMS This study aimed to investigate the genetic association between different types of cancer using GWAS data and a bioinformatics approach. METHODS AND RESULTS The significant GWAS variants associated with more than one cancer type were identified. Common linkage disequilibrium (LD) variants between different types of cancer were identified by 1000 genomes phase 3 LD data. Haplotype blocks were identified by analyzing 1000 Genomes phase 3 genotyping data in the GWAS populations. Subsequent analyses included functional SNP analyses and TCGA gene expression. The results associated with significant GWAS variants (P<5E-8) showed the following haplotype associations in European population: GT rs4808075-rs8170 haplotype on BABAM1 with breast and ovarian cancers, GC rs16857609-rs11693806 haplotype on DIRC3 with breast and thyroid cancers, GCG rs380286-rs401681-rs31487 haplotype on CLPTM1L with skin and lung cancers, GGG rs4430796-rs11651052-rs11263763 haplotype on HNF1B with prostate and endometrial cancers, and GT rs10505477-rs6983267 haplotype on CASC8 associated with colorectal and prostate cancers. All these genes had significantly different expressions in tumor tissues (P<1E-3). In addition, the rs11693806 variant is located in the hsa-miR-873-5p binding site and has an enhancing effect on the hsa-miR-873-5p:DIRC3 interaction. CONCLUSION These novel haplotype structures and miRNA:lncRNA interactions are important for understanding the common genetic link between cancers. These results can potentially be used in genetic panels.
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Affiliation(s)
- Morteza Gholami
- Department of Paramedicine, Amol School of Paramedical SciencesMazandaran University of Medical SciencesSariIran
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular‐Cellular Sciences InstituteTehran University of Medical SciencesTehranIran
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Wang S, Qiao C, Fang R, Yang S, Zhao G, Liu S, Li P. LncRNA CASC19: a novel oncogene involved in human cancer. Clin Transl Oncol 2023; 25:2841-2851. [PMID: 37029242 DOI: 10.1007/s12094-023-03165-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 03/20/2023] [Indexed: 04/09/2023]
Abstract
Multiple studies have shown that long non-coding RNAs (lncRNAs) play an important role in the occurrence and development of diverse cancers. Cancer susceptibility candidate 19 (CASC19), encoded by chromosome 8q24.21, is a newly discovered lncRNA that contains 324 nucleotides. CASC19 has been found to be significantly overexpressed in different human cancers, such as non-small cell lung carcinoma, gastric cancer, colorectal cancer, pancreatic cancer, clear cell renal cell carcinoma, glioma, cervical cancer, and nasopharyngeal carcinoma. Moreover, dysregulation of CASC19 was closely associated with clinicopathological parameters and cancer progression. CASC19 regulates a variety of cell phenotypes, including cell proliferation, apoptosis, cell cycle, migration, invasion, epithelial-mesenchymal transition, autophagy, and therapeutic resistance. In this study, we review recent studies on the characteristics and biological function of CASC19, as well as its role in human cancers. These findings suggest that CASC19 may be both a reliable biomarker and a potential therapeutic target in cancers.
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Affiliation(s)
- Shidong Wang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing, 100050, China
| | - Chen Qiao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing, 100050, China
| | - Rui Fang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing, 100050, China
| | - Shuyue Yang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing, 100050, China
| | - Guiping Zhao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, 100050, China
- National Clinical Research Center for Digestive Diseases, Beijing, 100050, China
| | - Si Liu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, 100050, China.
- National Clinical Research Center for Digestive Diseases, Beijing, 100050, China.
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, 100050, China.
- National Clinical Research Center for Digestive Diseases, Beijing, 100050, China.
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Rafikova G, Gilyazova I, Enikeeva K, Pavlov V, Kzhyshkowska J. Prostate Cancer: Genetics, Epigenetics and the Need for Immunological Biomarkers. Int J Mol Sci 2023; 24:12797. [PMID: 37628978 PMCID: PMC10454494 DOI: 10.3390/ijms241612797] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/08/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Epidemiological data highlight prostate cancer as a significant global health issue, with high incidence and substantial impact on patients' quality of life. The prevalence of this disease is associated with various factors, including age, heredity, and race. Recent research in prostate cancer genetics has identified several genetic variants that may be associated with an increased risk of developing the disease. However, despite the significance of these findings, genetic markers for prostate cancer are not currently utilized in clinical practice as reliable indicators of the disease. In addition to genetics, epigenetic alterations also play a crucial role in prostate cancer development. Aberrant DNA methylation, changes in chromatin structure, and microRNA (miRNA) expression are major epigenetic events that influence oncogenesis. Existing markers for prostate cancer, such as prostate-specific antigen (PSA), have limitations in terms of sensitivity and specificity. The cost of testing, follow-up procedures, and treatment for false-positive results and overdiagnosis contributes to the overall healthcare expenditure. Improving the effectiveness of prostate cancer diagnosis and prognosis requires either narrowing the risk group by identifying new genetic factors or enhancing the sensitivity and specificity of existing markers. Immunological biomarkers (both circulating and intra-tumoral), including markers of immune response and immune dysfunction, represent a potentially useful area of research for enhancing the diagnosis and prognosis of prostate cancer. Our review emphasizes the need for developing novel immunological biomarkers to improve the diagnosis, prognosis, and management of prostate cancer. We highlight the most recent achievements in the identification of biomarkers provided by circulating monocytes and tumor-associated macrophages (TAMs). We highlight that monocyte-derived and TAM-derived biomarkers can enable to establish the missing links between genetic predisposition, hormonal metabolism and immune responses in prostate cancer.
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Affiliation(s)
- Guzel Rafikova
- Institute of Urology and Clinical Oncology, Bashkir State Medical University, 450077 Ufa, Russia (K.E.); (V.P.)
| | - Irina Gilyazova
- Institute of Urology and Clinical Oncology, Bashkir State Medical University, 450077 Ufa, Russia (K.E.); (V.P.)
- Institute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of Sciences, 450054 Ufa, Russia
| | - Kadriia Enikeeva
- Institute of Urology and Clinical Oncology, Bashkir State Medical University, 450077 Ufa, Russia (K.E.); (V.P.)
| | - Valentin Pavlov
- Institute of Urology and Clinical Oncology, Bashkir State Medical University, 450077 Ufa, Russia (K.E.); (V.P.)
| | - Julia Kzhyshkowska
- Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, 634050 Tomsk, Russia
- Genetic Technology Laboratory, Siberian State Medical University, 634050 Tomsk, Russia
- Institute of Transfusion Medicine and Immunology, Mannheim Institute of Innate Immunosciences (MI3), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- German Red Cross Blood Service Baden-Württemberg—Hessen, 68167 Mannheim, Germany
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Bozgeyik E. Variations in genomic regions encoding long non-coding RNA genes associated with increased prostate cancer risk. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2023; 791:108456. [PMID: 36948485 DOI: 10.1016/j.mrrev.2023.108456] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 03/15/2023] [Accepted: 03/17/2023] [Indexed: 03/24/2023]
Abstract
From a single restriction fragment length polymorphism analysis to next generation sequencing analysis that screens the entire human genome, testing for genomic variations provides a great and robust approach to cancer testing. Non-coding RNAs have been shown to have a major impact on the development and progression of human cancers, including prostate cancer. However, the low stability of these molecules under laboratory conditions has made their clinical utility challenging, as in the case of PCA3 long non-coding RNA. Since testing for variations in genomic regions encoding non-coding RNAs offers a promising approach for cancer testing, identification and interpretation of single nucleotide polymorphisms associated with prostate cancer susceptibility is of great interest. Accordingly, here, for the first time, we review and discuss current available knowledge about genomic variation of long non-coding RNA molecules in prostate cancer.
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Affiliation(s)
- Esra Bozgeyik
- Department of Medical Services and Techniques, Vocational School of Health Services, Adiyaman University, Adiyaman, Turkey.
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Zamani M, Foroughmand AM, Hajjari MR, Bakhshinejad B, Johnson R, Galehdari H. CASC11 and PVT1 spliced transcripts play an oncogenic role in colorectal carcinogenesis. Front Oncol 2022; 12:954634. [PMID: 36052265 PMCID: PMC9424822 DOI: 10.3389/fonc.2022.954634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer is fundamentally a genetic disorder that alters cellular information flow toward aberrant growth. The coding part accounts for less than 2% of the human genome, and it has become apparent that aberrations within the noncoding genome drive important cancer phenotypes. The numerous carcinogenesis-related genomic variations in the 8q24 region include single nucleotide variations (SNVs), copy number variations (CNVs), and viral integrations occur in the neighboring areas of the MYC locus. It seems that MYC is not the only target of these alterations. The MYC-proximal mutations may act via regulatory noncoding RNAs (ncRNAs). In this study, gene expression analyses indicated that the expression of some PVT1 spliced linear transcripts, CircPVT1, CASC11, and MYC is increased in colorectal cancer (CRC). Moreover, the expression of these genes is associated with some clinicopathological characteristics of CRC. Also, in vitro studies in CRC cell lines demonstrated that CASC11 is mostly detected in the nucleus, and different transcripts of PVT1 have different preferences for nuclear and cytoplasmic parts. Furthermore, perturbation of PVT1 expression and concomitant perturbation in PVT1 and CASC11 expression caused MYC overexpression. It seems that transcription of MYC is under regulatory control at the transcriptional level, i.e., initiation and elongation of transcription by its neighboring genes. Altogether, the current data provide evidence for the notion that these noncoding transcripts can significantly participate in the MYC regulation network and in the carcinogenesis of colorectal cells.
