Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.

Nature communications. 2018 Nov 05*** epublish ***

Marco Matejcic, Edward J Saunders, Tokhir Dadaev, Mark N Brook, Kan Wang, Xin Sheng, Ali Amin Al Olama, Fredrick R Schumacher, Sue A Ingles, Koveela Govindasami, Sara Benlloch, Sonja I Berndt, Demetrius Albanes, Stella Koutros, Kenneth Muir, Victoria L Stevens, Susan M Gapstur, Catherine M Tangen, Jyotsna Batra, Judith Clements, Henrik Gronberg, Nora Pashayan, Johanna Schleutker, Alicja Wolk, Catharine West, Lorelei Mucci, Peter Kraft, Géraldine Cancel-Tassin, Karina D Sorensen, Lovise Maehle, Eli M Grindedal, Sara S Strom, David E Neal, Freddie C Hamdy, Jenny L Donovan, Ruth C Travis, Robert J Hamilton, Barry Rosenstein, Yong-Jie Lu, Graham G Giles, Adam S Kibel, Ana Vega, Jeanette T Bensen, Manolis Kogevinas, Kathryn L Penney, Jong Y Park, Janet L Stanford, Cezary Cybulski, Børge G Nordestgaard, Hermann Brenner, Christiane Maier, Jeri Kim, Manuel R Teixeira, Susan L Neuhausen, Kim De Ruyck, Azad Razack, Lisa F Newcomb, Davor Lessel, Radka Kaneva, Nawaid Usmani, Frank Claessens, Paul A Townsend, Manuela G Dominguez, Monique J Roobol, Florence Menegaux, Kay-Tee Khaw, Lisa A Cannon-Albright, Hardev Pandha, Stephen N Thibodeau, Daniel J Schaid, PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium , Fredrik Wiklund, Stephen J Chanock, Douglas F Easton, Rosalind A Eeles, Zsofia Kote-Jarai, David V Conti, Christopher A Haiman

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