Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 150, Issue 1, Pages 80-90Publisher
WILEY
DOI: 10.1002/ijc.33808
Keywords
gene expression; genetic factors; prostate cancer; transcriptome-wide association study
Categories
Funding
- Cancer Risk Prediction Center (CRisP)
- Linneus Centre [70867902]
- Swedish Cancer Foundation [12-823, 11-484, 09-0677]
- Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics
- U.S. National Institutes of Health, National Cancer Institute [U01-CA98758, U01-CA98216, U01-CA98710, U01-CA98233]
- Canadian Institutes of Health Research (CIHR)
- Breast Cancer Research Foundation
- Ovarian Cancer Research Fund
- Department of Defense [W81XWH10-1-0341]
- Post-Cancer GWAS initiative [1 U19 CA148112, 1 U19 CA148065, 1U19 CA148537]
- Cancer Research UK [C8197-A16565, C5047-A10692, C5047-A15007, C5047-A8384, C1281-A12014, C12292-A11174, C1287-A10710, C1287-A10118, C16913-A6135, C5047-A3354, C1287-A16563, C5047-A7357]
- European Community [223175, HEALTH-F2-2009-223175]
- US National Institutes of Health (NIH) [CA128813, CA128978, U19 CA 148537]
- National Human Genome Research Institute
- Cancer Council Victoria
- Whitten Foundation
- PricewaterhouseCoopers and Tattersall's
- National Health and Medical Research Council, Australia [614296, 940394, 623204, 504715, 504700, 450104, 396414, 251533, 209057, 126402]
- NIHR Biomedical Research Centre at The Institute of Cancer Research
- Royal Marsden NHS Foundation Trust
- Institute of Cancer Research
- Everyman Campaign
- Prostate Cancer Research Foundation
- Prostate Research Campaign UK (now PCUK)
- Orchid Cancer Appeal
- Rosetrees Trust
- National Cancer Research Network UK
- National Cancer Research Institute (NCRI) UK
- The National Institute of Health (NIH) Cancer Post-Cancer GWAS Initiative [1U19 CA 148537-01]
- Department of Education of Fujian Province, China
- Harbin Medical University Cancer Hospital
- NIH [R01GM140287, R01HG011138, R35HG010718, U01HG009086, AG068026]
- University of Hawaii Cancer Center
- Swedish Research Council [2014-2269, K2010-70X-20430-04-3]
- Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer
- Komen Foundation
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The study combines transcriptome-wide association study and validation to identify candidate genes potentially involved in prostate cancer development. Analysis revealed 573 genes associated with prostate cancer risk, including 451 novel genes and 122 previously reported genes.
A large proportion of heritability for prostate cancer risk remains unknown. Transcriptome-wide association study combined with validation comparing overall levels will help to identify candidate genes potentially playing a role in prostate cancer development. Using data from the Genotype-Tissue Expression Project, we built genetic models to predict normal prostate tissue gene expression using the statistical framework PrediXcan, a modified version of the unified test for molecular signatures and Joint-Tissue Imputation. We applied these prediction models to the genetic data of 79 194 prostate cancer cases and 61 112 controls to investigate the associations of genetically determined gene expression with prostate cancer risk. Focusing on associated genes, we compared their expression in prostate tumor vs normal prostate tissue, compared methylation of CpG sites located at these loci in prostate tumor vs normal tissue, and assessed the correlations between the differentiated genes' expression and the methylation of corresponding CpG sites, by analyzing The Cancer Genome Atlas (TCGA) data. We identified 573 genes showing an association with prostate cancer risk at a false discovery rate (FDR) <= 0.05, including 451 novel genes and 122 previously reported genes. Of the 573 genes, 152 showed differential expression in prostate tumor vs normal tissue samples. At loci of 57 genes, 151 CpG sites showed differential methylation in prostate tumor vs normal tissue samples. Of these, 20 CpG sites were correlated with expression of 11 corresponding genes. In this TWAS, we identified novel candidate susceptibility genes for prostate cancer risk, providing new insights into prostate cancer genetics and biology.
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