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Affiliation(s)
- Mina Zamani
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | | | - Mohammad-Reza Hajjari
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Babak Bakhshinejad
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Rory Johnson
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- School of Biology and Environmental Science, University College Dublin, Dublin, Ireland
- Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Hamid Galehdari
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
- *Correspondence: Hamid Galehdari,
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Larson NB, McDonnell SK, Fogarty Z, Liu Y, French AJ, Tillmans LS, Cheville JC, Wang L, Schaid DJ, Thibodeau SN. A microRNA Transcriptome-wide Association Study of Prostate Cancer Risk. Front Genet 2022; 13:836841. [PMID: 35432445 PMCID: PMC9006872 DOI: 10.3389/fgene.2022.836841] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/22/2022] [Indexed: 11/13/2022] Open
Abstract
Large genome-wide association studies have identified hundreds of single-nucleotide polymorphisms associated with increased risk of prostate cancer (PrCa), and many of these risk loci is presumed to confer regulatory effects on gene expression. While eQTL studies of long RNAs has yielded many potential risk genes, the relationship between PrCa risk genetics and microRNA expression dysregulation is understudied. We performed an microRNA transcriptome-wide association study of PrCa risk using small RNA sequencing and genome-wide genotyping data from N = 441 normal prostate epithelium tissue samples along with N = 411 prostate adenocarcinoma tumor samples from the Cancer Genome Atlas (TCGA). Genetically regulated expression prediction models were trained for all expressed microRNAs using the FUSION TWAS software. TWAS for PrCa risk was performed with both sets of models using single-SNP summary statistics from the recent PRACTICAL consortium PrCa case-control OncoArray GWAS meta-analysis. A total of 613 and 571 distinct expressed microRNAs were identified in the normal and tumor tissue datasets, respectively (overlap: 480). Among these, 79 (13%) normal tissue microRNAs demonstrated significant cis-heritability (median cis-h2 = 0.15, range: 0.03–0.79) for model training. Similar results were obtained from TCGA tumor samples, with 48 (9%) microRNA expression models successfully trained (median cis-h2 = 0.14, range: 0.06–0.60). Using normal tissue models, we identified two significant TWAS microRNA associations with PrCa risk: over-expression of mir-941 family microRNAs (PTWAS = 2.9E-04) and reduced expression of miR-3617-5p (PTWAS = 1.0E-03). The TCGA tumor TWAS also identified a significant association with miR-941 overexpression (PTWAS = 9.7E-04). Subsequent finemapping of the TWAS results using a multi-tissue database indicated limited evidence of causal status for each microRNA with PrCa risk (posterior inclusion probabilities <0.05). Future work will examine downstream regulatory effects of microRNA dysregulation as well as microRNA-mediated risk mechanisms via competing endogenous RNA relationships.
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Affiliation(s)
- Nicholas B. Larson
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
- *Correspondence: Nicholas B. Larson,
| | - Shannon K. McDonnell
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
| | - Zachary Fogarty
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
| | - Yuanhang Liu
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
| | - Amy J. French
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| | - Lori S. Tillmans
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| | - John C. Cheville
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| | - Liang Wang
- Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL, United States
| | - Daniel J. Schaid
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
| | - Stephen N. Thibodeau
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
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Metabolomics and the Multi-Omics View of Cancer. Metabolites 2022; 12:metabo12020154. [PMID: 35208228 PMCID: PMC8880085 DOI: 10.3390/metabo12020154] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 01/29/2022] [Accepted: 01/31/2022] [Indexed: 11/17/2022] Open
Abstract
Cancer is widely regarded to be a genetic disease. Indeed, over the past five decades, the genomic perspective on cancer has come to almost completely dominate the field. However, this genome-only view is incomplete and tends to portray cancer as a disease that is highly heritable, driven by hundreds of complex genetic interactions and, consequently, difficult to prevent or treat. New evidence suggests that cancer is not as heritable or purely genetic as once thought and that it really is a multi-omics disease. As highlighted in this review, the genome, the exposome, and the metabolome all play roles in cancer’s development and manifestation. The data presented here show that >90% of cancers are initiated by environmental exposures (the exposome) which lead to cancer-inducing genetic changes. The resulting genetic changes are, then, propagated through the altered DNA of the proliferating cancer cells (the genome). Finally, the dividing cancer cells are nourished and sustained by genetically reprogrammed, cancer-specific metabolism (the metabolome). As shown in this review, all three “omes” play roles in initiating cancer. Likewise, all three “omes” interact closely, often providing feedback to each other to sustain or enhance tumor development. Thanks to metabolomics, these multi-omics feedback loops are now much more evident and their roles in explaining the hallmarks of cancer are much better understood. Importantly, this more holistic, multi-omics view portrays cancer as a disease that is much more preventable, easier to understand, and potentially, far more treatable.
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11
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Sipeky C, Tammela TLJ, Auvinen A, Schleutker J. Novel prostate cancer susceptibility gene SP6 predisposes patients to aggressive disease. Prostate Cancer Prostatic Dis 2021; 24:1158-1166. [PMID: 34012061 PMCID: PMC8616752 DOI: 10.1038/s41391-021-00378-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 03/17/2021] [Accepted: 04/28/2021] [Indexed: 02/04/2023]
Abstract
Prostate cancer (PrCa) is one of the most common cancers in men, but little is known about factors affecting its clinical outcomes. Genome-wide association studies have identified more than 170 germline susceptibility loci, but most of them are not associated with aggressive disease. We performed a genome-wide analysis of 185,478 SNPs in Finnish samples (2738 cases, 2400 controls) from the international Collaborative Oncological Gene-Environment Study (iCOGS) to find underlying PrCa risk variants. We identified a total of 21 common, low-penetrance susceptibility loci, including 10 novel variants independently associated with PrCa risk. Novel risk loci were located in the 8q24 (CASC8 rs16902147, OR 1.86, padj = 3.53 × 10-8 and rs58809953, OR 1.71, padj = 4.00 × 10-6; intergenic rs79012498, OR 1.81, padj = 4.26 × 10-8), 17q21 (SP6 rs2074187, OR 1.66, padj = 3.75 × 10-5), 11q13 (rs12795301, OR 1.42, padj = 2.89 × 10-5) and 8p21 (rs995432, OR 1.38, padj = 3.00 × 10-11) regions. Here, we describe SP6, a transcription factor gene, as a new, potentially high-risk gene for PrCa. The intronic variant rs2074187 in SP6 was associated not only with overall susceptibility to PrCa (OR 1.66) but also with a higher odds ratio for aggressive PrCa (OR 1.89) and lower odds for non-aggressive PrCa (OR 1.43). Furthermore, the new intergenic variant rs79012498 at 8q24 conferred risk for aggressive PrCa. Our findings highlighted the power of a population-stratified approach to identify novel, clinically actionable germline PrCa risk loci and strongly suggested SP6 as a new PrCa candidate gene that may be involved in the pathogenesis of PrCa.
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Affiliation(s)
- Csilla Sipeky
- Institute of Biomedicine and FICAN West Cancer Centre, University of Turku and Turku University Hospital, Turku, Finland
- UCB Pharma, Data & Translational Sciences, Braine l'Alleud, Belgium
| | - Teuvo L J Tammela
- Department of Urology, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Anssi Auvinen
- Unit of Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland
| | - Johanna Schleutker
- Institute of Biomedicine and FICAN West Cancer Centre, University of Turku and Turku University Hospital, Turku, Finland.
- Department of Medical Genetics, Genomics, Laboratory Division, Turku University Hospital, Turku, Finland.
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12
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Abstract
The G84E germline mutation of HOXB13 predisposes to prostate cancer and is clinically tested for familial cancer care. We investigated the HOXB locus to define a potentially broader contribution to prostate cancer heritability. We sought HOXB locus germline variants altering prostate cancer risk in three European-ancestry case-control study populations (combined 7812 cases and 5047 controls): the International Consortium for Prostate Cancer Genetics Study; the Nashville Familial Prostate Cancer Study; and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Multiple rare genetic variants had concordant and strong risk effects in these study populations and exceeded genome-wide significance. Independent risk signals were best detected by sentinel variants rs559612720 within SKAP1 (OR = 8.1, P = 2E-9) and rs138213197 (G84E) within HOXB13 (OR = 5.6, P = 2E-11), separated by 567 kb. Half of carriers inherited both risk alleles, while others inherited either alone. Under mutual adjustment, the variants separately carried 3.6- and 3.1-fold risk, respectively, while joint inheritance carried 11.3-fold risk. These risks were further accentuated among men meeting criteria for hereditary prostate cancer, and further still for those with early-onset or aggressive disease. Among hereditary prostate cancer cases diagnosed under age 60 and with aggressive disease, joint inheritance carried a risk of OR = 27.7 relative to controls, P = 2E-8. The HOXB sentinel variant pair more fully captured genetic risk for prostate cancer within the study populations than either variant alone.
