Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.
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DOI：
10.1056/nejmoa1913948
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发表时间：
2021-02-04
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影响因子：
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通讯作者：
Easton DF
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作者：
Breast Cancer Association Consortium;Dorling L;Carvalho S;Allen J;González-Neira A;Luccarini C;Wahlström C;Pooley KA;Parsons MT;Fortuno C;Wang Q;Bolla MK;Dennis J;Keeman R;Alonso MR;Álvarez N;Herraez B;Fernandez V;Núñez-Torres R;Osorio A;Valcich J;Li M;Törngren T;Harrington PA;Baynes C;Conroy DM;Decker B;Fachal L;Mavaddat N;Ahearn T;Aittomäki K;Antonenkova NN;Arnold N;Arveux P;Ausems MGEM;Auvinen P;Becher H;Beckmann MW;Behrens S;Bermisheva M;Białkowska K;Blomqvist C;Bogdanova NV;Bogdanova-Markov N;Bojesen SE;Bonanni B;Børresen-Dale AL;Brauch H;Bremer M;Briceno I;Brüning T;Burwinkel B;Cameron DA;Camp NJ;Campbell A;Carracedo A;Castelao JE;Cessna MH;Chanock SJ;Christiansen H;Collée JM;Cordina-Duverger E;Cornelissen S;Czene K;Dörk T;Ekici AB;Engel C;Eriksson M;Fasching PA;Figueroa J;Flyger H;Försti A;Gabrielson M;Gago-Dominguez M;Georgoulias V;Gil F;Giles GG;Glendon G;Garcia EBG;Alnæs GIG;Guénel P;Hadjisavvas A;Haeberle L;Hahnen E;Hall P;Hamann U;Harkness EF;Hartikainen JM;Hartman M;He W;Heemskerk-Gerritsen BAM;Hillemanns P;Hogervorst FBL;Hollestelle A;Ho WK;Hooning MJ;Howell A;Humphreys K;Idris F;Jakubowska A;Jung A;Kapoor PM;Kerin MJ;Khusnutdinova E;Kim SW;Ko YD;Kosma VM;Kristensen VN;Kyriacou K;Lakeman IMM;Lee JW;Lee MH;Li J;Lindblom A;Lo WY;Loizidou MA;Lophatananon A;Lubiński J;MacInnis RJ;Madsen MJ;Mannermaa A;Manoochehri M;Manoukian S;Margolin S;Martinez ME;Maurer T;Mavroudis D;McLean C;Meindl A;Mensenkamp AR;Michailidou K;Miller N;Mohd Taib NA;Muir K;Mulligan AM;Nevanlinna H;Newman WG;Nordestgaard BG;Ng PS;Oosterwijk JC;Park SK;Park-Simon TW;Perez JIA;Peterlongo P;Porteous DJ;Prajzendanc K;Prokofyeva D;Radice P;Rashid MU;Rhenius V;Rookus MA;Rüdiger T;Saloustros E;Sawyer EJ;Schmutzler RK;Schneeweiss A;Schürmann P;Shah M;Sohn C;Southey MC;Surowy H;Suvanto M;Thanasitthichai S;Tomlinson I;Torres D;Truong T;Tzardi M;Valova Y;van Asperen CJ;Van Dam RM;van den Ouweland AMW;van der Kolk LE;van Veen EM;Wendt C;Williams JA;Yang XR;Yoon SY;Zamora MP;Evans DG;de la Hoya M;Simard J;Antoniou AC;Borg Å;Andrulis IL;Chang-Claude J;García-Closas M;Chenevix-Trench G;Milne RL;Pharoah PDP;Schmidt MK;Spurdle AB;Vreeswijk MPG;Benitez J;Dunning AM;Kvist A;Teo SH;Devilee P;Easton DF
乳腺癌易感性的基因检测被广泛应用，但对于许多基因来说，与乳腺癌相关的证据薄弱，潜在风险估计不准确，缺乏可靠的亚型特定风险估计。我们使用一组34个可能的易感基因对来自60,466名乳腺癌患者和53,461名对照的样本进行了测序。在对这些基因中蛋白质截断变异和罕见错义变异的单独分析中，我们估计了乳腺癌总体和肿瘤亚型的优势比。我们根据致病性的结构域和分类来评估错义-变异关联。5个基因(ATM、BRCA1、BRCA2、CHEK2和PALB2)的蛋白质截断变异与乳腺癌的总体风险相关，P值小于0.0001。其他4个基因(BARD1、RAD51C、RAD51D和TP53)的蛋白质截断变异与乳腺癌的总体风险相关，P值小于0.05，贝叶斯错误发现概率小于0.05。对于剩余25个基因中19个蛋白质截断的变异，乳腺癌总体优势比的95%可信区间上限小于2.0。对于ATM和CHEK2中的蛋白质截断变异，雌激素受体(ER)阳性疾病的优势比高于ER阴性疾病；对于BARD1、BRCA1、BRCA2、PALB2、RAD51C和RAD51D蛋白质截断变异，ER阴性疾病的优势比高于ER阳性疾病。ATM、CHEK2和TP53基因中罕见的错义变异(合计)与乳腺癌的总体风险相关，其P值小于0.001。对于BRCA1、BRCA2和TP53，根据标准标准被归类为致病的错义变异(合计)与乳腺癌的总体风险相关，风险与蛋白质截短变异相似。这项研究的结果定义了临床上最有用的基因，可以纳入乳腺癌风险预测小组，并提供与蛋白质截断变异相关的风险估计，以指导遗传咨询。(资金来自欧盟地平线2020计划和其他项目。)
Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)