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BRCA2 BRC 结构域种系突变与高级别浆液性卵巢癌化疗敏感性和生存的关系。

Association of somatic mutations in BRCA2 BRC domain with chemotherapy sensitivity and survival in high grade serous ovarian cancer.

机构信息

Department of Gynecologic Oncology, Sichuan Cancer Hospital, Chengdu, 610041, PR China.

Department of Gynecologic Oncology, Sichuan Cancer Hospital, Chengdu, 610041, PR China; Department of Ultrasound, Sichuan Cancer Hospital, Chengdu, 610041, PR China.

出版信息

Exp Cell Res. 2021 Sep 1;406(1):112742. doi: 10.1016/j.yexcr.2021.112742. Epub 2021 Jul 22.

DOI:10.1016/j.yexcr.2021.112742

PMID:34302857

Abstract

BACKGROUND

Mutations at sites crucial for the interaction between RAD51 and BRC domains impair the ability of BRCA2 homologous recombination. We aimed to clarify whether BRCA2 BRC domain-associated mutation correlates with sensibility of platinum-based chemotherapy and survival in high-grade serous ovarian cancer (HGSOC).

METHODS

We identified BRCA2 BRC domain mutations by sequencing PCR-amplified amplicons of genomic DNA isolated from tumor tissues and peripheral blood leukocytes (PBL)in 113 patients with advanced EOC, and assessed platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS).

RESULTS

21.23% (24 of 113) cases with somatic missense mutation but not germline mutation were identified. Among 24 cases with mutation, 33.3% (8 of 24) cases with nonsense mutation (C-terminal truncation) significantly prolonged median PFI (37 vs 8 months,P = 0.000), PFS (43 vs 14 months, p = 0.000) and OS (56 vs 31 months, P = 0.002); 66.7% (16 of 24) cases with missense mutation also prolonged median PFI (15 vs 8 months, P = 0.044), PFS (21 vs 14 months, P = 0.049) and OS (38 vs 31 months, P = 0.037), compared to those without any mutation.

CONCLUSIONS

Somatic mutations in BRCA2 BRC domain confer a higher sensitivity to platinum-based therapy and are associated with a favourable survival in HGSOC.

摘要

背景

RAD51 和 BRC 结构域之间相互作用的关键部位的突变，会削弱 BRCA2 同源重组的能力。我们旨在阐明 BRCA2 BRC 结构域相关突变是否与高级别浆液性卵巢癌（HGSOC）对铂类化疗的敏感性和生存相关。

方法

我们通过对 113 例晚期 EOC 患者肿瘤组织和外周血白细胞（PBL）基因组 DNA 扩增片段进行测序，鉴定 BRCA2 BRC 结构域突变，并评估无铂间隔时间（PFI）、无进展生存期（PFS）和总生存期（OS）。

结果

发现 24 例（21.23%）存在体细胞错义突变而无胚系突变。在 24 例突变患者中，33.3%（8 例）存在无义突变（C 端截断）显著延长了中位 PFI（37 个月 vs 8 个月，P = 0.000）、PFS（43 个月 vs 14 个月，P = 0.000）和 OS（56 个月 vs 31 个月，P = 0.002）；66.7%（16 例）的错义突变患者也延长了中位 PFI（15 个月 vs 8 个月，P = 0.044）、PFS（21 个月 vs 14 个月，P = 0.049）和 OS（38 个月 vs 31 个月，P = 0.037），与无任何突变的患者相比。