@article{2e8b8e113cc34972aae266f14b11c84c,
title = "Whole-exome sequencing of over 4100 men of African ancestry and prostate cancer risk",
abstract = "Prostate cancer is themost commonnon-skincancer inmales,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 contributionof 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% nonsynonymous (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) andPTPRR 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 formultiple hypothesis testing) in single variant or gene-level testing in the overall case-control or case-case analyses of disease aggressiveness. In this firstwhole-exome sequencing studyofprostate cancer, our findings donot provide strong support for the hypothesis thatNS 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.",
author = "Rand, {Kristin A.} and Nadin Rohland and Arti Tandon and Alex Stram and Xin Sheng and Ron Do and Bogdan Pasaniuc and Alex Allen and Dominique Quinque and Swapan Mallick and {Le Marchand}, Loic and Sam Kaggwa and Alex Lubwama and Stram, {Daniel O.} and Stephen Watya and Henderson, {Brian E.} and Conti, {David V.} and David Reich and Haiman, {Christopher A.} and Strom, {Sara S.} and Kittles, {Rick A.} and Rybicki, {Benjamin A.} and Stanford, {Janet L.} and Goodman, {Phyllis J.} and Berndt, {Sonja I.} and John Carpten and Graham Casey and Lisa Chu and Diver, {Ryan W.} and Hennis, {Anselm J M} and Klein, {Eric A.} and Suzanne Kolb and {Cristina Leske}, M. and Murphy, {Adam B.} and Christine Neslund-Dudas and Park, {Jong Y.} and John, {Esther M.} and Kibel, {Adam S.} and Curtis Pettaway and Gapstur, {Susan M.} and {Lilly Zheng}, S. and Wu, {Suh Yuh} and Witte, {John S.} and Jianfeng Xu and William Isaacs and Ingles, {Sue A.} and Ann Hsing and Barbara Nemesure and Blot, {William J.} and Eeles, {Rosalind A.} and {The African Ancestry Prostate Cancer GWAS Consortium (AAPC)} and {The ELLIPSE/GAME-ON Consortium}",
note = "Funding Information: This work was supported by NIH grants R01 CA 165862, UM1 CA 164973 and RC2 CA 148085. K.A.R. gratefully acknowledges Gretchen Ponty Smith and is supported, in part, by the Margaret Kersten Ponty postdoctoral fellowship endowment, Achievement Rewards for College Scientists (ARCS) Foundation, Los Angeles Founder Chapter. The African Ancestry Prostate Cancer GWAS Consortium is supported by NIH grants CA1326792, CA148085 and HG004726. The MEC was supported by NIH grants CA164973, CA63464 and CA54281. Genotyping of the PLCO samples was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, NCI, NIH. LAAPC was funded by grant 99-00524V-10258 from the Cancer Research Fund, under Interagency Agreement #97-12013 (University of California contract #98-00924V) with the Department of Health Services Cancer Research Program. Cancer incidence data for the MEC and LAAPC studies have been collected by the Los Angeles Cancer Surveillance Program of the University of Southern California with Federal funds from the NCI, NIH, Department of Health and Human Services, under Contract No. N01-PC-35139, and the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885, and grant number 1U58DP000807-3 from the Centers for Disease Control and Prevention. KCPCS was supported by NIH grants CA056678, CA082664 and CA092579, with additional support from the Fred Hutchinson Cancer Research Center and the Intramural Program of the National Human Genome Research Institute. MDA was support by grants, CA68578, ES007784, DAMD W81XWH-07-1-0645 and CA140388. GECAP was supported by NIH grant ES011126. CaP Genes was supported by CA88164 and CA127298. IPCG was support by DOD grant W81XWH-07-1-0122. DCPC was supported by NIH grant S06GM08016 and DOD grants DAMD W81XWH-07-1-0203, DAMD W81XWH-06-1-0066 and DOD W81XWH-10-1-0532. CPS-II is supported by the American Cancer Society. SELECT is funded by Public Health Service cooperative Agreement grant CA37429 awarded by the National Cancer Institute, National Institutes of Health. SCCS is funded by NIH grant CA092447. SCCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab that is supported in part by the Vanderbilt Ingram Cancer Center (CA68485). Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. The ELLIPSE (Elucidating Loci in Prostate Cancer Susceptibility)/ GAME-ON Consortium was supported by NCI U19 grant CA148537. UKGPCS is supported by the Institute of Cancer Research and The Everyman Campaign, Cancer Research UK C5047/A8384, Prostate Cancer Research Foundation (now Prostate Cancer UK), The Orchid Cancer Appeal, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. UKGPCS should also like to acknowledge the NCRN nurses, data managers and Consultants for their work in the UKGPCS study. CAPS: The Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Swedenwas supported by the Cancer Risk Prediction Center (CRisP;www.crispcenter.org), a Linneus Centre (Contract ID 70867902) financed by the Swedish Research Council, Swedish Research Council (grant no K2010- 70X-20430-04-3, 10-3674), the Swedish Cancer Foundation (grant no 09-0677, 11-484, 12-823), the Hedlund Foundation, the S{\"o}derberg Foundation, the Enqvist Foundation, ALF funds from the Stockholm County Council. Stiftelsen Johanna Hagstrand och Sigfrid Linn{\'e}r''s Minne, Karlsson''s Fund for urological and surgical research. The BPC3 was supported by the U.S. National Institutes of Health, National Cancer Institute (cooperative agreements U01- CA98233, U01-CA98710, U01-CA98216 and U01-CA98758, and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). The ATBC study was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. Additionally, this research was supported by U.S. Public Health Service contracts N01-CN- 45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C from the National Cancer Institute, Department of Health and Human Services. Genotyping in PEGASUS/PLCO was supported and funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, NCI, NIH. Publisher Copyright: {\textcopyright} The Author 2015. Published by Oxford University Press.",
year = "2016",
month = jan,
day = "15",
doi = "10.1093/hmg/ddv462",
language = "English (US)",
volume = "25",
pages = "371--381",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "2",
}
