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Genome-wide association study of prostate cancer identifies a second risk locus at 8q24

Nature Genetics volume 39, pages 645–649 (2007)Cite this article

Abstract

Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting a genome-wide association study in the Cancer Genetic Markers of Susceptibility project with 550,000 SNPs in a nested case-control study (1,172 cases and 1,157 controls of European origin), we identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal is 70 kb centromeric to the previously reported SNP, rs1447295, but shows little evidence of linkage disequilibrium with it. A combined analysis with four additional studies (total: 4,296 cases and 4,299 controls) confirms association with prostate cancer for rs6983267 in the centromeric locus (P = 9.42 × 10−13; heterozygote odds ratio (OR): 1.26, 95% confidence interval (c.i.): 1.13–1.41; homozygote OR: 1.58, 95% c.i.: 1.40–1.78). Each SNP remained significant in a joint analysis after adjusting for the other (rs1447295 P = 1.41 × 10−11; rs6983267 P = 6.62 × 10−10). These observations, combined with compelling evidence for a recombination hotspot between the two markers, indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. We estimate that the population attributable risk of the new locus, marked by rs6983267, is higher than the locus marked by rs1447295 (21% versus 9%).

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Figure 1: Association analysis of SNPs across a region of 8q24.
Figure 2: Association signal in the 8q24 region detected by ancestral recombination graph (ARG).
Figure 3: Centromeric and telomeric haplotypes of the 8q24 region associated with prostate cancer susceptibility in PLCO.

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Acknowledgements

The HPFS study is supported by NIH grants CA CA55075 and 5U01CA098233-04. The ACS study is supported by U01 CA098710. The ATBC study is supported by NIH contracts N01-CN-45165, N01-RC-45035 and N01-RC-37004. F.R.S. is supported by an NRSA training grant (T32 CA 09001). P.F. is supported by a UK Engineering and Physical Sciences Research Council Grant (GR/S18786). M.M. is supported by the Wellcome Trust. N.O., R.B.H., S.W., K.Y., N.C., M.T., J.F.F., R.H., S.J.C. and G.T. are supported by the Intramural Research Program of the National Cancer Institute (US National Institutes of Health, Department of Health and Human Services).

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Authors and Affiliations

  1. SAIC-Frederick, National Cancer Institute (NCI)-Frederick Cancer Research and Development Center, Frederick, 21702, Maryland, USA

    Meredith Yeager, Zhaoming Wang, Robert Welch & Brian J Staats

  2. Division of Cancer Epidemiology and Genetics, Department of Health and Human Services (DHHS), Center for Cancer Research, NCI, US National Institutes of Health (NIH), Bethesda, 20892, Maryland, USA

    Meredith Yeager, Richard B Hayes, Sholom Wacholder, Kai Yu, Nilanjan Chatterjee, Zhaoming Wang, Robert Welch, Brian J Staats, Demetrius Albanes, Stephanie Weinstein, Margaret Tucker, Joseph F Fraumeni Jr, Robert Hoover, David J Hunter, Stephen J Chanock & Gilles Thomas

  3. Department of Health and Human Services (DHHS), Pediatric Oncology Branch, Center for Cancer Research, NCI, US National Institutes of Health (NIH), Bethesda, 20892, Maryland, USA

    Nick Orr & Stephen J Chanock

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

    Kevin B Jacobs

  5. 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

  6. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK

    Mark J Minichiello

  7. Department of Mathematics and Statistics, Lancaster University, Lancaster, LA1 4YF, UK

    Paul Fearnhead

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

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

  9. Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki, FIN-00300, Finland

    Jarmo Virtamo

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

    Edward Giovannucci & Walter C Willett

  11. Centre de Recherche pour les Pathologies Prostatiques (CeRePP), Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, 75970, France

    Geraldine Cancel-Tassin, Olivier Cussenot & Antoine Valeri

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

    Gerald L Andriole

  13. Division of Hematology and Oncology, Columbia University, New York, 10032, New York, USA

    Edward P Gelmann

  14. Office of Cancer Genomics, NCI, NIH, DHHS, Bethesda, 20892, Maryland, USA

    Daniela S Gerhard

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Corresponding author

Correspondence to Stephen J Chanock.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Distribution of genotype counts and frequencies in cases and controls. (PDF 13 kb)

Supplementary Table 2

Results for single SNPs for all models tested. (PDF 15 kb)

Supplementary Table 3

Results for two-SNP model for all models tested and age and case status for single-SNP and two-SNP models. (PDF 96 kb)

Supplementary Table 4

Population-attributable risks. (PDF 10 kb)

Supplementary Methods (PDF 169 kb)

Supplementary Note (PDF 18 kb)

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Yeager, M., Orr, N., Hayes, R. et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 39, 645–649 (2007). https://doi.org/10.1038/ng2022

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