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.
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.
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DOI：
10.1158/1055-9965.epi-11-0888
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发表时间：
2012-04
期刊：
影响因子：
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通讯作者：
Consortium of Investigators of Modifiers of BRCA1/2
中科院分区：
文献类型：
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作者：
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
全基因组关联研究发现，在BRCA1和BRCA2突变携带者中，19p13.1和ZNF365(10q21.2)变异分别是乳腺癌的危险因素。我们通过BRCA1/2修饰物研究联盟(CIMBA)突变携带者中这些变异的肿瘤组织病理学研究，探索了这些变异与卵巢癌和乳腺癌的关系。结合40项研究中12,599名BRCA1和7,132名BRCA2突变携带者的基因分型数据。我们证实了19p13.1位rs8170与BRCA1突变携带者的乳腺癌风险(风险比HR=1.17；95%可信区间1.07-1.27；p=7.42×10−4)和ZNF365位rs16917302(HR=0.84；95%CI0.73-0.97；p=0.017)之间的关联，但与20q13.3位的rs311499(HR=1.11；95%CI0.94-1.31；p=0.22)和BRCA2突变携带者的乳腺癌风险无关。基于肿瘤组织病理学的分析表明，在BRCA1和BRCA2突变携带者中，19p13变异主要与雌激素受体(ER)阴性乳腺癌相关，而在BRCA1和BRCA2突变携带者中，ZNF365上的rs16917302主要与ER阳性乳腺癌相关。我们还首次发现在BRCA1(HR=1.16；95%CI 1.05~1.29；p=3.8×10−4)和BRCA2突变携带者(HR=1.3 0；95%CI 1.10~1.52；p=1.8×10−3)中，rs67397200与卵巢癌的风险增加有关。在BRCA1和BRCA2突变携带者中，19p13.1和ZNF365是卵巢癌和乳腺癌ER亚型的易感基因。这些发现有助于更好地了解肿瘤的发展，并可能被证明对BRCA1和BRCA2突变携带者的乳腺癌和卵巢癌风险预测有用。
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). Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers (hazard ratio (HR)=1.17; 95%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). 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. 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.