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13
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Ahmed M, Soares F, Xia JH, Yang Y, Li J, Guo H, Su P, Tian Y, Lee HJ, Wang M, Akhtar N, Houlahan KE, Bosch A, Zhou S, Mazrooei P, Hua JT, Chen S, Petricca J, Zeng Y, Davies A, Fraser M, Quigley DA, Feng FY, Boutros PC, Lupien M, Zoubeidi A, Wang L, Walsh MJ, Wang T, Ren S, Wei GH, He HH. CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer. Nat Commun 2021; 12:1781. [PMID: 33741908 PMCID: PMC7979745 DOI: 10.1038/s41467-021-21867-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 02/18/2021] [Indexed: 12/11/2022] Open
Abstract
Prostate cancer (PCa) risk-associated SNPs are enriched in noncoding cis-regulatory elements (rCREs), yet their modi operandi and clinical impact remain elusive. Here, we perform CRISPRi screens of 260 rCREs in PCa cell lines. We find that rCREs harboring high risk SNPs are more essential for cell proliferation and H3K27ac occupancy is a strong indicator of essentiality. We also show that cell-line-specific essential rCREs are enriched in the 8q24.21 region, with the rs11986220-containing rCRE regulating MYC and PVT1 expression, cell proliferation and tumorigenesis in a cell-line-specific manner, depending on DNA methylation-orchestrated occupancy of a CTCF binding site in between this rCRE and the MYC promoter. We demonstrate that CTCF deposition at this site as measured by DNA methylation level is highly variable in prostate specimens, and observe the MYC eQTL in the 8q24.21 locus in individuals with low CTCF binding. Together our findings highlight a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture, advocating for the integration of genetics and epigenetics in assessing risks conferred by genetic predispositions.
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Affiliation(s)
- Musaddeque Ahmed
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada
| | - Fraser Soares
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada
| | - Ji-Han Xia
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Yue Yang
- Changhai Hospital, Shanghai, China
| | - Jing Li
- Changhai Hospital, Shanghai, China
| | - Haiyang Guo
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada
| | - Peiran Su
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Yijun Tian
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Hyung Joo Lee
- Department of Genetics, Washington University in St. Louis, St. Louis, MO, USA
| | - Miranda Wang
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada
| | - Nayeema Akhtar
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada
| | - Kathleen E Houlahan
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
- Ontario Institute for Cancer Research, Toronto, ON, Canada
- Vector Institute, Toronto, ON, Canada
- Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Almudena Bosch
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stanley Zhou
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Parisa Mazrooei
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Junjie T Hua
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Sujun Chen
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Jessica Petricca
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Yong Zeng
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada
| | - Alastair Davies
- The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, BC, Canada
| | - Michael Fraser
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - David A Quigley
- Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA
- Department of Urology, University of California at San Francisco, San Francisco, CA, USA
| | - Felix Y Feng
- Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA
- Department of Urology, University of California at San Francisco, San Francisco, CA, USA
- Department of Medicine, University of California at San Francisco, San Francisco, CA, USA
- Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA, USA
| | - Paul C Boutros
- Vector Institute, Toronto, ON, Canada
- Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA
| | - Mathieu Lupien
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Amina Zoubeidi
- The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, BC, Canada
| | - Liang Wang
- Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Martin J Walsh
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ting Wang
- Department of Genetics, Washington University in St. Louis, St. Louis, MO, USA
| | | | - Gong-Hong Wei
- Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
- Fudan University Shanghai Cancer Center, School of Basic Medical Sciences, Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Shanghai, China.
| | - Housheng Hansen He
- Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
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14
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Saunders EJ, Kote-Jarai Z, Eeles RA. Identification of Germline Genetic Variants that Increase Prostate Cancer Risk and Influence Development of Aggressive Disease. Cancers (Basel) 2021; 13:760. [PMID: 33673083 PMCID: PMC7917798 DOI: 10.3390/cancers13040760] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/08/2021] [Accepted: 02/09/2021] [Indexed: 12/15/2022] Open
Abstract
Prostate cancer (PrCa) is a heterogeneous disease, which presents in individual patients across a diverse phenotypic spectrum ranging from indolent to fatal forms. No robust biomarkers are currently available to enable routine screening for PrCa or to distinguish clinically significant forms, therefore late stage identification of advanced disease and overdiagnosis plus overtreatment of insignificant disease both remain areas of concern in healthcare provision. PrCa has a substantial heritable component, and technological advances since the completion of the Human Genome Project have facilitated improved identification of inherited genetic factors influencing susceptibility to development of the disease within families and populations. These genetic markers hold promise to enable improved understanding of the biological mechanisms underpinning PrCa development, facilitate genetically informed PrCa screening programmes and guide appropriate treatment provision. However, insight remains largely lacking regarding many aspects of their manifestation; especially in relation to genes associated with aggressive phenotypes, risk factors in non-European populations and appropriate approaches to enable accurate stratification of higher and lower risk individuals. This review discusses the methodology used in the elucidation of genetic loci, genes and individual causal variants responsible for modulating PrCa susceptibility; the current state of understanding of the allelic spectrum contributing to PrCa risk; and prospective future translational applications of these discoveries in the developing eras of genomics and personalised medicine.
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Affiliation(s)
- Edward J. Saunders
- The Institute of Cancer Research, London SM2 5NG, UK; (Z.K.-J.); (R.A.E.)
| | - Zsofia Kote-Jarai
- The Institute of Cancer Research, London SM2 5NG, UK; (Z.K.-J.); (R.A.E.)
| | - Rosalind A. Eeles
- The Institute of Cancer Research, London SM2 5NG, UK; (Z.K.-J.); (R.A.E.)
- Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
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15
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Liu H, Zheng W, Chen Q, Zhou Y, Pan Y, Zhang J, Bai Y, Shao C. lncRNA CASC19 Contributes to Radioresistance of Nasopharyngeal Carcinoma by Promoting Autophagy via AMPK-mTOR Pathway. Int J Mol Sci 2021; 22:ijms22031407. [PMID: 33573349 PMCID: PMC7866785 DOI: 10.3390/ijms22031407] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/21/2021] [Accepted: 01/28/2021] [Indexed: 02/07/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is one of the most frequent head and neck malignant tumors and is majorly treated by radiotherapy. However, radiation resistance remains a serious obstacle to the successful treatment of NPC. The aim of this study was to discover the underlying mechanism of radioresistance and to elucidate novel genes that may play important roles in the regulation of NPC radiosensitivity. By using RNA-seq analysis of NPC cell line CNE2 and its radioresistant cell line CNE2R, lncRNA CASC19 was screened out as a candidate radioresistance marker. Both in vitro and in vivo data demonstrated that a high expression level of CASC19 was positively correlated with the radioresistance of NPC, and the radiosensitivity of NPC cells was considerably enhanced by knockdown of CASC19. The incidence of autophagy was enhanced in CNE2R in comparison with CNE2 and another NPC cell line HONE1, and silencing autophagy with LC3 siRNA (siLC3) sensitized NPC cells to irradiation. Furthermore, CASC19 siRNA (siCASC19) suppressed cellular autophagy by inhibiting the AMPK/mTOR pathway and promoted apoptosis through the PARP1 pathway. Our results revealed for the first time that lncRNA CASC19 contributed to the radioresistance of NPC by regulating autophagy. In significance, CASC19 might be a potential molecular biomarker and a new therapeutic target in NPC.
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16
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Wang L, Lin C, Sun N, Wang Q, Ding X, Sun Y. Long non-coding RNA CASC19 facilitates non-small cell lung cancer cell proliferation and metastasis by targeting the miR-301b-3p/LDLR axis. J Gene Med 2020; 22:e3254. [PMID: 32677267 DOI: 10.1002/jgm.3254] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 06/02/2020] [Accepted: 06/02/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is a lethal tumor resulting in a large number of cancer-related deaths globally. Long noncoding RNAs (lncRNAs) may modulate tumor initiation and metastasis. Although dysregulation of lncRNA cancer susceptibility 19 (CASC19) is validated in NSCLC, further exploration of the CASC19-regulated mechanism in NSCLC is still needed. METHODS CASC19 expression was examined in NSCLC cells by a quantitative reverse transcriptase-polymerase chain reaction. The specific role of CASC19 in NSCLC was analyzed by cell counting kit-8, EdU, Transwell and western blot assays. The interaction between miR-301b-3p and CASC19 or low-density lipoprotein receptor (LDLR) was confirmed by luciferase reporter and RNA immunoprecipitation assays. RESULTS CASC19 is markedly overexpressed in NSCLC. Its deficiency impairs cell proliferation, as well as metastasis in NSCLC. Molecular mechanism experiments indicated that CASC19 negatively modulates the expression of miR-301b-3p and miR-301b-3p can bind with CASC19 in NSCLC. In addition, miR-301b-3p binds to LDLR to impair its expression in NSCLC. Finally, rescue experiments showed that miR-301b-3p inhibition or LDLR overexpression counteracted the CASC19 knockdown-mediated function on cell proliferation and metastasis in NSCLC. CONCLUSIONS CASC19 facilitates NSCLC cell proliferation and metastasis by targeting the miR-301b-3p/LDLR axis, offering a possible strategy for lncRNA-targeted treatment in NSCLC.
