Germline variation at 8q24 and prostate cancer risk in men of European ancestry
Authors: Matejcic Marco , Saunders Edward J. , Dadaev Tokhir , Brook Mark N. , Wang Kan , Sheng Xin , Olama Ali Amin Al , Schumacher Fredrick R. , Ingles Sue A. , Govindasami Koveela , Benlloch Sara , Berndt Sonja I. , Albanes Demetrius , Koutros Stella , Muir Kenneth , Stevens Victoria L. , Gapstur Susan M. , Tangen Catherine M. , Batra Jyotsna , Clements Judith , Gronberg Henrik , Pashayan Nora , Schleutker Johanna , Wolk Alicja , West Catharine , Mucci Lorelei , Kraft Peter , Cancel-Tassin Géraldine , Sorensen Karina D. , Maehle Lovise , Grindedal Eli M. , Strom Sara S. , Neal David E. , Hamdy Freddie C. , Donovan Jenny L. , Travis Ruth C. , Hamilton Robert J. , Rosenstein Barry , Lu Yong-Jie , Giles Graham G. , Kibel Adam S. , Vega Ana , Bensen Jeanette T. , Kogevinas Manolis , Penney Kathryn L. , Park Jong Y. , Stanford Janet L. , Cybulski Cezary , Nordestgaard Børge G. , Brenner Hermann , Maier Christiane , Kim Jeri , Teixeira Manuel R. , Neuhausen Susan L. , De Ruyck Kim , Razack Azad , Newcomb Lisa F. , Lessel Davor , Kaneva Radka , Usmani Nawaid , Claessens Frank , Townsend Paul A. , Gago-Dominguez Manuela , Roobol Monique J. , Menegaux Florence , Khaw Kay-Tee , Cannon-Albright Lisa A. , Pandha Hardev , Thibodeau Stephen N. , Schaid Daniel J. ,   The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Henderson Brian E. , Stern Mariana C. , Thwaites Alison , Guy Michelle , Whitmore Ian , Morgan Angela , Fisher Cyril , Hazel Steve , Livni Naomi , Cook Margaret , Fachal Laura , Weinstein Stephanie , Beane Freeman Laura E. , Hoover Robert N. , Machiela Mitchell J. , Lophatananon Artitaya , Carter Brian D. , Goodman Phyllis , Moya Leire , Srinivasan Srilakshmi , Kedda Mary-Anne , Yeadon Trina , Eckert Allison , Eklund Martin , Cavalli-Bjoerkman Carin , Dunning Alison M. , Sipeky Csilla , Hakansson Niclas , Elliott Rebecca , Ranu Hardeep , Giovannucci Edward , Turman Constance , Hunter David J. , Cussenot Olivier , Orntoft Torben Falck , Lane Athene , Lewis Sarah J. , Davis Michael , Key Tim J. , Brown Paul , Kulkarni Girish S. , Zlotta Alexandre R. , Fleshner Neil E. , Finelli Antonio , Mao Xueying , Marzec Jacek , MacInnis Robert J. , Milne Roger , Hopper John L. , Aguado Miguel , Bustamante Mariona , Castaño-Vinyals Gemma , Gracia-Lavedan Esther , Cecchini Lluís , Stampfer Meir , Ma Jing , Sellers Thomas A. , Geybels Milan S. , Park Hyun , Zachariah Babu , Kolb Suzanne , Wokolorczyk Dominika , Jan Lubinski  , Kluzniak Wojciech , Nielsen Sune F. , Weisher Maren , Cuk Katarina , Vogel Walther , Luedeke Manuel , Logothetis Christopher J. , Paulo Paula , Cardoso Marta , Maia Sofia , Silva Maria P. , Steele Linda , Ding Yuan Chun , De Meerleer Gert , De Langhe Sofie , Thierens Hubert , Lim Jasmine , Tan Meng H. , Ong Aik T. , Lin Daniel W. , Kachakova Darina , Mitkova Atanaska , Mitev Vanio , Parliament Matthew , Jenster Guido , Bangma Christopher , Schroder F. H. , Truong Thérèse , Koudou Yves Akoli , Michael Agnieszka , Kierzek Andrzej , Karlsson Ami , Broms Michael , Wu Huihai , Aukim-Hastie Claire , Tillmans Lori , Riska Shaun , McDonnell Shannon K. , Dearnaley David , Spurdle Amanda , Gardiner Robert , Hayes Vanessa , Butler Lisa , Taylor Renea , Papargiris Melissa , Saunders Pamela , Kujala Paula , Talala Kirsi , Taari Kimmo , Bentzen Søren , Hicks Belynda , Vogt Aurelie , Hutchinson Amy , Cox Angela , George Anne , Toi Ants , Evans Andrew , van der Kwast Theodorus H. , Imai Takashi , Saito Shiro , Zhao Shan-Chao , Ren Guoping , Zhang Yangling , Yu Yongwei , Wu Yudong , Wu Ji , Zhou Bo , Pedersen John , Lobato-Busto Ramón , Ruiz-Dominguez José Manuel , Mengual Lourdes , Alcaraz Antonio , Pow-Sang Julio , Herkommer Kathleen , Vlahova Aleksandrina , Dikov Tihomir , Christova Svetlana , Carracedo Angel , Tretarre Brigitte , Rebillard Xavier , Mulot Claire , Jan Adolfsson  , Stattin Par , Johansson Jan-Erik , Martin Richard M. , Thompson Ian M. , Chambers Suzanne , Aitken Joanne , Horvath Lisa , Haynes Anne-Maree , Tilley Wayne , Risbridger Gail , Aly Markus , Nordström Tobias , Pharoah Paul , Tammela Teuvo L. J. , Murtola Teemu , Auvinen Anssi , Burnet Neil , Barnett Gill , Andriole Gerald , Klim Aleksandra , Drake Bettina F. , Borre Michael , Kerns Sarah , Ostrer Harry , Zhang Hong-Wei , Cao Guangwen , Lin Ji , Ling Jin , Li Meiling , Feng Ninghan , Li Jie , He Weiyang , Guo Xin , Sun Zan , Wang Guomin , Guo Jianming , Southey Melissa C. , FitzGerald Liesel M. , Marsden Gemma , Gómez-Caamaño Antonio , Carballo Ana , Peleteiro Paula , Calvo Patricia , Szulkin Robert , Llorca Javier , Dierssen-Sotos Trinidad , Gomez-Acebo Ines , Lin Hui-Yi , Ostrander Elaine A. , Bisbjerg Rasmus , Klarskov Peter , Røder Martin Andreas , Iversen Peter , Holleczek Bernd , Stegmaier Christa , Schnoeller Thomas , Bohnert Philipp , John Esther M. , Ost Piet , Teo Soo-Hwang , Gamulin Marija , Kulis Tomislav , Kastelan Zeljko , Slavov Chavdar , Popov Elenko , Van den Broeck Thomas , Joniau Steven , Larkin Samantha , Castelao Jose Esteban , Martinez Maria Elena , van Schaik Ron H. N. , Xu Jianfeng , Lindström Sara , Riboli Elio , Berry Clare , Siddiq Afshan , Canzian Federico , Kolonel Laurence N. , Le Marchand Loic , Freedman Matthew , Cenee Sylvie , Sanchez Marie , Wiklund Fredrik , Chanock Stephen J. , Easton Douglas F. , Eeles Rosalind A. , Kote-Jarai Zsofia , Conti David V. , Haiman Christopher A. 
Published: October 2018

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.