种系BRCA基因突变检测是乳腺癌患者诊疗常规之一。不过，BRCA基因突变仅占家族性乳腺癌的一小部分，故有必要对中国家族性乳腺癌患者的种系BRCA基因突变检测进行个体化。
2019年4月13日，美国癌症学会和国际抗癌联盟《癌症医学》在线发表中国医学科学院北京协和医学院附属肿瘤医院中国癌症中心王佳玉和徐兵河、广州拓普基因科技、解放军总医院第五医学中心黄焰、辽宁省肿瘤医院孙涛、湖南省人民医院范培芝、四川大学华西医院吕青、南昌市第三医院雷秋模、广东省人民医院廖宁、中国医科大学附属第一医院金锋、四川省肿瘤医院李卉、华中科技大学同济医学院附属协和医院黄韬、蚌埠医学院第一附属医院钱军、中山大学附属佛山医院庞丹梅、中山大学附属肿瘤医院王树森、中南大学湘雅医院唐利立、湖北省肿瘤医院吴新红、中山大学附属第一医院林颖等学者的研究报告，对中国家族性乳腺癌患者22个乳腺癌或卵巢癌易感基因种系突变谱进行了测序分析。
结果发现，中国28家医院481例女性乳腺癌患者其中携带致病或可能致病突变患者135例（28.1%），对应12种不同的癌症易感基因（BRCA1基因70例占14.6%，BRCA2基因24例占5.0%，非BRCA基因突变41例占8.5%）。此外，未知意义突变119例占24.7%。
最常见的致病突变为8例BRCA1基因c.5470_5477缺失伴BRIP1基因2392位点胞嘧啶→胸腺嘧啶。所有检测到的突变主要见于同源重组修复通路。BRCA1突变与BRCA2突变相比，年轻女性患者发生率显著较高（P<0.01）。
既往无肿瘤病史的患者家族成员检出一些致病突变，其中新突变92个（BRCA基因突变31个，包括致病突变2个、可能致病突变16个、未知意义突变13个；非BRCA基因突变61个，包括可能致病突变9个、未知意义突变52个）。家族癌症成员≥3个与1～2个的患者相比，BRCA突变检出率较高，不过无显著统计学意义。
因此，该研究结果表明，多基因组检测可以提高乳腺癌高风险患者的突变检出率，详细的家族史有助于对新突变进行分类。
Cancer Med. 2019 Apr 13. [Epub ahead of print]
Germline mutation landscape of Chinese patients with familial breast/ovarian cancer in a panel of 22 susceptibility genes.
Wang J, Li W, Shi Y, Huang Y, Sun T, Tang L, Lu Q, Lei Q, Liao N, Jin F, Li H, Huang T, Qian J, Pang D, Wang S, Fan P, Wu X, Lin Y, Qin H, Xu B.
National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Top Gene Tech (Guangzhou) Co., Ltd., Guangzhou, China; Chinese People's Liberation Army, Beijing, China; Liaoning Cancer Hospital, Shenyang, China; Hunan Cancer Hospital, Changsha, China; West China Hospital of Sichuan university, Chengdu, China; The Third Hospital of Nanchang, Nanchang, China; Guangdong General Hospital, Guangzhou, China; The First Hospital of China Medical University, Shenyang, China; SiChuan Cancer Hospital, Chengdu, Sichuan, China; Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; The First affiliated Hospital of Bengbu medical college, Benghu, China; Foshan Hospital of Sun Yat-Sen Unversity, Foshan, China; Sun Yat-Sen University, Guangzhou, China; Xiangya Hospital of Central South University, Changsha, China; Hubei Cancer Hospital, Benghu, China; First affiliated Hospital of Sun Yat-Sen Unversity, Guangzhou, China.
Genetic testing for germline mutations in BRCA1/2 of patients with breast cancer (BC) is part of routine patient care. However, BRCA1/2 mutations account only for a fraction of familial BC. A custom panel of 22 gene sequencing was performed on each patient. Among the 481 female patients, 135 patients were detected to carry pathogenic (P)/likely pathogenic (LP) mutations (28.1%), which corresponded to 12 different cancer predisposition genes [14.6% (70/481) on BRCA1 gene, 5.0% (24/481) on BRCA2 gene, 8.5% (41/481) on non-BRCA1/2 genes]. Moreover, 24.7% (119/481) of patients had mutation of unknown significance (VUS) in these genes. The most common (8/481) pathogenic mutation is BRCA1 c.5470_5477del, while BRIP1 2392 C > T of patients was detected. All the mutations detected were mainly seen in the homologous recombinant repair pathway. Compared to BRCA2 mutation, BRCA1 mutation is higher in younger female patients (P < 0.01). Some pathogenic mutations were detected in the patients' familiy members without the past history of tumor and 92 novel mutations were detected (31 on BRCA including 2 P, 16 LP, 13 VUS; 61 on non-BRCA1/2 including 9 LP, 52 VUS). The detection rate of BRCA1/2 mutations was higher in patients with three or more cancer family members than those with one or two. However, the difference was not statistically different. The results suggest that multigene panel testing can increase mutation detection rate for high-risk BC patients. Detailed family history can help to categorize new mutations.
KEYWORDS: BRCA1; BRCA2; familial breast cancer; multigenes; novel mutation
PMID: 30982232
DOI: 10.1002/cam4.2093
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