Year: 2015
Type: article
Study design: Observational Study
Abstract: Prostate cancer is the most common non-skin cancer in males, with a ∼1.5-2-fold higher incidence in African American men when compared with whites. Epidemiologic evidence supports a large heritable contribution to prostate cancer, with over 100 susceptibility loci identified to date that can explain ∼33% of the familial risk. To explore the contribution of both rare and common variation in coding regions to prostate cancer risk, we sequenced the exomes of 2165 prostate cancer cases and 2034 controls of African ancestry at a mean coverage of 10.1×. We identified 395 220 coding variants down to 0.05% frequency [57% non-synonymous (NS), 42% synonymous and 1% gain or loss of stop codon or splice site variant] in 16 751 genes with the strongest associations observed in SPARCL1 on 4q22.1 (rs13051, Ala49Asp, OR = 0.78, P = 1.8 × 10(-6)) and PTPRR on 12q15 (rs73341069, Val239Ile, OR = 1.62, P = 2.5 × 10(-5)). In gene-level testing, the two most significant genes were C1orf100 (P = 2.2 × 10(-4)) and GORAB (P = 2.3 × 10(-4)). We did not observe exome-wide significant associations (after correcting for multiple hypothesis testing) in single variant or gene-level testing in the overall case-control or case-case analyses of disease aggressiveness. In this first whole-exome sequencing study of prostate cancer, our findings do not provide strong support for the hypothesis that NS coding variants down to 0.5-1.0% frequency have large effects on prostate cancer risk in men of African ancestry. Higher-coverage sequencing efforts in larger samples will be needed to study rarer variants with smaller effect sizes associated with prostate cancer risk.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddv462
Institutions: University of Southern California, USC Norris Comprehensive Cancer Center, Broad Institute, Harvard University, Massachusetts Institute of Technology, University of California, Los Angeles, Howard Hughes Medical Institute, University of Hawaiʻi at Mānoa, University of Hawaii System, Makerere University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: University of Southern California, Cancer Research UK, National Institute for Health and Care Research, Ministerio de Economía y Competitividad, National Institutes of Health, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences, National Center for Chronic Disease Prevention and Health Promotion
Awards: Southern Community Cohort Study, NIHR Senior Investigator Award, ENVIRONMENTAL &GENETIC DETERMINANTS OF PROSTATE CANCER, G1590068161, The Howard University SCORE Program, G1632577609, G1740625458, G1798569254, A Multiethnic Genome-Wide Scan of Prostate Cancer, PROSTATE CANCER IN RELATION TO VASECTOMY, G2089819271, G2349108260, G2419028985, GENETIC POLYMORPHISMS AND PROSTATE CANCER RISK, PCPT and SELECT cohorts: Core Infrastructure Support for Cancer Research, G3157549237, SWOG NCORP Research Base, Genome-wide sequencing of prostate cancer in men of African ancestry, Genetic Epidemiology of Prostate Cancer Risk and Progression, Characterizing Genetic Susceptibility to Breast and Prostate Cancer: The BPC3., Elucidating Loci Involved in Prostate Cancer Suceptibility, G3948222162, G4146105916, G422195599, G4407166175, G4494057802, G4513176822, Characterizing Genetic Susceptibility to Breast and Prostate Cancer; the BPC3, A NESTED CASE-CONTROL STUDY OF PROSTATE CARCINOGENESIS, Mechanisms and Prevention of Environmental Disease, G5654214539, G586064783, Understanding Ethnic Differences in Cancer: The Multiethnic Cohort Study, G6191305262, NSAIDS and Other Medications in Prostate Cancer Etiology, Characterizing Genetic Susceptibility to Breast and Prostate Cancer; the BPC3, G6703222393, Characterizing Genetic Susceptibility to Breast and Prostate Cancer; the BPC3, G7605512422, G767466929, SWOG Community Clinical Oncology Program Research Base, G7978929429, Genomewide Association Study of Prostate Cancer, G804659861, Expanding resources for understanding the genetic basis for prostate cancer in Af, G828535024, G8332978792, G8850026470, G894009200, G9000084571, G9000216949, G9000286278, Cancer Center Support Grant, Understanding Population Differences in Cancer: The MEC Study
OpenAlex ID: W2258353569