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MESH Headings
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/secondary
- Cell Movement
- Cell Proliferation
- Gene Expression Regulation, Neoplastic
- Humans
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- MicroRNAs/genetics
- RNA, Long Noncoding/genetics
- Receptors, LDL/genetics
- Receptors, LDL/metabolism
- Tumor Cells, Cultured
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Affiliation(s)
- Lijun Wang
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Cunzhi Lin
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Nina Sun
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Qiang Wang
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Xiaoqian Ding
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yong Sun
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
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17
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Li N, Cui Z, Gao M, Li S, Song M, Wang Y, Tong L, Bi Y, Zhang Z, Wang S, Zhou B, Yin Z. Genetic Polymorphisms of PRNCR1 and Lung Cancer Risk in Chinese Northeast Population: A Case-Control Study and Meta-Analysis. DNA Cell Biol 2020; 40:132-144. [PMID: 33226844 DOI: 10.1089/dna.2020.6194] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) play vital roles in development and progression of various cancers. To investigate the relationship between three tag single-nucleotide polymorphisms (SNPs) (rs13252298, rs1016343, and rs1456315) in lncRNA prostate cancer-associated noncoding RNA 1 (PRNCR1) and lung cancer (LC) risk, we conducted this study. First, we performed a case-control study, including 576 LC patients and 612 cancer-free controls. Second, a meta-analysis was used to evaluate the association of selected SNPs with risk of overall cancer. We found that rs13252298 and rs1456315 were strongly correlated with risk of LC, nonsmall cell lung cancer (NSCLC), and lung adenocarcinoma. For rs13252298, individuals carrying GG genotype had increased risks of LC compared with those carrying AA genotype (adjusted odds ratio [OR] = 1.565, 95% CI = 1.091-2.245, p = 0.015). A significant result was also found in recessive model with adjusted OR of 1.719. Individuals with GG genotype of rs1456315 were at increased risks of LC compared with those carrying AA genotype. Similar results were found in NSCLC patients. Meta-analysis showed that rs1016343 and rs13252298 were associated with overall cancer. But for rs1016343, no significant association was observed in Asians. In conclusion, rs13252298 and rs1456315 in PRNCR1 may be genetic susceptibility factors for LC in Chinese population. These results need to be confirmed by further studies.
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Affiliation(s)
- Na Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China
| | - Zhigang Cui
- School of Nursing, China Medical University, Shenyang, P.R. China
| | - Min Gao
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China
| | - Sixuan Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China
| | - Mingyang Song
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China
| | - Ying Wang
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China
| | - Lianwei Tong
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China
| | - Yanhong Bi
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China
| | - Ziwei Zhang
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China
| | - Shengli Wang
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China
| | - Baosen Zhou
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China
| | - Zhihua Yin
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, P.R. China
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18
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Fiorica PN, Schubert R, Morris JD, Abdul Sami M, Wheeler HE. Multi-ethnic transcriptome-wide association study of prostate cancer. PLoS One 2020; 15:e0236209. [PMID: 32986714 PMCID: PMC7521738 DOI: 10.1371/journal.pone.0236209] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/11/2020] [Indexed: 12/13/2022] Open
Abstract
The genetic risk for prostate cancer has been governed by a few rare variants with high penetrance and over 150 commonly occurring variants with lower impact on risk; however, most of these variants have been identified in studies containing exclusively European individuals. People of non-European ancestries make up less than 15% of prostate cancer GWAS subjects. Across the globe, incidence of prostate cancer varies with population due to environmental and genetic factors. The discrepancy between disease incidence and representation in genetics highlights the need for more studies of the genetic risk for prostate cancer across diverse populations. To better understand the genetic risk for prostate cancer across diverse populations, we performed PrediXcan and GWAS in a case-control study of 4,769 self-identified African American (2,463 cases and 2,306 controls), 2,199 Japanese American (1,106 cases and 1,093 controls), and 2,147 Latin American (1,081 cases and 1,066 controls) individuals from the Multiethnic Genome-wide Scan of Prostate Cancer. We used prediction models from 46 tissues in GTEx version 8 and five models from monocyte transcriptomes in the Multi-Ethnic Study of Atherosclerosis. Across the three populations, we predicted 19 gene-tissue pairs, including five unique genes, to be significantly (lfsr < 0.05) associated with prostate cancer. One of these genes, NKX3-1, replicated in a larger European study. At the SNP level, 110 SNPs met genome-wide significance in the African American study while 123 SNPs met significance in the Japanese American study. Fine mapping revealed three significant independent loci in the African American study and two significant independent loci in the Japanese American study. These identified loci confirm findings from previous GWAS of prostate cancer in diverse populations while PrediXcan-identified genes suggest potential new directions for prostate cancer research in populations across the globe.
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Affiliation(s)
- Peter N. Fiorica
- Department of Chemistry & Biochemistry, Loyola University Chicago, Chicago, IL, United States of America
- Department of Biology, Loyola University Chicago, Chicago, IL, United States of America
| | - Ryan Schubert
- Department of Biology, Loyola University Chicago, Chicago, IL, United States of America
- Program in Bioinformatics, Loyola University Chicago, Chicago, IL, United States of America
- Department of Statistics, Loyola University Chicago, Chicago, IL, United States of America
| | - John D. Morris
- Department of Biology, Loyola University Chicago, Chicago, IL, United States of America
- Program in Bioinformatics, Loyola University Chicago, Chicago, IL, United States of America
| | - Mohammed Abdul Sami
- Department of Biology, Loyola University Chicago, Chicago, IL, United States of America
| | - Heather E. Wheeler
- Department of Chemistry & Biochemistry, Loyola University Chicago, Chicago, IL, United States of America
- Department of Biology, Loyola University Chicago, Chicago, IL, United States of America
- Program in Bioinformatics, Loyola University Chicago, Chicago, IL, United States of America
- Department of Public Health, Loyola University Chicago, Chicago, IL, United States of America
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19
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Miller JB, Ward E, Staley LA, Stevens J, Teerlink CC, Tavana JP, Cloward M, Page M, Dayton L, Cannon-Albright LA, Kauwe JSK. Identification and genomic analysis of pedigrees with exceptional longevity identifies candidate rare variants. Neurobiol Dis 2020; 143:104972. [PMID: 32574725 PMCID: PMC7461696 DOI: 10.1016/j.nbd.2020.104972] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 05/05/2020] [Accepted: 06/12/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Longevity as a phenotype entails living longer than average and typically includes living without chronic age-related diseases. Recently, several common genetic components to longevity have been identified. This study aims to identify additional genetic variants associated with longevity using unique and powerful analyses of pedigrees with a statistical excess of healthy elderly individuals identified in the Utah Population Database (UPDB). METHODS From an existing biorepository of Utah pedigrees, six independent cousin pairs were selected from four extended pedigrees that exhibited an excess of healthy elderly individuals; whole exome sequencing (WES) was performed on two elderly individuals from each pedigree who were either first cousins or first cousins once removed. Rare (<.01 population frequency) variants shared by at least one elderly cousin pair in a region likely to be identical by descent were identified as candidates. Ingenuity Variant Analysis was used to prioritize putative causal variants based on quality control, frequency, and gain or loss of function. The variant frequency was compared in healthy cohorts and in an Alzheimer's disease cohort. Remaining variants were filtered based on their presence in genes reported to have an effect on the aging process, aging of cells, or the longevity process. Validation of these candidate variants included tests of segregation on other elderly relatives. RESULTS Fifteen rare candidate genetic variants spanning 17 genes shared within cousins were identified as having passed prioritization criteria. Of those variants, six were present in genes that are known or predicted to affect the aging process: rs78408340 (PAM), rs112892337 (ZFAT), rs61737629 (ESPL1), rs141903485 (CEBPE), rs144369314 (UTP4), and rs61753103 (NUP88 and RABEP1). ESPL1 rs61737629 and CEBPE rs141903485 show additional evidence of segregation with longevity in expanded pedigree analyses (p-values = .001 and .0001, respectively). DISCUSSION This unique pedigree analysis efficiently identified several novel rare candidate variants that may affect the aging process and added support to seven genes that likely contribute to longevity. Further analyses showed evidence for segregation for two rare variants, ESPL1 rs61737629 and CEBPE rs141903485, in the original longevity pedigrees in which they were initially observed. These candidate genes and variants warrant further investigation.
