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Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

2018; Nature Portfolio; Volume: 50; Issue: 7 Linguagem: Inglês

10.1038/s41588-018-0142-8

1546-1718

Fredrick R. Schumacher, Ali Amin Al Olama, Sonja I. Berndt, Sara Benlloch, Mahbubl Ahmed, Edward J. Saunders, Tokhir Dadaev, Daniel Leongamornlert, Ezequiel Anokian, Clara Cieza-Borrella, Chee Goh, Mark N. Brook, Xin Sheng, Laura Fachal, Joe Dennis, Jonathan P. Tyrer, Kenneth Muir, Artitaya Lophatananon, Victoria L. Stevens, Susan M. Gapstur, Brian D. Carter, Catherine M. Tangen, Phyllis J. Goodman, Ian M. Thompson, Jyotsna Batra, Suzanne K. Chambers, Leire Moya, Judith A. Clements, Lisa G. Horvath, Wayne D. Tilley, Gail P. Risbridger, Henrik Grönberg, Markus Aly, Tobias Nordström, Paul D.P. Pharoah, Nora Pashayan, Johanna Schleutker, Teuvo L.J. Tammela, Csilla Sipeky, Anssi Auvinen, Demetrius Albanes, Stephanie J. Weinstein, Alicja Wolk, Niclas Håkansson, Catharine West, Alison M. Dunning, N.G. Burnet, Lorelei A. Mucci, Edward Giovannucci, Gerald L. Andriole, Olivier Cussenot, Géraldine Cancel‐Tassin, Stella Koutros, Laura E. Beane Freeman, Karina D. Sørensen, Torben F. Ørntoft, Michael Borre, Lovise Mæhle, Eli Marie Grindedal, David E. Neal, Jenny Donovan, Freddie C. Hamdy, Richard M. Martin, Ruth C. Travis, Timothy J. Key, Robert J. Hamilton, Neil E. Fleshner, Antonio Finelli, Sue A. Ingles, Mariana C. Stern, Barry S. Rosenstein, Sarah L. Kerns, Harry Ostrer, Yong‐Jie Lu, Hong-Wei Zhang, Ninghan Feng, Xueying Mao, Xin Guo, Guomin Wang, Zan Sun, Graham G. Giles, Melissa C. Southey, Robert J. MacInnis, Liesel M. FitzGerald, Adam S. Kibel, Bettina F. Drake, Ana Vega, Antonio Gómez‐Caamaño, Robert Szulkin, Martin Eklund, Manolis Kogevinas, Javier Llorca, Gemma Castaño‐Vinyals, Kathryn L. Penney, Meir J. Stampfer, Jong Y. Park, Thomas A. Sellers, Hui‐Yi Lin, Janet L. Stanford, Cezary Cybulski, Dominika Wokołorczyk, Jan Lubiński, Elaine A. Ostrander, Milan S. Geybels, Børge G. Nordestgaard, Sune F. Nielsen, Maren Weischer, Rasmus Bisbjerg, Martin Andreas Røder, Peter Iversen, Hermann Brenner, Katarina Ćuk, Bernd Holleczek, Christiane Maier, Manuel Luedeke, Thomas Schnoeller, Jeri Kim, Christopher J. Logothetis, Esther M. John, Manuel R. Teixeira, Paula Paulo, Marta Cardoso, Susan L. Neuhausen, Linda Steele, Yuan Chun Ding, Kim De Ruyck, Gert De Meerleer, Piet Ost, Azad Hassan Abdul Razack, Jasmine Lim, Soo‐Hwang Teo, Daniel W. Lin, Lisa F. Newcomb, Davor Lessel, Marija Gamulin, Tomislav Kuliš, Radka Kaneva, Nawaid Usmani, Sandeep K. Singhal, Chavdar Slavov, Vanio Mitev, Matthew Parliament, Frank Claessens, Steven Joniau, Thomas Van den Broeck, Samantha Larkin, Paul A. Townsend, Claire Aukim-Hastie, Manuela Gago‐Dominguez, Jose E. Castelao, Marı́a Elena Martı́nez, Monique J. Roobol, Guido Jenster, Ron H. N. van Schaik, F. Ménégaux, Thérèse Truong, Yves Akoli Koudou, Jianfeng Xu, Kay‐Tee Khaw, Lisa Cannon‐Albright, Hardev Pandha, Agnieszka Michael, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Sara Lindström, Constance Turman, Jing Ma, David J. Hunter, Elio Ríboli, Afshan Siddiq, Federico Canzian, Laurence N. Kolonel, Loı̈c Le Marchand, Robert N. Hoover, Mitchell J. Machiela, Zuxi Cui, Peter Kraft, Christopher I. Amos, David V. Conti, Douglas F. Easton, Fredrik Wiklund, Stephen J. Chanock, Brian E. Henderson, Zsofia Kote‐Jarai, Christopher A. Haiman, Rosalind A. Eeles,

Prostate Cancer Diagnosis and Treatment

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10−8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10−9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10−9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55–2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04–6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1. A large meta-analysis combining genome-wide and custom high-density genotyping array data identifies 63 new susceptibility loci for prostate cancer, enhancing fine-mapping efforts and providing insights into the underlying biology.