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Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study

Abstract

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10−8 to P = 2.7 × 10−24). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining 25% of the familial risk in this disease, have now been identified.

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Figure 1: Forest plots for the ten SNPs genotyped in stages 1–4.
Figure 2: Regional plots of four of the associated SNPs at 5p15 (a), 3q23 (b), 5p12 (c) and 6p21 (d).

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Acknowledgements

The full acknowledgments are detailed in the Supplementary Note.

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Authors and Affiliations

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Contributions

R.A.E. and D.F.E. designed the study and are joint principal investigators (PIs) on the GWAS. R.A.E. is the PI of the UK Genetic Prostate Cancer Study (UKGPCS) and project managed the overall study. Z.K.-J., R.A.E., D.F.E. and A.A.A.O. wrote the paper, and Z.K.-J. coordinated and managed the stage 3 and the PRACTICAL stage 4 genotyping. Z.K.-J., D.A.L., M.T., E.J.S. and N.M. coordinated sample collation for stage 3 and the PRACTICAL stage 4 set genotyped in the UK. A.A.A.O. and D.F.E. performed the statistical analyses. S.B. collated the dataset. G.G.G., J.L.H., D.R.E. and G.S. are PIs of the Australian studies. M.C. Southey manages the molecular work. J. Schleutker is PI of the Tampere study. T.W. collected clinical data, performed sample selection and collated data. T.L.J.T. coordinated sample collection. M.W. is the PI of the CPCS1 and CPCS2 studies. P. Klarskov, B.G.E., M.A.R., A.T.-H. and S.E.B. have collected samples and data and contributed to the genotyping of this study. F.C.H., D.E.N. and J.L. Donovan are joint PIs of ProtecT. A.L. is the study coordinator and M.D. the database manager. A.C. assisted with sample selection, retrieval and processing. D.A. and J.V. are PIs of the ATBC Study and were responsible for the original collection of the ATBC DNA samples. S.C. was responsible for assembly and genotyping. S.I.B. is the PI of the PLCO study, A.G. is the PI for the St. Louis screening center for PLCO and M.Y. oversaw the genotyping for PLCO. H.B. is the PI of the ESTHER study; D.R. and C.S. contributed to design and data collection; and H.M. is the study coordinator. C.C. and J.L.H. are PIs of the Poland study. C.C. and D.W. genotyped the samples. C.M. and W.V. are PIs of the Ulm study. A.E.R. identified and collected clinical material, processed samples, undertook genotyping and collated data. T. Dörk is the PI of the Hannover Prostate Cancer Study. A.M. and J.S. coordinated sample collation, provided molecular advice and conducted molecular work. J.L. Dickinson is the PI of the Tasprac study. J.R.M. performed the Tasmanian genotyping and collated data; B.P. provided molecular advice and assistance with collating data. P. Kraft coordinated data collection and management for the HPFS. T.F.Ø. and K.D.S. are PIs of the Aarhus study. M.B. coordinated sample collection and registration of clinical data. K.D.S. led the sample genotyping. E.R. is PI of EPIC; D.C. and F.C. typed EPIC samples. T.K. is the PI of the EPIC-Oxford cohort and collected clinical material. R.T. collated data. S.M.G. and M.J.T. are the PIs of the ACS CPS-II study, and W.R.D. is the data manager for this study. B.E.H. and L.L.M. are the PIs of the MEC, and C.A.H. and F.S. are co-investigators (CIs). Y.-J.L. and H.-W.Z. are joint PIs of CHSH, Y.-J.L. is study coordinator and H.-W.Z. participated in and closely supervised the CHSH study. J.L.S. is the PI of the Fred Hutchinson study and E.A.O. is PI of the NHGRI genotyping for PROGRESS, and L.M.F. and J.S.K. coordinated data collation. S.A.I. is the PI of the USC study, E.M.J. is the PI of the NCCC study and M.C. Stern and R.C. led the genotyping of both studies. S.N.T. and D.S. are PIs of the Mayo clinic study, and S.K.D. coordinated data collation. J.Y.P. is the PI of the Moffitt study, and T.A.S. and H.-Y.L. are contributors to this study. J.A.C. and A.B.S. are PIs of the molecular genetics arm of the Proscan study, and with J.B. and F.L. coordinated all risk factor data and genetic data collection for prostate cancer cases from Proscan, the Brisbane Retrospective Study, the Australian Prostate Cancer BioResource Brisbane node and controls from two Queensland control sets. S.C., J.A. and R.A.F.G. are PIs of the Proscan study and were responsible for the original platform study initiation, conceptualization and collection of the Proscan study cases. K.A.C. is the PI of the FMHS study. L.C.-A. is the PI of the Utah study, and R.K. is the PI of the PCMUS study. H.G. is PI of CAPS and STHM1; F.K. directed the genotyping. D.J.H. directs the CPSII. S.I. directs the NCCC. R.B.H. and G.A. direct the PLCO. P.P. directs the SEARCH study. T.H. is PI of the Japan study. K.M. is co-PI of the PCRF study which provided some controls for the UK sets. A.T., A.D.J., A.L.H., L.T.O., R.A.W., E.C.P., E.J.S., D.P.D., A.H., R.A.H., V.S.K., C.C.P., N.V.A., C.J.W., A.T., T.C., C.O., L.N.K., L.L.M., A.A., A.C., D.M.K., E.M.K., A.D.J., A. Shahabi, T.A.S., J.P.S., S.C., J.A., R.A.F.G., J.B., F.L., A.P., B.P., J. Serth, F.W., T. Dadaev, M.G., J.M., C.S.C., B.G.N., M.A., S.L., S.G., L.F., S.K., S.K.M., R.A.S., A.R., N.T., S.N., G.-W.C., A.M., A.E.R., K.L., A.M.R., E.M.L., J.F., H.K. and C.S. identified and collected clinical material, and V.M. coordinated data collation. Other members of the UK Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of Oncology, The UK ProtecT Study Collaborators and The PRACTICAL Consortium members (membership lists provided in the Supplementary Note) collected clinical samples, assisted in genotyping and provided data management. All study acronyms are defined in the Supplementary Note.

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Correspondence to Rosalind A Eeles.

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The authors declare no competing financial interests.

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A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

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Supplementary Text and Figures

Supplementary Figures 1 and 2, Supplementary Tables 1–5 and Supplementary Note (PDF 688 kb)

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Kote-Jarai, Z., Olama, A., Giles, G. et al. Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study. Nat Genet 43, 785–791 (2011). https://doi.org/10.1038/ng.882

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