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Affiliation(s)
- Justin B Miller
- Department of Biology, Brigham Young University, Provo, UT 84602, USA
| | - Elizabeth Ward
- Department of Biology, Brigham Young University, Provo, UT 84602, USA
| | - Lyndsay A Staley
- Department of Biology, Brigham Young University, Provo, UT 84602, USA
| | - Jeffrey Stevens
- Genetic Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA
| | - Craig C Teerlink
- Genetic Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA
| | - Justina P Tavana
- Department of Biology, Brigham Young University, Provo, UT 84602, USA
| | - Matthew Cloward
- Department of Biology, Brigham Young University, Provo, UT 84602, USA
| | - Madeline Page
- Department of Biology, Brigham Young University, Provo, UT 84602, USA
| | - Louisa Dayton
- Department of Biology, Brigham Young University, Provo, UT 84602, USA
| | - Lisa A Cannon-Albright
- Genetic Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA
| | - John S K Kauwe
- Department of Biology, Brigham Young University, Provo, UT 84602, USA.
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20
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Zou H, Wu LX, Tan L, Shang FF, Zhou HH. Significance of Single-Nucleotide Variants in Long Intergenic Non-protein Coding RNAs. Front Cell Dev Biol 2020; 8:347. [PMID: 32523949 PMCID: PMC7261909 DOI: 10.3389/fcell.2020.00347] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 04/20/2020] [Indexed: 12/15/2022] Open
Abstract
Single-nucleotide variants (SNVs) are the most common genetic variants and universally present in the human genome. Genome-wide association studies (GWASs) have identified a great number of disease or trait-associated variants, many of which are located in non-coding regions. Long intergenic non-protein coding RNAs (lincRNAs) are the major subtype of long non-coding RNAs; lincRNAs play crucial roles in various disorders and cellular models via multiple mechanisms. With rapid growth in the number of the identified lincRNAs and genetic variants, there is great demand for an investigation of SNVs in lincRNAs. Hence, in this article, we mainly summarize the significant role of SNVs within human lincRNA regions. Some pivotal variants may serve as risk factors for the development of various disorders, especially cancer. They may also act as important regulatory signatures involved in the modulation of lincRNAs in a tissue- or disorder-specific manner. An increasing number of researches indicate that lincRNA variants would potentially provide additional options for genetic testing and disease risk assessment in the personalized medicine era.
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Affiliation(s)
- Hecun Zou
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Lan-Xiang Wu
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Lihong Tan
- Chongqing Medical and Pharmaceutical College, Chongqing, China.,Xiangya Hospital, Central South University, Changsha, China
| | - Fei-Fei Shang
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Hong-Hao Zhou
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China.,Xiangya Hospital, Central South University, Changsha, China
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21
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Dupont WD, Breyer JP, Plummer WD, Chang SS, Cookson MS, Smith JA, Blue EE, Bamshad MJ, Smith JR. 8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer. Nat Commun 2020; 11:1523. [PMID: 32251286 PMCID: PMC7089954 DOI: 10.1038/s41467-020-15122-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Accepted: 02/18/2020] [Indexed: 01/09/2023] Open
Abstract
The 8q24 genomic locus is tied to the origin of numerous cancers. We investigate its contribution to hereditary prostate cancer (HPC) in independent study populations of the Nashville Familial Prostate Cancer Study and International Consortium for Prostate Cancer Genetics (combined: 2,836 HPC cases, 2,206 controls of European ancestry). Here we report 433 variants concordantly associated with HPC in both study populations, accounting for 9% of heritability and modifying age of diagnosis as well as aggressiveness; 183 reach genome-wide significance. The variants comprehensively distinguish independent risk-altering haplotypes overlapping the 648 kb locus (three protective, and four risk (peak odds ratios: 1.5, 4, 5, and 22)). Sequence of the near-Mendelian haplotype reveals eleven causal mutation candidates. We introduce a linkage disequilibrium-based algorithm discerning eight independent sentinel variants, carrying considerable risk prediction ability (AUC = 0.625) for a single locus. These findings elucidate 8q24 locus structure and correlates for clinical prediction of prostate cancer risk.
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Affiliation(s)
- William D Dupont
- Department of Biostatistics, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN, 37203, USA
| | - Joan P Breyer
- Department of Medicine, Division of Genetic Medicine, Vanderbilt-Ingram Cancer Center, and Vanderbilt Genetics Institute, Vanderbilt University Medical Center, 507 Light Hall, 2215 Garland Avenue, Nashville, TN, 37232, USA
- Medical Research Service, Tennessee Valley Healthcare System, Veterans Administration, 1310 24th Avenue South, Nashville, TN, 37212, USA
| | - W Dale Plummer
- Department of Biostatistics, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN, 37203, USA
| | - Sam S Chang
- Department of Urology, Vanderbilt University Medical Center, A-1302 Medical Center North, 1161 21st Avenue South, Nashville, TN, 37232, USA
| | - Michael S Cookson
- Department of Urology, University of Oklahoma Health Sciences Center, Suite 3150, 920 SL Young Boulevard, Oklahoma City, OK, 73104, USA
| | - Joseph A Smith
- Department of Urology, Vanderbilt University Medical Center, A-1302 Medical Center North, 1161 21st Avenue South, Nashville, TN, 37232, USA
| | - Elizabeth E Blue
- Department of Medicine, Division of Medical Genetics, University of Washington, HSB H132, Seattle, WA, 98195, USA
| | - Michael J Bamshad
- Department of Pediatrics, Division of Genetic Medicine, and Center for Mendelian Genomics, University of Washington, HSB RR349, 1959 NE Pacific Street, Seattle, WA, 98195, USA
| | - Jeffrey R Smith
- Department of Medicine, Division of Genetic Medicine, Vanderbilt-Ingram Cancer Center, and Vanderbilt Genetics Institute, Vanderbilt University Medical Center, 507 Light Hall, 2215 Garland Avenue, Nashville, TN, 37232, USA.
- Medical Research Service, Tennessee Valley Healthcare System, Veterans Administration, 1310 24th Avenue South, Nashville, TN, 37212, USA.
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22
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Olson JE, Ryu E, Hathcock MA, Gupta R, Bublitz JT, Takahashi PY, Bielinski SJ, St Sauver JL, Meagher K, Sharp RR, Thibodeau SN, Cicek M, Cerhan JR. Characteristics and utilisation of the Mayo Clinic Biobank, a clinic-based prospective collection in the USA: cohort profile. BMJ Open 2019; 9:e032707. [PMID: 31699749 PMCID: PMC6858142 DOI: 10.1136/bmjopen-2019-032707] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 10/14/2019] [Accepted: 10/15/2019] [Indexed: 12/15/2022] Open
Abstract
PURPOSE The Mayo Clinic Biobank was established to provide a large group of patients from which comparison groups (ie, controls) could be selected for case-control studies, to create a prospective cohort with sufficient power for common outcomes and to support electronic health record (EHR) studies. PARTICIPANTS A total of 56 862 participants enrolled (21% response rate) into the Mayo Clinic Biobank from Rochester, Minnesota (77%, n=43 836), Jacksonville, Florida (18%, n=10 368) and La Crosse, Wisconsin (5%, n=2658). Participants were all Mayo Clinic patients, 18 years of age or older and US residents. FINDINGS TO DATE Overall, 43% of participants were 65 years of age or older and female participants were more frequent (59%) than males at all sites. Most participants resided in the Upper Midwest regions of the USA (Minnesota, Iowa, Illinois or Wisconsin), Florida or Georgia. Self-reported race among Biobank participants was 90% white. Here we provide examples of the types of studies that have successfully utilised the resource, including (1) investigations of the population itself, (2) provision of controls for case-control studies, (3) genotype-driven research, (4) EHR-based research and (5) prospective recruitment to other studies. Over 270 projects have been approved to date to access Biobank data and/or samples; over 200 000 sample aliquots have been approved for distribution. FUTURE PLANS The data and samples in the Mayo Clinic Biobank can be used for various types of epidemiological and clinical studies, especially in the setting of case-control studies for which the Biobank samples serve as control samples. We are planning cohort studies with additional follow-up and acquisition of genetic information on a large scale.
