Breast and Ovarian Cancer Penetrance Estimates Derived From Germline Multiple-Gene Sequencing Results in Women
Breast and Ovarian Cancer Penetrance Estimates Derived From Germline Multiple-Gene Sequencing Results in Women
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DOI：
10.1200/po.16.00066
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发表时间：
2017-01-01
影响因子：
4.6
通讯作者：
Hall, Michael J.
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文献类型：
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作者：
Kurian, Allison W.;Hughes, Elisha;Hall, Michael J.
多基因、新一代测序板越来越多地用于评估具有不同个人和家族癌症史的患者的遗传性癌症风险。乳腺癌和卵巢癌风险的大小与许多临床测试的基因相关，并且独立于家族癌症史，仍然有待量化。（APC、ATM、BARD 1、BMPR 1A、BRCA 1、BRCA 2、BRIP 1、CDH 1、CDK 4、CHEK 2、MLH 2、MSH 2、MSH 6、MUTYH、NBN、P14 ARF、P16、PALB 2、PMS 2、PTEN、RAD 51 C、RAD 51 D、SMAD 4、STK 11和TP 53）下一代测序组。多变量逻辑回归模型解释家族史被用来检查致病性突变和乳腺癌或卵巢癌之间的关联。作为验证方法，进行了匹配的病例对照分析，将病例定义为乳腺癌或卵巢癌患者，对照定义为未患癌症的女性。结果在95，561名女性中，有6，775人（7%）检测到一种或多种致病性突变。8个基因（ATM、BARD 1、BRCA 1、BRCA 2、CHEK 2、PALB 2、PTEN和TP 53）与乳腺癌相关，比值比（OR）范围为2倍（ATM：OR，1.74; 95% CI，1.46至2.07）至6倍（BRCA 1：OR，5.91; 95% CI，5.25至6.67）。11个基因（ATM、BRCA 1、BRCA 2、BRIP 1、MLH 1、MSH 2、MSH 6、NBN、STK 11、RAD 51 C和RAD 51 D）与卵巢癌相关，OR范围为2倍（ATM：OR，1.69; 95%CI，1.19至2.40）至40倍（STK 11：OR，41.9; 95%CI，5.55至315）。多变量模型和匹配的病例对照分析产生了类似的结果。结论在近10万临床测试的妇女，7%携带一个或多个癌症相关基因的致病性突变。在控制家族史后，相关的乳腺癌和卵巢癌风险范围为2至40倍。这些结果可以为癌症风险咨询提供信息。(C)2017年美国临床肿瘤学会
Purpose Multiple-gene, next-generation sequencing panels are increasingly used to assess hereditary cancer risks of patients with diverse personal and family cancer histories. The magnitude of breast and ovarian cancer risk associated with many clinically tested genes, and independent of family cancer history, remains to be quantified.Methods We queried a commercial laboratory database of 95,561 women tested clinically for hereditary cancer risk with a 25-gene (APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CHEK2, MLH2, MSH2, MSH6, MUTYH, NBN, P14ARF, P16, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53) next-generation sequencing panel. Multivariable logistic regression models accounting for family history were used to examine the association between pathogenic mutations and breast or ovarian cancer. As a confirmatory approach, a matched case-control analysis was conducted, defining cases as patients with breast or ovarian cancer and controls as women without cancer.Results One or more pathogenic mutations were detected in 6,775 (7%) of 95,561 women. Eight genes (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, PTEN, and TP53) were associated with breast cancer, with odds ratios (ORs) ranging from two-fold (ATM: OR, 1.74; 95% CI, 1.46 to 2.07) to six-fold (BRCA1: OR, 5.91; 95% CI, 5.25 to 6.67). Eleven genes (ATM, BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, NBN, STK11, RAD51C, and RAD51D) were associated with ovarian cancer, with OR ranging from two-fold (ATM: OR, 1.69; 95% CI, 1.19 to 2.40) to 40-fold (STK11: OR, 41.9; 95% CI, 5.55 to 315). Multivariable models and matched case-control analyses yielded similar results.Conclusion Among nearly 100,000 clinically tested women, 7% carried a pathogenic mutation in one or more cancer-associated genes. Associated breast and ovarian cancer risks ranged from two-to 40-fold after controlling for family history. These results may inform cancer risk counseling. (C) 2017 by American Society of Clinical Oncology