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

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Date
2018-07
ICR Author
Eeles, Rosalind
Kote-Jarai, Zsofia
Saunders, Edward
Brook, Mark
Author
Schumacher, FR
Al Olama, AA
Berndt, SI
Benlloch, S
Ahmed, M
Saunders, EJ
Dadaev, T
Leongamornlert, D
Anokian, E
Cieza-Borrella, C
Goh, C
Brook, MN
Sheng, X
Fachal, L
Dennis, J
Tyrer, J
Muir, K
Lophatananon, A
Stevens, VL
Gapstur, SM
Carter, BD
Tangen, CM
Goodman, PJ
Thompson, IM
Batra, J
Chambers, S
Moya, L
Clements, J
Horvath, L
Tilley, W
Risbridger, GP
Gronberg, H
Aly, M
Nordström, T
Pharoah, P
Pashayan, N
Schleutker, J
Tammela, TLJ
Sipeky, C
Auvinen, A
Albanes, D
Weinstein, S
Wolk, A
Håkansson, N
West, CML
Dunning, AM
Burnet, N
Mucci, LA
Giovannucci, E
Andriole, GL
Cussenot, O
Cancel-Tassin, G
Koutros, S
Beane Freeman, LE
Sorensen, KD
Orntoft, TF
Borre, M
Maehle, L
Grindedal, EM
Neal, DE
Donovan, JL
Hamdy, FC
Martin, RM
Travis, RC
Key, TJ
Hamilton, RJ
Fleshner, NE
Finelli, A
Ingles, SA
Stern, MC
Rosenstein, BS
Kerns, SL
Ostrer, H
Lu, Y-J
Zhang, H-W
Feng, N
Mao, X
Guo, X
Wang, G
Sun, Z
Giles, GG
Southey, MC
MacInnis, RJ
FitzGerald, LM
Kibel, AS
Drake, BF
Vega, A
Gómez-Caamaño, A
Szulkin, R
Eklund, M
Kogevinas, M
Llorca, J
Castaño-Vinyals, G
Penney, KL
Stampfer, M
Park, JY
Sellers, TA
Lin, H-Y
Stanford, JL
Cybulski, C
Wokolorczyk, D
Lubinski, J
Ostrander, EA
Geybels, MS
Nordestgaard, BG
Nielsen, SF
Weischer, M
Bisbjerg, R
Røder, MA
Iversen, P
Brenner, H
Cuk, K
Holleczek, B
Maier, C
Luedeke, M
Schnoeller, T
Kim, J
Logothetis, CJ
John, EM
Teixeira, MR
Paulo, P
Cardoso, M
Neuhausen, SL
Steele, L
Ding, YC
De Ruyck, K
De Meerleer, G
Ost, P
Razack, A
Lim, J
Teo, S-H
Lin, DW
Newcomb, LF
Lessel, D
Gamulin, M
Kulis, T
Kaneva, R
Usmani, N
Singhal, S
Slavov, C
Mitev, V
Parliament, M
Claessens, F
Joniau, S
Van den Broeck, T
Larkin, S
Townsend, PA
Aukim-Hastie, C
Gago-Dominguez, M
Castelao, JE
Martinez, ME
Roobol, MJ
Jenster, G
van Schaik, RHN
Menegaux, F
Truong, T
Koudou, YA
Xu, J
Khaw, K-T
Cannon-Albright, L
Pandha, H
Michael, A
Thibodeau, SN
McDonnell, SK
Schaid, DJ
Lindstrom, S
Turman, C
Ma, J
Hunter, DJ
Riboli, E
Siddiq, A
Canzian, F
Kolonel, LN
Le Marchand, L
Hoover, RN
Machiela, MJ
Cui, Z
Kraft, P
Amos, CI
Conti, DV
Easton, DF
Wiklund, F
Chanock, SJ
Henderson, BE
Kote-Jarai, Z
Haiman, CA
Eeles, RA
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
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Type
Journal Article
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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<sup>-8</sup>) 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<sup>-9</sup>; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10<sup>-9</sup>; 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<sup>1</sup>.
URI
https://repository.icr.ac.uk/handle/internal/2229
DOI
https://doi.org/10.1038/s41588-018-0142-8
Collections
  • Genetics and Epidemiology
  • Radiotherapy and Imaging
Subject
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
Research team
Oncogenetics
Language
eng
Date accepted
2018-04-05
License start date
2018-07
Citation
Nature genetics, 2018, 50 (7), pp. 928 - 936

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