Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Breast Center, Beijing Cancer Hospital and Institute, Peking University Cancer Hospital, Beijing, China.
Cancer Sci. 2019 Oct;110(10):3368-3374. doi: 10.1111/cas.14175. Epub 2019 Sep 19.
BRCA1/2 genes are the most frequently germline mutated DNA-repair genes, and the survival of BRCA1/2 carriers has been extensively explored in breast cancer. However, the prevalence of germline mutations in non-BRCA1/2 DNA-repair genes and the survival of carriers are largely unknown in a large cohort of unselected breast cancer patients. Germline mutations in 16 DNA-repair genes were determined using a multigene panel in 7657 BRCA1/2-negative breast cancer patients who were unselected for family history of cancer or age at diagnosis. Among the 7657 BRCA1/2-negative breast cancer patients, 257 (3.4%) carried at least 1 pathogenic germline mutation in the 16 DNA-repair genes. The prevalence of DNA-repair gene mutations was significantly higher in familial breast cancers (5.2%, P = 0.002) and early-onset breast cancers (diagnosed at and before the age of 40) (4.5%, P = 0.003) than that of sporadic breast cancers (2.9%) (diagnosed above age of 40), respectively. The DNA-repair gene mutation carriers were significantly more likely to have a larger tumor (P = 0.04) and axillary lymph node metastasis (P = 0.03). Moreover, DNA-repair gene mutation was an independent unfavorable factor for recurrence-free survival (adjusted hazard ratio [HR] = 1.38, 95% CI: 1.00-1.91, P = 0.05) and disease-specific survival (adjusted HR=1.63, 95% CI: 1.04-2.57, P = 0.03) in this cohort. Overall, 3.4% of BRCA1/2-negative breast cancer patients carried germline mutations in the 16 DNA-repair genes, and the DNA-repair gene mutation carriers exhibited an aggressive phenotype and had poor survival compared with noncarriers.
BRCA1/2 基因是最常见的种系突变 DNA 修复基因,BRCA1/2 携带者的生存情况已在乳腺癌中得到广泛研究。然而,在大量未经选择的乳腺癌患者中,非 BRCA1/2 DNA 修复基因的种系突变的发生率以及携带者的生存情况尚不清楚。使用多基因panel 在 7657 例 BRCA1/2 阴性乳腺癌患者中检测了 16 个 DNA 修复基因的种系突变,这些患者未经选择,也没有癌症家族史或诊断时的年龄。在 7657 例 BRCA1/2 阴性乳腺癌患者中,有 257 例(3.4%)至少携带 16 个 DNA 修复基因中的 1 种致病性种系突变。在家族性乳腺癌(5.2%,P=0.002)和早发性乳腺癌(诊断年龄在 40 岁及以下)(4.5%,P=0.003)中,DNA 修复基因突变的发生率明显高于散发性乳腺癌(2.9%,诊断年龄在 40 岁以上)。携带 DNA 修复基因突变的患者肿瘤更大(P=0.04)和腋窝淋巴结转移的可能性更高(P=0.03)。此外,在该队列中,DNA 修复基因突变是无复发生存(调整后的危险比[HR] = 1.38,95%CI:1.00-1.91,P=0.05)和疾病特异性生存(调整后的 HR=1.63,95%CI:1.04-2.57,P=0.03)的独立不利因素。总的来说,3.4%的 BRCA1/2 阴性乳腺癌患者携带 16 个 DNA 修复基因中的种系突变,与非携带者相比,携带 DNA 修复基因突变的患者表现出侵袭性表型,生存情况较差。