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Affiliation(s)
- Janet E Olson
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Euijung Ryu
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Matthew A Hathcock
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Ruchi Gupta
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Joshua T Bublitz
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Paul Y Takahashi
- Division of Primary Care Internal Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Suzette J Bielinski
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Jennifer L St Sauver
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Karen Meagher
- Biomedical Ethics Research Program, Mayo Clinic, Rochester, Minnesota, USA
| | - Richard R Sharp
- Biomedical Ethics Research Program, Mayo Clinic, Rochester, Minnesota, USA
| | - Stephen N Thibodeau
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Mine Cicek
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - James R Cerhan
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
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23
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Ramnarine VR, Kobelev M, Gibb EA, Nouri M, Lin D, Wang Y, Buttyan R, Davicioni E, Zoubeidi A, Collins CC. The evolution of long noncoding RNA acceptance in prostate cancer initiation, progression, and its clinical utility in disease management. Eur Urol 2019; 76:546-559. [PMID: 31445843 DOI: 10.1016/j.eururo.2019.07.040] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 07/26/2019] [Indexed: 02/07/2023]
Abstract
CONTEXT It is increasingly evident that non-protein-coding regions of the genome can give rise to transcripts that form functional layers of the cancer genome. One of most abundant classes in these regions is long noncoding RNAs (lncRNAs). They have gained increasing attention in prostate cancer (PCa) and paved the way for a greater understanding of these cryptic regulators in cancer. OBJECTIVE To review current research exploring the functional biology of lncRNAs in PCa over the past three decades. EVIDENCE ACQUISITION A systematic review was performed using PubMed to search for reports with terms "long noncoding RNA", "prostate", and "cancer" over the past 30 yr (1988-2018). EVIDENCE SYNTHESIS We comprehensively surveyed the literature collected and summarise experiments leading to the characterisation of lncRNAs in PCa. A historical timeline of lncRNA identification is described, where each lncRNA is categorised mechanistically and within the primary areas of carcinogenesis: tumour risk and initiation, tumour promotion, tumour suppression, and tumour treatment resistance. We describe select lncRNAs that exemplify these areas. We also review whether these lncRNAs have a clinical utility in PCa diagnosis, prognosis, and prediction, and as therapeutic targets. CONCLUSIONS The biology of lncRNA is multifaceted, demonstrating a complex array of molecular and cellular functions. These studies reveal that lncRNAs are involved in every stage of PCa. Their clinical utility for diagnosis, prognosis, and prediction of PCa is well supported, but further evaluation for their therapeutic candidacy is needed. We provide a detailed resource and view inside the lncRNA landscape for other cancer biologists, oncologists, and clinicians. PATIENT SUMMARY In this study, we review current knowledge of the non-protein-coding genome in prostate cancer (PCa). We conclude that many of these regions are functional and a source of accurate biomarkers in PCa. With a strong research foundation, they hold promise as future therapeutic targets, yet clinical trials are necessary to determine their intrinsic value to PCa disease management.
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Affiliation(s)
- Varune Rohan Ramnarine
- Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Maxim Kobelev
- Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Ewan A Gibb
- Decipher Biosciences Inc., Vancouver, BC, Canada
| | - Mannan Nouri
- Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Dong Lin
- Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada
| | - Yuzhuo Wang
- Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada
| | - Ralph Buttyan
- Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | | | - Amina Zoubeidi
- Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Colin C Collins
- Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
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24
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Wang WJ, Guo CA, Li R, Xu ZP, Yu JP, Ye Y, Zhao J, Wang J, Wang WA, Zhang A, Li HT, Wang C, Liu HB. Long non-coding RNA CASC19 is associated with the progression and prognosis of advanced gastric cancer. Aging (Albany NY) 2019; 11:5829-5847. [PMID: 31422382 PMCID: PMC6710062 DOI: 10.18632/aging.102190] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 08/10/2019] [Indexed: 12/24/2022]
Abstract
Evidence indicates that aberrantly expressed long non-coding RNAs (lncRNAs) are involved in the development and progression of advanced gastric cancer (AGC). Using RNA sequencing data and clinical information obtained from The Cancer Gene Atlas, we combined differential lncRNA expression profiling and weighted gene co-expression network analysis to identify key lncRNAs associated with AGC progression and prognosis. Cancer susceptibility 19 (CASC19) was the top hub lncRNA among the lncRNAs included in the gene module most significantly correlated with AGC’s pathological variables. CASC19 was upregulated in AGC clinical samples and was significantly associated with higher pathologic TNM stage, pathologic T stage, lymph node metastasis, and poor overall survival. Multivariable Cox analysis confirmed that CASC19 overexpression is an independent prognostic factor for overall survival. Furthermore, quantitative real-time PCR assay confirmed that CASC19 expression in four human gastric cancer cells (AGS, BGC-823, MGC-803, and HGC-27) was significantly upregulated compared with human normal gastric mucosal epithelial cell line (GES-1). Functionally, CASC19 knockdown inhibited GC cell proliferation and migration in vitro. These findings suggest that CASC19 may be a novel prognostic biomarker and a potential therapeutic target for AGC.
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Affiliation(s)
- Wen-Jie Wang
- Second Clinical Medical College, Lanzhou University, Lanzhou 730030, Gansu, P.R. China.,Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, P.R. China.,Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, Lanzhou 730050, Gansu, China
| | - Chang-An Guo
- Second Clinical Medical College, Lanzhou University, Lanzhou 730030, Gansu, P.R. China.,Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, Lanzhou 730050, Gansu, China.,Department of Emergency, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, P.R. China
| | - Rui Li
- Second Clinical Medical College, Lanzhou University, Lanzhou 730030, Gansu, P.R. China.,Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, P.R. China
| | - Zi-Peng Xu
- Second Clinical Medical College, Lanzhou University, Lanzhou 730030, Gansu, P.R. China.,Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou 730050, Gansu, P.R. China.,Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, Lanzhou 730050, Gansu, China
| | - Jian-Ping Yu
- Second Clinical Medical College, Lanzhou University, Lanzhou 730030, Gansu, P.R. China.,Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou 730050, Gansu, P.R. China
| | - Yan Ye
- Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, Lanzhou 730050, Gansu, China
| | - Jun Zhao
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, P.R. China
| | - Jing Wang
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou 730050, Gansu, P.R. China.,Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, Lanzhou 730050, Gansu, China.,Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou 730030, Gansu, P.R. China
| | - Wen-An Wang
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou 730050, Gansu, P.R. China.,Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, Lanzhou 730050, Gansu, China.,Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou 730030, Gansu, P.R. China
| | - An Zhang
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou 730050, Gansu, P.R. China.,Key Laboratory of Stem Cells and Gene Drugs of Gansu Province, Lanzhou 730050, Gansu, China.,Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou 730030, Gansu, P.R. China
| | - Hong-Tao Li
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou 730050, Gansu, P.R. China
| | - Chen Wang
- Second Clinical Medical College, Lanzhou University, Lanzhou 730030, Gansu, P.R. China.,Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, P.R. China
| | - Hong-Bin Liu
- Second Clinical Medical College, Lanzhou University, Lanzhou 730030, Gansu, P.R. China.,Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou 730050, Gansu, P.R. China
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25
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Yu H, Shi Z, Wu Y, Wang CH, Lin X, Perschon C, Isaacs WB, Helfand BT, Lilly Zheng S, Duggan D, Mo Z, Lu D, Xu J. Concept and benchmarks for assessing narrow-sense validity of genetic risk score values. Prostate 2019; 79:1099-1105. [PMID: 31037745 DOI: 10.1002/pros.23821] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 04/08/2019] [Accepted: 04/12/2019] [Indexed: 01/08/2023]
Abstract
BACKGROUND While higher genetic risk score (GRS) has been statistically associated with increased disease risk (broad-sense validity), the concept and tools for assessing the validity of reported GRS values from tests (narrow-sense validity) are underdeveloped. METHODS We propose two benchmarks for assessing the narrow-sense validity of GRS. The baseline benchmark requires that the mean GRS value in a general population approximates 1.0. The calibration benchmark assesses the agreement between observed risks and estimated risks (GRS values). We assessed benchmark performance for three prostate cancer (PCa) GRS tests, derived from three SNP panels with increasing stringency of selection criteria, in a PCa chemoprevention trial where 714 of 3225 men were diagnosed with PCa during the 4-year follow-up. RESULTS GRS from Panels 1, 2, and 3 were all statistically associated with PCa risk; P = 5.58 × 10-3 , P = 1 × 10-3 , and P = 1.5 × 10-13 , respectively (broad-sense validity). For narrow-sense validity, the mean GRS value among men without PCa was 1.33, 1.09, and 0.98 for Panels 1, 2, and 3, respectively (baseline benchmark). For assessing the calibration benchmark, observed risks were calculated for seven groups of men with GRS values <0.3, 0.3-0.79, 0.8-1.19, 1.2-1.49, 1.5-1.99, 2-2.99, and ≥3. The calibration slope (higher is better) was 0.15, 0.12, and 0.60, and the bias score (lower is better) between the observed risks and GRS values was 0.08, 0.08, and 0.02 for Panels 1, 2, and 3, respectively. CONCLUSION Performance differed considerably among GRS tests. We recommend that all GRS tests be evaluated using the two benchmarks before clinical implementation for individual risk assessment.
