Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
J Natl Cancer Inst. 2020 Dec 14;112(12):1231-1241. doi: 10.1093/jnci/djaa023.
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.
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.
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 > 2.00) or strong (odds ratio > 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 at least 20.0% for breast cancer.
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.
与雌激素受体（ER）、孕激素受体（PR）和 HER2 定义的每种临床乳腺癌亚型风险增加相关的种系癌症易感性基因尚未明确。
对 54555 例浸润性乳腺癌患者的 56480 个乳腺癌肿瘤进行临床遗传性癌症多基因panel 检测。通过比较肿瘤亚型之间各基因的突变频率以及各肿瘤亚型与参考对照之间的关联研究，评估种系癌症易感性基因在临床乳腺癌亚型中的异质性。
在 ER+/HER2-患者中，有 8.6%检测到 15 种癌症易感性基因的突变；在 ER+/HER2+患者中，有 8.9%检测到突变；在 ER-/HER2+患者中，有 7.7%检测到突变；在 ER-/PR-/HER2-肿瘤中，有 14.4%检测到突变。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/或 HER2+肿瘤中富集。在病例对照分析中，所有基因与至少一种乳腺癌亚型的中度（优势比>2.00）或高度（优势比>5.00）风险相关。ATM、BARD1、BRCA1、BRCA2、CHEK2、PALB2、RAD51C、RAD51D 和 TP53 基因突变的个体终生患乳腺癌的绝对风险至少为 20.0%。
遗传性癌症panel 基因的种系突变赋予乳腺癌亚型特异性风险。综合肿瘤亚型、乳腺癌诊断时的年龄以及乳腺癌和/或卵巢癌家族史信息，可为考虑基因检测的女性提供突变流行率的精细分类估计。
