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Title: Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
Authors: Couch FJ,  Gaudet MM,  Antoniou AC,  Ramus SJ,  Kuchenbaecker KB,  Soucy P,  Beesley J,  Chen X,  Wang X,  Kirchhoff T,  McGuffog L,  Barrowdale D,  Lee A,  Healey S,  Sinilnikova OM,  Andrulis IL,  OCGN,  Ozcelik H,  Mulligan AM,  Thomassen M,  Gerdes AM,  Jensen UB,  Skytte AB,  Kruse TA,  Caligo MA,  von Wachenfeldt A,  Barbany-Bustinza G,  Loman N,  Soller M,  Ehrencrona H,  Karlsson P,  SWE-BRCA,  Nathanson KL,  Rebbeck TR,  Domchek SM,  Jakubowska A,  Lubinski J,  Jaworska K,  Durda K,  Zlowocka E,  Huzarski T,  Byrski T,  Gronwald J,  Cybulski C,  Górski B,  Osorio A,  Durán M,  Tejada MI,  Benitez J,  Hamann U,  Hogervorst FB,  HEBON,  van Os TA,  van Leeuwen FE,  Meijers-Heijboer HE,  Wijnen J,  Blok MJ,  Kets M,  Hooning MJ,  Oldenburg RA,  Ausems MG,  Peock S,  Frost D,  Ellis SD,  Platte R,  Fineberg E,  Evans DG,  Jacobs C,  Eeles RA,  Adlard J,  Davidson R,  Eccles DM,  Cole T,  Cook J,  Paterson J,  Brewer C,  Douglas F,  Hodgson SV,  Morrison PJ,  Walker L,  Porteous ME,  Kennedy MJ,  Side LE,  EMBRACE,  Bove B,  Godwin AK,  Stoppa-Lyonnet D,  GEMO Study Collaborators,  Fassy-Colcombet M,  Castera L,  Cornelis F,  Mazoyer S,  Léoné M,  Boutry-Kryza N,  Bressac-de Paillerets B,  Caron O,  Pujol P,  Coupier I,  Delnatte C,  Akloul L,  Lynch HT,  Snyder CL,  Buys SS,  Daly MB,  Terry M,  Chung WK,  John EM,  Miron A,  Southey MC,  Hopper JL,  Goldgar DE,  Singer CF,  Rappaport C,  Tea MK,  Fink-Retter A,  Hansen TV,  Nielsen FC,  Arason A,  Vijai J,  Shah S,  Sarrel K,  Robson ME,  Piedmonte M,  Phillips K,  Basil J,  Rubinstein WS,  Boggess J,  Wakeley K,  Ewart-Toland A,  Montagna M,  Agata S,  Imyanitov EN,  Isaacs C,  Janavicius R,  Lazaro C,  Blanco I,  Feliubadalo L,  Brunet J,  Gayther SA,  Pharoah PP,  Odunsi KO,  Karlan BY,  Walsh CS,  Olah E,  Teo SH,  Ganz PA,  Beattie MS,  van Rensburg EJ,  Dorfling CM,  Diez O,  Kwong A,  Schmutzler RK,  Wappenschmidt B,  Engel C,  Meindl A,  Ditsch N,  Arnold N,  Heidemann S,  Niederacher D,  Preisler-Adams S,  Gadzicki D,  Varon-Mateeva R,  Deissler H,  Gehrig A,  Sutter C,  Kast K,  Fiebig B,  Heinritz W,  Caldes T,  de la Hoya M,  Muranen TA,  Nevanlinna H,  Tischkowitz MD,  Spurdle AB,  Neuhausen SL,  Ding YC,  Lindor NM,  Fredericksen Z,  Pankratz VS,  Peterlongo P,  Manoukian S,  Peissel B,  Zaffaroni D,  Barile M,  Bernard L,  Viel A,  Giannini G,  Varesco L,  Radice P,  Greene MH,  Mai PL,  Easton DF,  Chenevix-Trench G,  kConFab investigators,  Offit K,  Simard J,  Consortium of Investigators of Modifiers of BRCA1/2
Journal: Cancer Epidemiol Biomarkers Prev
Date: 2012 Apr
Branches: CGB
PubMed ID: 22351618
PMC ID: PMC3319317
Abstract: BACKGROUND: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). METHODS: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. RESULTS: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)). CONCLUSIONS: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. IMPACT: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.