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Affiliation(s)
- Hongjie Yu
- Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois
| | - Zhuqing Shi
- Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois
- State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China
| | - Yishuo Wu
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chi-Hsiung Wang
- Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois
| | - Xiaoling Lin
- State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chelsea Perschon
- Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois
| | - William B Isaacs
- Department of Urology and the James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Brian T Helfand
- Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois
| | - S Lilly Zheng
- Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois
| | - David Duggan
- Genetic Basis of Human Disease Division, Translational Genomics Research Institute, Phoenix, Arizona
| | - Zengnan Mo
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Daru Lu
- State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China
| | - Jianfeng Xu
- Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois
- State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, Shanghai, China
- Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
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26
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Wang XD, Lu J, Lin YS, Gao C, Qi F. Functional role of long non-coding RNA CASC19/miR-140-5p/CEMIP axis in colorectal cancer progression in vitro. World J Gastroenterol 2019; 25:1697-1714. [PMID: 31011255 PMCID: PMC6465939 DOI: 10.3748/wjg.v25.i14.1697] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 03/06/2019] [Accepted: 03/15/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) are widely involved in tumor regulation. Nevertheless, the role of the lncRNA cancer susceptibility 19 (CASC19) in colorectal cancer (CRC) has yet to be fully clarified. AIM To explore the effect of CASC19 on proliferation and metastasizing ability of CRC cells. METHODS CASC19 expression in human CRC tissues, pair-matched adjacent normal colon tissues, and CRC cells was detected using quantitative real-time PCR (qRT-PCR). CASC19 expression, as well as its relation to overall survival, was extrapolated by Kaplan-Meier survival analysis together with multivariable Cox regression assay. In vitro experiments were performed to confirm whether CASC19 regulates CRC cell invasion, migration, proliferation, and apoptosis. RESULTS CASC19 expression was markedly upregulated in CRC tissues and CRC cell lines (P < 0.05). qRT-PCR revealed that CASC19 expression was higher in 25 tissue samples from patients with aggressive CRC compared with the 27 tissue samples from patients with nonaggressive CRC (P < 0.05). Higher CASC19 expression was associated with poorer patient prognoses. Furthermore, in vitro experiments demonstrated that CASC19 overexpression enhanced CRC cell invasion, migration, and proliferation. CASC19 overexpression enhanced the expression of cell migration inducing hyaluronidase 1 (CEMIP) and epithelial-mesenchymal transition markers. MiR-140-5p was found to be able to bind directly to CASC19 and CEMIP. Overexpression of miR-140-5p reversed the effect of CASC19 on cell proliferation and tumor migration, as well as suppressed CASC19-induced CEMIP expression. CONCLUSION CASC19 positively regulates CEMIP expression through targeting miR-140-5p. CASC19 may possess an oncogenic function in CRC progression, highlighting its potential as an essential biomarker in CRC diagnosis and therapy.
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Affiliation(s)
- Xiao-Dong Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Jian Lu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yun-Shou Lin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Chao Gao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Feng Qi
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
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27
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DeRycke MS, Larson MC, Nair AA, McDonnell SK, French AJ, Tillmans LS, Riska SM, Baheti S, Fogarty ZC, Larson NB, O’Brien DR, Cheville JC, Wang L, Schaid DJ, Thibodeau SN. An expanded variant list and assembly annotation identifies multiple novel coding and noncoding genes for prostate cancer risk using a normal prostate tissue eQTL data set. PLoS One 2019; 14:e0214588. [PMID: 30958860 PMCID: PMC6453468 DOI: 10.1371/journal.pone.0214588] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 03/17/2019] [Indexed: 01/01/2023] Open
Abstract
Prostate cancer (PrCa) is highly heritable; 284 variants have been identified to date that are associated with increased prostate cancer risk, yet few genes contributing to its development are known. Expression quantitative trait loci (eQTL) studies link variants with affected genes, helping to determine how these variants might regulate gene expression and may influence prostate cancer risk. In the current study, we performed eQTL analysis on 471 normal prostate epithelium samples and 249 PrCa-risk variants in 196 risk loci, utilizing RNA sequencing transcriptome data based on ENSEMBL gene definition and genome-wide variant data. We identified a total of 213 genes associated with known PrCa-risk variants, including 141 protein-coding genes, 16 lncRNAs, and 56 other non-coding RNA species with differential expression. Compared to our previous analysis, where RefSeq was used for gene annotation, we identified an additional 130 expressed genes associated with known PrCa-risk variants. We detected an eQTL signal for more than half (n = 102, 52%) of the 196 loci tested; 52 (51%) of which were a Group 1 signal, indicating high linkage disequilibrium (LD) between the peak eQTL variant and the PrCa-risk variant (r2>0.5) and may help explain how risk variants influence the development of prostate cancer.
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Affiliation(s)
- Melissa S. DeRycke
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, SW, Rochester, Minnesota, United States of America
| | - Melissa C. Larson
- Department of Health Sciences Research, Mayo Clinic College of Medicine, SW, Rochester, Minnesota, United States of America
| | - Asha A. Nair
- Department of Health Sciences Research, Mayo Clinic College of Medicine, SW, Rochester, Minnesota, United States of America
| | - Shannon K. McDonnell
- Department of Health Sciences Research, Mayo Clinic College of Medicine, SW, Rochester, Minnesota, United States of America
| | - Amy J. French
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, SW, Rochester, Minnesota, United States of America
| | - Lori S. Tillmans
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, SW, Rochester, Minnesota, United States of America
| | - Shaun M. Riska
- Department of Health Sciences Research, Mayo Clinic College of Medicine, SW, Rochester, Minnesota, United States of America
| | - Saurabh Baheti
- Department of Health Sciences Research, Mayo Clinic College of Medicine, SW, Rochester, Minnesota, United States of America
| | - Zachary C. Fogarty
- Department of Health Sciences Research, Mayo Clinic College of Medicine, SW, Rochester, Minnesota, United States of America
| | - Nicholas B. Larson
- Department of Health Sciences Research, Mayo Clinic College of Medicine, SW, Rochester, Minnesota, United States of America
| | - Daniel R. O’Brien
- Department of Health Sciences Research, Mayo Clinic College of Medicine, SW, Rochester, Minnesota, United States of America
| | - John C. Cheville
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, SW, Rochester, Minnesota, United States of America
| | - Liang Wang
- Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Daniel J. Schaid
- Department of Health Sciences Research, Mayo Clinic College of Medicine, SW, Rochester, Minnesota, United States of America
| | - Stephen N. Thibodeau
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, SW, Rochester, Minnesota, United States of America
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Zou H, Zhou HH. WITHDRAWN: Single nucleotide polymorphism, a putative driver for the role of long intergeneric non-coding RNA. Cancer Lett 2018:S0304-3835(18)30691-8. [PMID: 30503557 DOI: 10.1016/j.canlet.2018.11.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/18/2018] [Accepted: 11/21/2018] [Indexed: 11/18/2022]
Abstract
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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Affiliation(s)
- Hecun Zou
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
| | - Hong-Hao Zhou
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China
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29
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Winter JM, Curry NL, Gildea DM, Williams KA, Lee M, Hu Y, Crawford NPS. Modifier locus mapping of a transgenic F2 mouse population identifies CCDC115 as a novel aggressive prostate cancer modifier gene in humans. BMC Genomics 2018; 19:450. [PMID: 29890952 PMCID: PMC5996485 DOI: 10.1186/s12864-018-4827-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 05/25/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND It is well known that development of prostate cancer (PC) can be attributed to somatic mutations of the genome, acquired within proto-oncogenes or tumor-suppressor genes. What is less well understood is how germline variation contributes to disease aggressiveness in PC patients. To map germline modifiers of aggressive neuroendocrine PC, we generated a genetically diverse F2 intercross population using the transgenic TRAMP mouse model and the wild-derived WSB/EiJ (WSB) strain. The relevance of germline modifiers of aggressive PC identified in these mice was extensively correlated in human PC datasets and functionally validated in cell lines. RESULTS Aggressive PC traits were quantified in a population of 30 week old (TRAMP x WSB) F2 mice (n = 307). Correlation of germline genotype with aggressive disease phenotype revealed seven modifier loci that were significantly associated with aggressive disease. RNA-seq were analyzed using cis-eQTL and trait correlation analyses to identify candidate genes within each of these loci. Analysis of 92 (TRAMP x WSB) F2 prostates revealed 25 candidate genes that harbored both a significant cis-eQTL and mRNA expression correlations with an aggressive PC trait. We further delineated these candidate genes based on their clinical relevance, by interrogating human PC GWAS and PC tumor gene expression datasets. We identified four genes (CCDC115, DNAJC10, RNF149, and STYXL1), which encompassed all of the following characteristics: 1) one or more germline variants associated with aggressive PC traits; 2) differential mRNA levels associated with aggressive PC traits; and 3) differential mRNA expression between normal and tumor tissue. Functional validation studies of these four genes using the human LNCaP prostate adenocarcinoma cell line revealed ectopic overexpression of CCDC115 can significantly impede cell growth in vitro and tumor growth in vivo. Furthermore, CCDC115 human prostate tumor expression was associated with better survival outcomes. CONCLUSION We have demonstrated how modifier locus mapping in mouse models of PC, coupled with in silico analyses of human PC datasets, can reveal novel germline modifier genes of aggressive PC. We have also characterized CCDC115 as being associated with less aggressive PC in humans, placing it as a potential prognostic marker of aggressive PC.
