Publications

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

Author(s): 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 Jr,  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 YJ,  Zhang HW,  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 HY,  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 SH,  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 KT,  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

Journal: Nat Genet

Date: 2018 Jul

Major Program(s) or Research Group(s): PLCO

PubMed ID: 29892016

PMC ID: PMC6568012

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 PrCa1.