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Multiple newly identified loci associated with prostate cancer susceptibility

Abstract

Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at ≤60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 × 10−8 to P = 8.7 × 10−29). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3.

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Figure 1: Quantile-quantile plot for the test statistics (Cochran-Armitage 1-d.f. χ2 trend tests) for stage 1.
Figure 2: Summary of results.

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Acknowledgements

We should like to thank all the individuals with prostate cancer and control men who took part in this study. This work was supported by Cancer Research UK Grant C5047/A3354. D.F.E. is a Principal Research Fellow of Cancer Research UK. J.L.H. is an Australia Fellow of the NHMRC. We would also like to 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 known as Prostate UK), The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK, grants from the National Health and Medical Research Council, Australia (209057, 251533, 450104), VicHealth, The Cancer Council Victoria, The Whitten Foundation, and Tattersall's. We are grateful to the staff at Illumina: K.Viaud, C. McBride, J. Bernd, R. Morey, and the rest of the Illumina Genotyping Service Laboratory, and S. McBean, K. Cook, F. Amini, M.Laurent and M. Gibbs. We are also grateful to those at Tepnel Life Sciences for their help with this study: S. Doyle, A. Priest, A. Barlow, S. Howe and L. Holliday. We acknowledge the contribution of all members of the UKGPCS, BAUS and ProtecT study research groups, especially those listed in the supplementary material. We would like to acknowledge the help of N. Gauge, C. Bamber, S. Barrett and P. Kelham for sample collection and retrieval and L. Barakzai and P. Hamilton for assistance with preparing the manuscript. The ProtecT study is ongoing and is funded by the Health Technology Assessment Programme (projects 96/20/06, 96/20/99). The ProtecT trial and its linked ProMPT and CAP (Comparison Arm for ProtecT) studies are supported by Department of Health, England; Cancer Research UK grant number C522/A8649, Medical Research Council of England grant number G0500966, ID 75466 and The NCRI, UK. The epidemiological data for ProtecT were generated though funding from the Southwest National Health Service Research and Development. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health of England.

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R.A.E. and D.F.E. designed and directed the study and obtained financial support. Z.K-J. directed the genotyping of stage 2. D.F.E. and A.A.A.O. conducted the statistical analysis. J.M. and H.I.F. provided bioinformatics support. M.G. co-ordinated the UKGPCS. G.G.G., J.L.H. and D.R.E. directed the Australian studies. M.C.S. and G.S. co-ordinated the Australian studies. D.E.N., J.L.D. and F.C.H. directed the ProtecT study. The remaining authors collated samples and performed laboratory analyses. R.A.E. and D.F.E. drafted the manuscript.

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Correspondence to Rosalind A Eeles.

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Supplementary Tables 1–8, Supplementary Note (PDF 365 kb)

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Eeles, R., Kote-Jarai, Z., Giles, G. et al. Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 40, 316–321 (2008). https://doi.org/10.1038/ng.90

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