BACKGROUND The germline cancer predisposition genes associated with increased risk of each clinical subtype of breast cancer, defined by estrogen receptor (ER), progesterone receptor (PR), and HER2, are not well defined. METHODS A total of 54,555 invasive breast cancer patients with 56,480 breast tumors were subjected to clinical hereditary cancer multigene panel testing. Heterogeneity for predisposition genes across clinical breast cancer subtypes was assessed by comparing mutation frequencies by gene among tumor subtypes and by association studies between each tumor subtype and reference controls. RESULTS Mutations in 15 cancer predisposition genes were detected in 8.6% of patients with ER+/HER2-; 8.9% with ER+/HER2+; 7.7% with ER-/HER2+; and 14.4% of ER-/PR-/HER2- tumors. BRCA1, BRCA2, BARD1 and PALB2 mutations were enriched in ER- and HER2- tumors, RAD51C and RAD51D mutations were enriched in ER- tumors only, TP53 mutations were enriched in HER2+ tumors, and ATM and CHEK2 mutations were enriched in both ER+ and/or HER2+ tumors. All genes were associated with moderate (odds ratio (OR)>2.00) or strong (OR > 5.00) risks of at least one subtype of breast cancer in case-control analyses. Mutations in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53 had predicted lifetime absolute risks of ≥ 20.0% for breast cancer. CONCLUSIONS Germline mutations in hereditary cancer panel genes confer subtype-specific risks of breast cancer. Combined tumor subtype, age at breast cancer diagnosis, and family history of breast and/or ovarian cancer information provides refined categorical estimates of mutation prevalence for women considering genetic testing.

中文翻译：

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临床基因检测队列中种系易感性基因突变对浸润性乳腺癌临床亚型的贡献。


背景与乳腺癌每种临床亚型（由雌激素受体（ER）、孕激素受体（PR）和 HER2 定义）风险增加相关的种系癌症易感基因尚未明确定义。方法 对54,555名浸润性乳腺癌患者和56,480个乳腺肿瘤进行临床遗传性癌症多基因组检测。通过比较肿瘤亚型之间基因的突变频率以及每个肿瘤亚型与参考对照之间的关联研究，评估了临床乳腺癌亚型之间易感基因的异质性。结果 8.6%的ER+/HER2-患者检测到15个癌症易感基因突变； ER+/HER2+ 为 8.9%； ER-/HER2+ 为 7.7%； 14.4% 的 ER-/PR-/HER2- 肿瘤。 BRCA1、BRCA2、BARD1 和 PALB2 突变在 ER- 和 HER2- 肿瘤中富集，RAD51C 和 RAD51D 突变仅在 ER- 肿瘤中富集，TP53 突变在 HER2+ 肿瘤中富集，ATM 和 CHEK2 突变在 ER+ 和/ 肿瘤中富集。或 HER2+ 肿瘤。在病例对照分析中，所有基因均与至少一种乳腺癌亚型的中度（比值比 (OR)> 2.00）或强（OR > 5.00）风险相关。 ATM、BARD1、BRCA1、BRCA2、CHEK2、PALB2、RAD51C、RAD51D 和 TP53 突变预测终生乳腺癌绝对风险≥20.0%。结论 遗传性癌症组基因中的种系突变赋予乳腺癌亚型特异性风险。结合肿瘤亚型、乳腺癌诊断年龄以及乳腺癌和/或卵巢癌家族史信息，为考虑进行基因检测的女性提供了突变患病率的精确分类估计。