Letter | Published:

Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Abstract

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10−8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10−9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10−9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55–2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04–6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.

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Change history

  • 08 January 2019

    In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.

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Acknowledgements

We pay tribute to Brian Henderson for his vision and leadership; he was a driving force behind the OncoArray project and he unfortunately passed away before seeing its fruition. We also thank the individuals who participated in these studies enabling this work.

Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) (U19 CA 148537 for the ELLIPSE project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract no. HHSN268201200008I. Additional analytical support was provided by NIH NCI U01 CA188392 (to F.R.S.).

Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, and C8197/A16565), the NIH (CA128978) and Post-Cancer GWAS Initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112; the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund.

This work was supported by the Canadian Institutes of Health Research; the European Commission's Seventh Framework Programme grant agreement no. 223175 (HEALTH-F2-2009-223175); Cancer Research UK grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, and C16913/A6135; and NIH Cancer Post-Cancer GWAS initiative grant no. 1 U19 CA 148537-01 (the GAME-ON initiative).

We also thank the following for funding support: the Institute of Cancer Research and the Everyman Campaign, the Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), the Orchid Cancer Appeal, the National Cancer Research Network UK, and the National Cancer Research Institute (NCRI) UK. We are grateful for the support of NIHR funding to the NIHR Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust.

The Prostate Cancer Program of Cancer Council Victoria also acknowledges grant support from the National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394, and 614296), VicHealth, Cancer Council Victoria, the Prostate Cancer Foundation of Australia, the Whitten Foundation, PricewaterhouseCoopers, and Tattersall’s. E.A.O., D.M.K., and E.M.K. acknowledge the Intramural Program of the National Human Genome Research Institute for support.

The BPC3 was supported by the NIH, National Cancer Institute (cooperative agreements U01-CA98233 to D.J.H., U01-CA98710 to S.M.G., U01-CA98216 to E.R., and U01-CA98758 to B.E.H., and the Intramural Research Program of the NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics).

The CAPS GWAS study was supported by the Swedish Cancer Foundation (grant nos. 09-0677, 11-484, and 12-823), the Cancer Risk Prediction Center (CRisP; http://ki.se/en/meb/crisp/), a Linneus Centre grant (contract ID 70867902) financed by the Swedish Research Council, and the Swedish Research Council (grant nos. K2010-70X-20430-04-3, and 2014-2269).

PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH.

A full description of funding and acknowledgements can be found in the Supplementary Note.

Author information

Writing group: F.R.S., C.A.H., D.V.C., A.A.A.O., S.I.B., M. Ahmed, Z.S.K.-J., and R.A.E. Conception and coordination of OncoArray synthesis: F.R.S., C.I.A., D.F.E., S.J.C., C.A.H., B.E.H., and F.W. Database management: S.B., M.N.B., X.S., K.M., and A.L. Bioinformatics support: E.J.S., T.D., D. Leongamornlert, E.A., C.C.-B., and C.G. Genotyping calling and QC: L.F., J.D., and J.T. Provision of DNA samples and/or phenotypic data: V.L.S., S.M.G., B.D.C., C.M.T., P.J.G., I.M.T., J.B., S.C., L. Moya, J.C., L.H., W.T., G.P.R., H.G., M. Aly, T.N., P. Pharoah, N.P., J.S., T.L.J.T., C. Slavov, A.A., D.A., S.W., A.W., N.H., C.M.L.W., A.M.D., N.B., L.A.M., E.G., G.L.A., O.C.,G.C.T., S.K., L.E.B.F., K.D.S., T.F.O., M.B., L. Maehle, E.M.G., D.E.N., J.L.D., F.C.H., R.M.M., R.C.T., T.J.K., R.J.H., N.E.F., A.F., S.A.I., M.C. Stern, B.S.R., S.L.K., H.O., Y.-J.L., H.-W.Z., N.F., X.M., X.G., G.W., Z.S., G.G.G., M.C. Southey, R.J.M., L.M.F., A.S.K., B.M.K., J. Lubinski, G.C.-V., K.L.P., M.S., J.Y.P., T.A.S., H.-Y.L., J.L.S., C.C., D.W., J. Lim, E.A.O., M.S.G., B.G.N., S.F.N., M.W., R.B., M.A.R., P.I., H.B., K.C., B.H.,C.M., M.L., T.S., J.K., C.J.L., E.M.J., M.R.T., P. Paulo, M.C., S.L.N., L.S., Y.C.D., K.D.R., G.D.M., P.O., A.R., J. Llorca, S.-H.T., D.W.L., L.F.N., D. Lessel, M.G., T.K., R.K., N.U., S.S., C. Sipeky, V.M., M.P., F. Canzian, S.J., T.V.d.B., S. Larkin, P.A.T., C.A.H., M.G.D., J.E.C., M.E.M., M.J.R., G.J., R.H.N.v.S., F.M., T.T., Y.A.K., J.X., K.-T.K., L.C.-A., H.P., A.M., S.N.T., S.K.M., D.J.S., S. Lindstrom, C.T., J.M., D.J.H., E.R., A.S., F. Claessens, L.N.K., L.L.M., R.N.H., M.J.M., Z.C., P.K., F.W., S.J.C., B.E.H., C.A.-H., R.A.E., A.V., A.G.-C., B.F.D., G.C.-T., APCB investigators, IMPACT Study, Canary PASS investigators, BPC3, PRACTICAL, CAPS, PEGASUS, GAME-ON/ELLIPSE, and Profile Study Steering Committee. All authors read and approved the final version of the manuscript.

Competing interests

The authors declare no competing interests.

Correspondence to Fredrick R. Schumacher or Ali Amin Al Olama or Rosalind A. Eeles.

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Further reading

Fig. 1: ELLIPSE/PRACTICAL study overview of PrCa GWAS meta-analysis.
Fig. 2: Locus Explorer plots depicting the statistical association with PrCa and biological context of variants from four of the newly identified PrCa-risk loci (n = 74,849 biologically independent samples).