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对于不同种族，乳腺癌易感基因（BRCA）致病突变位置和比例可能不同，某些人群可能存在始祖突变，即由一位祖先首先发生突变并将其引入该人群，当这个人群扩大时，该突变被不断遗传播散。目前，尚不明确中国女性是否存在高发始祖突变。 2020年1月20日，国际抗癌联盟《国际癌症杂志》在线发表北京大学肿瘤医院孟桦、姚璐、袁华、徐晔、欧阳涛、李金峰、王天峰、范照青、范铁、林本耀、解云涛等学者的研究报告，调查了中国汉族女性乳腺癌易感基因BRCA始祖突变。 该单中心队列回顾研究对2003年12月～2015年5月北京大学肿瘤医院连续9505例中国汉族乳腺癌患者血液DNA大规模并行测序或双脱氧链终止法测序结果进行回顾分析。 结果，471例患者（5.0%）携带BRCA致病突变，其中161例患者携带的25种致病突变（BRCA1致病突变8种、BRCA2致病突变17种）重复出现于至少4例无血缘关系患者。 根据同源染色体等位基因分析，最常见的致病突变为c. 5470 _ 5477 del，可见于来自29个无血缘关系家族的30例乳腺癌患者，携带该突变的29例无血缘关系患者其中27例同源染色体等位基因相同，表明该突变为中国汉族人群始祖突变。 此外，该突变携带者与未携带者相比，无病生存、总生存显著较差（P=0.049、0.029）。 因此，该研究结果表明，BRCA1致病突变c.5470_5477del是中国汉族人群的始祖突变，该突变携带者与未携带者相比，生存结局较差。 Int J Cancer. 2020 Jan 20. [Epub ahead of print] BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients. Meng H, Yao L, Yuan H, Xu Y, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Xie Y. Peking University Cancer Hospital & Institute, Beijing, China. The spectrum and frequency of BRCA1/2 pathogenic variants may be ethnicity-specific. Whether high-frequency founder mutations are present in Chinese women is still largely unknown. In the current study, germline pathogenic variants in the BRCA1/2 genes were determined in 9505 unselected Chinese Han breast cancer patients by next-generation and/ or Sanger sequencing. Four hundred and seventy-one (5.0%) breast cancer patients carried BRCA1/2 pathogenic variants in this cohort. A total of 25 recurrent pathogenic variants (at least found in 4 unrelated patients) were identified in this cohort (8 BRCA1 and 17 BRCA2 recurrent pathogenic variants), 161 patients carried one of these recurrent pathogenic variants in this cohort of 9505 patients. All of these 25 recurrent pathogenic variants were further explored whether they had founder effect through haplotype analysis. The most common pathogenic variant, BRCA1 c.5470_5477del, was found in 30 breast cancer patients from 29 unrelated families. Twenty-seven of these 29 unrelated patients who carried this BRCA1 c.5470_5477del mutation shared an identical haplotype, indicating that BRCA1 c.5470_5477del was a founder mutation in the Chinese Han population. Furthermore, BRCA1 c.5470_5477del mutation carriers had a significantly worse survival than non-carriers (disease-free survival, P = 0.049; overall survival, P = 0.029). Taken together, our data suggested that BRCA1 c.5470_5477del is a founder mutation in the Chinese Han population and BRCA1 c.5470_5477del mutation carriers have a poor survival. KEYWORDS: Breast cancer; BRCA1; Haplotype; Founder mutation; Chinese DOI: 10.1002/ijc.32877
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