We performed an in-depth and well-powered investigation of genetic variation across the cancer susceptibility region at chromosome 8q24 (127.6-129.0 Mb) to search for novel risk variants associated with prostate cancer (PCa) risk in the European ancestry population. We combined genotyped and imputed data from the PRACTICAL/ELLIPSE OncoArray and iCOGS consortia consisting of 71,535 PrCa cases and 52,935 controls of European ancestry. Variants with high imputation quality score (>0.8) were retained for a total of 5,600 overlapping variants between the two datasets. Associations of genetic variants with PCa risk were evaluated using unconditional logistic regression with adjustment for country and ten principal components. The marginal risk estimates for the 5,600 variants that passed quality control were combined by a fixed effects meta-analysis. A meta-stepwise selection was performed on variants marginally associated with PCa risk from the meta results (P<0.05). A polygenic risk score and the contribution to the familial relative risk of PCa were estimated for variants from the final model. Of the 5,600 variants at 8q24 retained for analysis, 1,268 (23%) were associated with PCa risk at P<5x10-8 while 2,772 (49%) were marginally associated at P<0.05. In the stepwise model, 12 variants remained statistically significantly associated with PCa risk with conditional meta p-values between 2.93x10-137 and 4.28x10-15. The independent stepwise signals were confirmed by Joint Analysis of Marginal (JAM) summary statistics, which defined the credible sets of variants driving those signals. Three of the variants (rs1914295, rs190257175, rs12549761) were weakly correlated (r2≤0.17) with any known PCa risk marker, and may define novel association signals. Men in the top 1% of the polygenic risk score distribution had a 3.97-fold relative risk (95%CI=3.87-4.07) compared to men with "average risk" (25th-75th percentiles). The 12 independent signals at 8q24 capture 11.54% (95%CI=9.86-13.65) of the familial relative risk of PCa, which is approximately one quarter of the total PCa familial relative risk explained by known genetic risk factors. Most of the independently associated signals have good evidence for biologic functionality; in particular, many reside within putative transcriptional enhancers and/or binding sites for AR and FOXA1 transcription factors in prostate cell lines. In summary, we defined 12 independent association signals among men of European ancestry, with three of the risk variants representing putative novel association signals. Whereas the individual associations of these variants with PCa risk are relatively modest (ORs<2.0), their cumulative effects are substantial, and their contribution to the overall familial relative risk of PCa is substantially greater than any other known prostate cancer risk locus.
Citation Format: Marco Matejcic, Edward J. Saunders, Tokhir Dadaev, Mark Brook, Ali Amin Al Olama, Fredrick R. Schumacher, Sonja I. Berndt, Sara Benlloch, Kenneth Muir, Koveela Govindasami, Victoria L. Stevens, Susan M. Gapstur, Catherine M. Tangen, Jyotsna Batra, Judith Clements, APCB (Australian Prostate Cancer Bio Resource), Henrik Gronberg, Nora Pashayan, Johanna Schleutker, Demetrius Albanes, Alicja Wolk, Catharine West, Lorelei Mucci, Peter Kraft, Géraldine Cancel-Tassin, Stella Koutros, Karina Dalsgaard Sorensen, Lovise Maehle, Eli Marie Grindedal, Sara Strom, David E. Neal, Freddie C. Hamdy, Jenny L. Donovan, Ruth C. Travis, Robert J. Hamilton, Sue Ann Ingles, Barry Rosenstein, Yong-Jie Lu, Graham G. Giles, Adam S. Kibel, Ana Vega, Jeanette Bensen, Manolis Kogevinas, Fredrik Wiklund, Stephen Chanock, Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai, David V. Conti, Christopher A. Haiman. Germline variation at 8q24 and prostate cancer risk in men of European ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 227.
