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胚系 DNA 修复基因突变与 BRCA1/2 阴性乳腺癌患者的不良预后相关。

Germline mutation in DNA-repair genes is associated with poor survival in BRCA1/2-negative breast cancer patients.

机构信息

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Breast Center, Beijing Cancer Hospital and Institute, Peking University Cancer Hospital, Beijing, China.

出版信息

Cancer Sci. 2019 Oct;110(10):3368-3374. doi: 10.1111/cas.14175. Epub 2019 Sep 19.

Abstract

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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dcab/7938415/93f12b37ed6b/CAS-110-3368-g001.jpg

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