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Affiliation(s)
- Jean M Winter
- Metastasis Genetics Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA.,Present address: Dame Roma Mitchell Cancer Research Laboratories, Adelaide Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, 5000, Australia
| | - Natasha L Curry
- Metastasis Genetics Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA
| | - Derek M Gildea
- Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA
| | - Kendra A Williams
- Metastasis Genetics Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA
| | - Minnkyong Lee
- Metastasis Genetics Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA
| | - Ying Hu
- Center for Biomedical Informatics and Information Technology, National Cancer Institute, NIH, Rockville, MD, 20892, USA
| | - Nigel P S Crawford
- Metastasis Genetics Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA. .,, Present address: Sanofi, 55 Corporate Dr., Bridgewater, NJ, 08897, USA.
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30
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Patel R, Khalifa AO, Isali I, Shukla S. Prostate cancer susceptibility and growth linked to Y chromosome genes. Front Biosci (Elite Ed) 2018; 10:423-436. [PMID: 29293466 PMCID: PMC6152832 DOI: 10.2741/e830] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The role of Y chromosome in prostate cancer progression and incidence is not well known. Among the 46 chromosomes, Y chromosome determines the male gender. The Y chromosome is smaller than the X chromosome and contains only 458 genes compared to over 2000 genes found in the X chromosome. The Y chromosome is prone to high mutation rates, created exclusively in sperm cells due to the highly oxidative environment of the testis. Y chromosome harbors epigenetic information, which affects the expression of genes associated with the incidence and progression of prostate cancer. In this review, we focus on Y chromosome related genetic abnormalities, likely to be involved in the development and progression of prostate cancer.
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Affiliation(s)
- Riddhi Patel
- Department of Urology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH, USA
| | - Ahmad O Khalifa
- Urology Dept. Case Western Reserve University, Cleveland, Ohio and Menofia University, Shebin Al kom, Egpt
| | - Ilaha Isali
- Department of Urology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH, USA
| | - Sanjeev Shukla
- Department of Urology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH, USA,
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31
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Larson NB, McDonnell SK, Fogarty Z, Larson MC, Cheville J, Riska S, Baheti S, Weber AM, Nair AA, Wang L, O’Brien D, Davila J, Schaid DJ, Thibodeau SN. Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci. Oncotarget 2017; 8:85896-85908. [PMID: 29156765 PMCID: PMC5689655 DOI: 10.18632/oncotarget.20717] [Citation(s) in RCA: 2] [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: 04/26/2017] [Accepted: 07/29/2017] [Indexed: 12/19/2022] Open
Abstract
Large-scale genome-wide association studies have identified multiple single-nucleotide polymorphisms associated with risk of prostate cancer. Many of these genetic variants are presumed to be regulatory in nature; however, follow-up expression quantitative trait loci (eQTL) association studies have to-date been restricted largely to cis-acting associations due to study limitations. While trans-eQTL scans suffer from high testing dimensionality, recent evidence indicates most trans-eQTL associations are mediated by cis-regulated genes, such as transcription factors. Leveraging a data-driven gene co-expression network, we conducted a comprehensive cis-mediator analysis using RNA-Seq data from 471 normal prostate tissue samples to identify downstream regulatory associations of previously identified prostate cancer risk variants. We discovered multiple trans-eQTL associations that were significantly mediated by cis-regulated transcripts, four of which involved risk locus 17q12, proximal transcription factor HNF1B, and target trans-genes with known HNF response elements (MIA2, SRC, SEMA6A, KIF12). We additionally identified evidence of cis-acting down-regulation of MSMB via rs10993994 corresponding to reduced co-expression of NDRG1. The majority of these cis-mediator relationships demonstrated trans-eQTL replicability in 87 prostate tissue samples from the Gene-Tissue Expression Project. These findings provide further biological context to known risk loci and outline new hypotheses for investigation into the etiology of prostate cancer.
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Affiliation(s)
- Nicholas B. Larson
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Shannon K. McDonnell
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Zach Fogarty
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Melissa C. Larson
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - John Cheville
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Shaun Riska
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Saurabh Baheti
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Alexandra M. Weber
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Asha A. Nair
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Liang Wang
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Daniel O’Brien
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Jaime Davila
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Daniel J. Schaid
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Stephen N. Thibodeau
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
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Li R, Qin Z, Tang J, Han P, Xing Q, Wang F, Si S, Wu X, Tang M, Wang W, Zhang W. Association between 8q24 Gene Polymorphisms and the Risk of Prostate Cancer: A Systematic Review and Meta-Analysis. J Cancer 2017; 8:3198-3211. [PMID: 29158792 PMCID: PMC5665036 DOI: 10.7150/jca.20456] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 08/07/2017] [Indexed: 12/22/2022] Open
Abstract
Though numerous studies have been conducted to investigate the associations between five 8q24 polymorphisms (rs6983267 T>G, rs1447295 C>A, rs16901979 C>A, rs6983561 A>C and rs10090154 C>T) and prostate cancer (PCa) risk, the available results remained contradictory. Therefore, we performed a comprehensive meta-analysis to derive a precise estimation of such associations. We searched electronic databases PubMed, EMBASE, Web of Science and Wan Fang for the relevant available studies up to February 1st, 2017, and 39 articles were ultimately adopted in this meta-analysis. All data were extracted independently by two investigators and recorded in a unified form. The strength of association between 8q24 polymorphisms and PCa susceptibility was evaluated by the pooled odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analysis was conducted based on ethnicity, source of controls and genotypic method. Overall, a total of 39 articles containing 80 studies were adopted in this meta-analysis. The results of this meta-analysis indicated that five 8q24 polymorphisms above were all related to PCa susceptibility. Besides, in the subgroup analysis by ethnicity, all selected 8q24 polymorphisms were significantly associated with PCa risk in Asian population. In addition, stratification analysis by source of controls showed that significant results were mostly concentrated in the studies' controls from general population. Moreover, when stratified by genotypic method, significant increased PCa risks were found by TaqMan method. Therefore, this meta-analysis demonstrated that 8q24 polymorphisms (rs6983267 T>G, rs1447295 C>A, rs16901979 C>A, rs6983561 A>C and rs10090154 C>T) were associated with the susceptibility to PCa, which held the potential biomarkers for PCa risk.
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Affiliation(s)
- Ran Li
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Zhiqiang Qin
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Jingyuan Tang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Peng Han
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Qianwei Xing
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.,Department of Urology, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Feng Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Shuhui Si
- Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xiaolu Wu
- Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Min Tang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Wei Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Wei Zhang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
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Lin YY, Yu MW, Lin SM, Lee SD, Chen CL, Chen DS, Chen PJ. Genome-wide association analysis identifies a GLUL haplotype for familial hepatitis B virus-related hepatocellular carcinoma. Cancer 2017; 123:3966-3976. [PMID: 28662289 DOI: 10.1002/cncr.30851] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 05/02/2017] [Accepted: 05/08/2017] [Indexed: 12/24/2022]
Abstract
BACKGROUND A family history of liver cancer increases the risk of developing hepatocellular carcinoma (HCC) by 2-fold to 10-fold among patients with chronic hepatitis B virus (HBV). Previous genome-wide association studies have identified many possible susceptible loci associated with sporadic HBV-related HCC. However, despite family history being a well-known risk factor for HBV-related HCC, to the authors' knowledge its genetic mechanisms and associating loci remain largely unknown or unexplored, most likely due to the relative rarity of familial HCC and the difficulty of sample collection. METHODS The authors conducted a genome-wide association study with 139 male cases with familial HBV-related HCC and 139 non-HCC male controls with chronic HBV. The results were corroborated further with an independent cohort of 101 patients with familial HBV-related HCC and comparison with both the 1000 Genomes Project and the Taiwan Biobank. RESULTS A total of 51 risk single-nucleotide polymorphisms (P≤1E-04) were identified in the association analyses, which included 2 clusters of associated single-nucleotide polymorphisms and haplotypes at 1q25.3 (glutamate-ammonia ligase [GLUL]/transmembrane epididymal protein 1 [TEDDM1]/long intergenic non-protein-coding RNA 272 [LINC00272]/regulator of G-protein signaling-like 1 [RGSL1]) and 17q11.2 (solute carrier family 13 member 2 [SLC13A2]/forkhead box N1 [FOXN1]). Both the GLUL and SLC13A2/FOXN1 haplotypes have large effect sizes and were found to be different from those found from genome-wide association studies of sporadic HCCs. CONCLUSIONS To the authors' knowledge, the current study is the first genome-wide association study to identify genetic factors for familial HBV-related HCC. The results identified 2 large effect susceptible haplotypes located at GLUL and SLC13A2/FOXN1. The current study findings also suggest different genetic susceptibility between familial and sporadic HBV-related HCC. Cancer 2017;123:3966-76. © 2017 American Cancer Society.
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Affiliation(s)
- You-Yu Lin
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
| | - Ming-Whei Yu
- Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan
| | - Shi-Ming Lin
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan
| | - Chih-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
| | - Ding-Shinn Chen
- Hepatitis Research Center, National Taiwan University, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
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