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Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.
| File | Description | Size | Format | |
|---|---|---|---|---|
 RESUB_PC_OncoArray_Main_FINAL_WORD.docx | Accepted version | 3.49 MB | Microsoft Word | View/Open |
| Title: | Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. |
| Authors: | Schumacher, FR Al Olama, AA Berndt, SI Benlloch, S Ahmed, M Saunders, EJ Dadaev, T Leongamornlert, D Anokian, E Cieza-Borrella, C Goh, C Drake, BF Vega, A Gómez-Caamaño, A Szulkin, R Eklund, M Kogevinas, M Llorca, J Castaño-Vinyals, G Penney, KL Røder, MA Canary PASS Investigators Stampfer, M Park, JY Sellers, TA Lin, H-Y Stanford, JL Cybulski, C Iversen, P Brook, MN Brenner, H Cuk, K Breast and Prostate Cancer Cohort Consortium (BPC3) Holleczek, B Maier, C Luedeke, M Schnoeller, T Kim, J Logothetis, CJ John, EM Teixeira, MR Sheng, X Paulo, P PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium Cardoso, M Neuhausen, SL Steele, L Ding, YC De Ruyck, K De Meerleer, G Ost, P Razack, A Lim, J Fachal, L Cancer of the Prostate in Sweden (CAPS) Teo, S-H Lin, DW Newcomb, LF Lessel, D Gamulin, M Kulis, T Kaneva, R Usmani, N Singhal, S Slavov, C Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci (PEGASUS) Dennis, J Mitev, V Parliament, M Claessens, F Joniau, S Van den Broeck, T Larkin, S Townsend, PA Aukim-Hastie, C Dominguez, MG Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium Castelao, JE Tyrer, J Martinez, ME Roobol, MJ Jenster, G Van Schaik, RHN Menegaux, F Truong, T Koudou, YA Profile Study Amos, CI Xu, J Khaw, K-T Muir, K Cannon-Albright, L Pandha, H Michael, A Thibodeau, SN McDonnell, SK Schaid, DJ Lindstrom, S Conti, DV Turman, C Ma, J Hunter, DJ Lophatananon, A Riboli, E Siddiq, A Canzian, F Kolonel, LN Le Marchand, L Hoover, RN Easton, DF Machiela, MJ Cui, Z Kraft, P Australian Prostate Cancer BioResource (APCB) Stevens, VL IMPACT Study Gapstur, SM Wokolorczyk, D Wiklund, F Chanock, SJ Henderson, BE Kote-Jarai, Z Haiman, CA Eeles, RA Carter, BD Tangen, CM Goodman, PJ Thompson, IM Lubinski, J Batra, J Chambers, S Moya, L Clements, J Horvath, L Tilley, W Risbridger, GP Gronberg, H Aly, M Nordström, T Ostrander, EA Pharoah, P Pashayan, N Schleutker, J Tammela, TLJ Sipeky, C Auvinen, A Albanes, D Weinstein, S Wolk, A Håkansson, N Geybels, MS West, CML Dunning, AM Burnet, N Mucci, LA Giovannucci, E Andriole, GL Cussenot, O Cancel-Tassin, G Koutros, S Beane Freeman, LE Nordestgaard, BG Sorensen, KD Orntoft, TF Borre, M Maehle, L Grindedal, EM Neal, DE Donovan, JL Hamdy, FC Martin, RM Travis, RC Nielsen, SF Key, TJ Hamilton, RJ Fleshner, NE Finelli, A Ingles, SA Stern, MC Rosenstein, BS Kerns, SL Ostrer, H Lu, Y-J Weischer, M Zhang, H-W Feng, N Mao, X Guo, X Wang, G Sun, Z Giles, GG Southey, MC MacInnis, RJ FitzGerald, LM Bisbjerg, R Kibel, AS |
| Item Type: | Journal Article |
| Abstract: | 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 PrCa 1 . |
| Issue Date: | 11-Jun-2018 |
| Date of Acceptance: | 5-Apr-2018 |
| URI: | http://hdl.handle.net/10044/1/60278 |
| DOI: | https://doi.org/10.1038/s41588-018-0142-8 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Start Page: | 928 |
| End Page: | 936 |
| Journal / Book Title: | Nature Genetics |
| Volume: | 50 |
| Copyright Statement: | © 2018 Nature America Inc., part of Springer Nature. All rights reserved. The final publication is available at Springer via https://doi.org/10.1038/s41588-018-0142-8 |
| Sponsor/Funder: | Imperial College Trust |
| Funder's Grant Number: | P47328 |
| Keywords: | Science & Technology Life Sciences & Biomedicine Genetics & Heredity GENOME-WIDE ASSOCIATION MULTIPLE LOCI RISK GENE METAANALYSIS VARIANTS PATHWAY IDENTIFICATION CONSORTIUM PREDICTION Case-Control Studies Genetic Loci Genetic Predisposition to Disease Genome-Wide Association Study Genotype Humans Male Polymorphism, Single Nucleotide Prostatic Neoplasms Risk Profile Study Australian Prostate Cancer BioResource (APCB) IMPACT Study Canary PASS Investigators Breast and Prostate Cancer Cohort Consortium (BPC3) PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium Cancer of the Prostate in Sweden (CAPS) Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci (PEGASUS) Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium Humans Prostatic Neoplasms Genetic Predisposition to Disease Risk Case-Control Studies Genotype Polymorphism, Single Nucleotide Male Genome-Wide Association Study Genetic Loci Developmental Biology 11 Medical and Health Sciences 06 Biological Sciences |
| Publication Status: | Published |
| Conference Place: | United States |
| Online Publication Date: | 2018-06-11 |
| Appears in Collections: | School of Public Health |