中国三阴性乳腺癌易感基因致病变异
乳腺癌易感基因BRCA1和BRCA2是重要的抑癌基因，一旦发生致病变异，容易发生三阴性乳腺癌等恶性肿瘤。根据美国三阴性乳腺癌患者的两项大样本BRCA筛查结果，种系致病变异发生率分别为8.4%和10.4%。根据中国三阴性乳腺癌患者的两项大样本BRCA筛查结果，种系致病变异发生率分别为10.1%和11.2%。不过，如果根据西方国家的BRCA筛查指南，对全中国年龄≤60岁的三阴性乳腺癌患者进行BRCA筛查，可能经济负担太大。由于中国女性乳腺癌的发病高峰年龄大约为50～55岁，比西方国家女性年轻5～10岁，故对年龄≤55岁的中国三阴性乳腺癌患者进行BRCA筛查，可能有助于优化BRCA检测对中国三阴性乳腺癌患者的成本效益。
2021年7月13日，德国癌症学会《癌症研究与临床肿瘤学杂志》在线发表复旦大学附属肿瘤医院季刚、朱晓丽、柏乾明、邵志敏、杨文涛、周晓燕等学者的研究报告，对年龄≤55岁的中国三阴性乳腺癌患者种系和肿瘤BRCA致病变异发生率及其生存结局进行了调查。
该研究对2015年在复旦大学附属肿瘤医院接受手术的124例年龄≤55岁中国三阴性乳腺癌患者血液及其肿瘤DNA进行BRCA致病变异分析，并长期随访直至2021年1月。随后，对诊断年龄、家族史、生存结局随访数据等临床病理特征进一步分析。
结果发现，种系和肿瘤BRCA致病变异发生率分别为21.0%和25%。其中，通过大规模并行测序在发现20例性细胞（16.1%）和5例体细胞（4.0%）BRCA单核苷酸变异、插入、缺失，通过多重连接依赖性探针扩增在血液DNA中发现6例（4.8%）BRCA1大基因组重排。
这些患者的遗传性乳腺癌和卵巢癌家族史与种系BRCA致病变异之间存在显著相关性。
肿瘤BRCA致病变异携带者与未携带者相比，无进展生存结局显著较好（P=0.047）。各种突变状态对总生存结局的影响不显著。
BRCA1或BRCA2致病变异携带者与未携带者相比，无进展生存或总生存结局未见显著差异。
因此，该单中心小样本研究结果表明，年龄≤55岁的中国三阴性乳腺癌患者种系和肿瘤BRCA致病变异发生率较高，肿瘤BRCA致病变异携带者与未携带者相比，无进展生存结局显著较好，故有必要进一步开展多中心大样本研究进行验证，在每种特定临床情况下进行BRCA致病变异检测对于患者而言可能更具成本效益。
相关链接
J Cancer Res Clin Oncol. 2021 Jul 13. Online ahead of print.
Germline and tumor BRCA1/2 pathogenic variants in Chinese triple-negative breast carcinomas.
Ji G, Bao L, Yao Q, Zhang J, Zhu X, Bai Q, Shao Z, Yang W, Zhou X.
Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Institute of Pathology, Fudan University, Shanghai, China.
PURPOSE: BRCA1/2 screening for all triple-negative breast cancer (TNBC) patients younger than 60 years may still be an economic burden in China. Further evidences that include incidence and outcome of BRCA1/2 pathogenic variants (PV) screened based on younger age or family history (FH) are worth discussing for improving the cost-effectiveness of BRCA1/2 testing in Chinese TNBC. We aimed to investigate the prevalence of germline and tumor BRCA1/2 PV based on age screening in Chinese TNBC patients.
METHODS: Paired blood and tumor DNA from 124 unselected Chinese TNBC patients with less than or equal to 55 years were collected and analyzed for BRCA1/2 PV. Clinicopathological characteristics including age at diagnosis, FH and follow-up data were collected for further analysis.
RESULTS: The entire frequency of germline and tumor BRCA1/2 PV was 21.0 and 25%, respectively. Among them, 20 (16.1%) germline and 5 (4.0%) somatic BRCA1/2 single-nucleotide variant/insertion/deletions were found by NGS testing, 6 (4.8%) BRCA1 large genomic rearrangements were detected in blood DNA by MPLA. There was significant correlation between FH of HBOC and germline BRCA1/2 PVs among these patients. Patients with tumor BRCA1/2 PVs had significant improvements than non-carriers in PFS (p = 0.047). No significant impacts were found between various mutation status in OS outcomes. No significant differences were found between BRCA1 or BRCA2 and non-carriers in PFS or OS.
CONCLUSION: There is a high incidence of germline and tumor BRCA1/2 PVs in Chinese TNBC patients with less than or equal to 55 years old. Tumor BRCA1/2 PV carriers showed an improved survival outcome. Our results suggest that BRCA1/2 PVs testing addressed within each specific clinical scenario could be more cost-effective for patients.
KEYWORDS: BRCA1/2; Large genomic rearrangement (LRG); Somatic mutation; Triple-negative breast cancer (TNBC)
PMID: 34254208
DOI: 10.1007/s00432-021-03696-2