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Multiple loci identified in a genome-wide association study of prostate cancer

Nature Genetics volume 40, pages 310–315 (2008)Cite this article

Abstract

We followed our initial genome-wide association study (GWAS) of 527,869 SNPs on 1,172 individuals with prostate cancer and 1,157 controls of European origin—nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial prospective study—by testing 26,958 SNPs in four independent studies (total of 3,941 cases and 3,964 controls). In the combined joint analysis, we confirmed three previously reported loci (two independent SNPs at 8q24 and one in HNF1B (formerly known as TCF2 on 17q); P < 10−10). In addition, loci on chromosomes 7, 10 (two loci) and 11 were highly significant (between P < 7.31 × 10−13 and P < 2.14 × 10−6). Loci on chromosome 10 include MSMB, which encodes β-microseminoprotein, a primary constituent of semen and a proposed prostate cancer biomarker, and CTBP2, a gene with antiapoptotic activity; the locus on chromosome 7 is at JAZF1, a transcriptional repressor that is fused by chromosome translocation to SUZ12 in endometrial cancer. Of the nine loci that showed highly suggestive associations (P < 2.5 × 10−5), four best fit a recessive model and included candidate susceptibility genes: CPNE3, IL16 and CDH13. Our findings point to multiple loci with moderate effects associated with susceptibility to prostate cancer that, taken together, in the future may predict high risk in select individuals.

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Figure 1: Association analysis of combined joint analysis in two-stage GWAS of prostate cancer.
Figure 2: Location of the association signal and LD across the MSMB region.
Figure 3: Distribution of odds ratios for prostate cancer risk in the European population.

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Acknowledgements

The Prostate Lung Colorectal Ovarian Cancer Screening Trial (PLCO) was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, US National Institutes of Health, Department of Health and Human Services. The Health Professionals Follow-up Study (HPFS) study is supported by the US National Institutes of Health grant CA55075 and U01CA098233. The American Cancer Society (ACS) study is supported by U01 CA098710. The Alpha Tocopherol Beta-Carotene Cancer Prevention study (ATBC) Study is supported by the Intramural Research Program of the National Cancer Institute, NIH, and by US Public Health Service contracts N01-CN-45165, N01-RC-45035, and N01-RC-37004 from the National Cancer Institute, Department of Health and Human Services. F.R.S. is supported by a NRSA training-grant (T32 CA 09001). Centre de Recherche pour les Pathologies Prostatiques (CeRePP) thanks J.P.B. and Generali for their charitable donations which have contributed to this project. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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Authors and Affiliations

  1. Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Gilles Thomas, Meredith Yeager, Sholom Wacholder, Nick Orr, Kai Yu, Nilanjan Chatterjee, Robert Welch, Amy Hutchinson, Andrew Crenshaw, Brian J Staats, Zhaoming Wang, Jesus Gonzalez-Bosquet, Jun Fang, Xiang Deng, Sonja I Berndt, Demetrius Albanes, Stephanie Weinstein, Margaret Tucker, Joseph F Fraumeni Jr, Robert Hoover, Richard B Hayes, David J Hunter & Stephen J Chanock

  2. Bioinformed Consulting Services, Gaithersburg, Maryland, 20877, USA

    Kevin B Jacobs

  3. Core Genotyping Facility, Advanced Technology Program, SAIC Frederick, Inc., NCI-Frederick, Frederick, 21702, Maryland, USA

    Meredith Yeager, Robert Welch, Amy Hutchinson, Andrew Crenshaw, Brian J Staats, Zhaoming Wang & Xiang Deng

  4. Department of Epidemiology, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, 02115, Massachusetts, USA

    Peter Kraft, Fredrick R Schumacher & David J Hunter

  5. CeRePP Hopital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, 75970, France

    Geraldine Cancel-Tassin, Olivier Cussenot & Antoine Valeri

  6. Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, 30329, Georgia, USA

    Eugenia E Calle, Heather Spencer Feigelson, Michael J Thun & Carmen Rodriguez

  7. Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki, FIN-0030, Finland

    Jarmo Virtamo

  8. Department of Nutrition, Harvard School of Public Health, Boston, 02115, Massachusetts, USA

    Edward Giovannucci & Walter C Willett

  9. Division of Urologic Surgery, Washington University School of Medicine, St. Louis, 63108, Missouri, USA

    Gerald L Andriole

  10. Department of Surgery, University of Colorado at Denver and Health Sciences Center, Denver, 80014, Colorado, USA

    E David Crawford

  11. Department of Health and Human Services, Office of Cancer Genomics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Daniela S Gerhard

  12. Department of Health and Human Services, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Stephen J Chanock

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  1. Gilles Thomas
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  2. Kevin B Jacobs
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  30. Antoine Valeri
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  31. Gerald L Andriole
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  32. E David Crawford
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  36. Robert Hoover
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  37. Richard B Hayes
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  39. Stephen J Chanock
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Corresponding author

Correspondence to Stephen J Chanock.

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Supplementary Methods, Supplementary Tables 1–9, Supplementary Figures 1 and 2 (PDF 1670 kb)

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Thomas, G., Jacobs, K., Yeager, M. et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet 40, 310–315 (2008). https://doi.org/10.1038/ng.91

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