A Population-Based Study of Genes Previously Implicated in Breast Cancer.
A Population-Based Study of Genes Previously Implicated in Breast Cancer.
复制标题
一项以人群为基础的乳腺癌相关基因研究
DOI：
10.1056/nejmoa2005936
复制
发表时间：
2021-02-04
期刊：
影响因子：
--
通讯作者：
Couch FJ
中科院分区：
文献类型：
--
作者：
Hu C;Hart SN;Gnanaolivu R;Huang H;Lee KY;Na J;Gao C;Lilyquist J;Yadav S;Boddicker NJ;Samara R;Klebba J;Ambrosone CB;Anton-Culver H;Auer P;Bandera EV;Bernstein L;Bertrand KA;Burnside ES;Carter BD;Eliassen H;Gapstur SM;Gaudet M;Haiman C;Hodge JM;Hunter DJ;Jacobs EJ;John EM;Kooperberg C;Kurian AW;Le Marchand L;Lindstroem S;Lindstrom T;Ma H;Neuhausen S;Newcomb PA;O'Brien KM;Olson JE;Ong IM;Pal T;Palmer JR;Patel AV;Reid S;Rosenberg L;Sandler DP;Scott C;Tamimi R;Taylor JA;Trentham-Dietz A;Vachon CM;Weinberg C;Yao S;Ziogas A;Weitzel JN;Goldgar DE;Domchek SM;Nathanson KL;Kraft P;Polley EC;Couch FJ
对癌症易感基因的胚系致病变异相关的乳腺癌风险进行基于人群的估计，对于具有遗传致病变异的妇女的风险评估和管理是至关重要的。在一项基于人群的病例对照研究中，我们使用一个定制的基于多基因扩增的小组进行测序，在32,247名乳腺癌患者(病例患者)和32,544名未受影响的女性(对照)中，确定了28个癌症易感基因中的种系致病变异。评估了每个基因的致病变异与乳腺癌风险之间的关系。5.03%的病例组和1.63%的对照组在12个已建立的乳腺癌易感基因中检测到致病变异。BRCA1和BRCA2的致病变异与乳腺癌的高危相关，优势比分别为7.62(95%可信区间，5.33~11.27)和5.23(95%可信区间，4.09~6.77)。PALB2致病变异与中等风险相关(优势比为3.83；95%可信区间为2.68至5.63)。BARD1、RAD51C和RAD51D的致病变异与雌激素受体阴性乳腺癌和三阴性乳腺癌的风险增加相关，而ATM、CDH1和CHEK2的致病变异与雌激素受体阳性乳腺癌的风险增加相关。16个候选乳腺癌易感基因的致病变异，包括NBN中的c.657_661del5方正致病变异，与乳腺癌风险的增加无关。这项研究对美国人群中与已知乳腺癌易感基因的致病变异相关的乳腺癌患病率和风险进行了估计。这些估计可以为癌症测试和筛查提供信息，并改进对具有这些基因遗传致病变异的普通人群中的妇女的临床管理策略。(由美国国立卫生研究院和乳腺癌研究基金会资助。)
Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. In a population-based case–control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. Pathogenic variants in 12 established breast cancer–predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor–negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor–positive breast cancer. Pathogenic variants in 16 candidate breast cancer–predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer–predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.)