種系BRCA基因突變檢測是乳腺癌患者診療常規(guī)之一。不過，BRCA基因突變僅占家族性乳腺癌的一小部分，故有必要對中國家族性乳腺癌患者的種系BRCA基因突變檢測進行個體化。

　　2019年4月13日，美國癌癥學(xué)會和國際抗癌聯(lián)盟《癌癥醫(yī)學(xué)》在線發(fā)表中國醫(yī)學(xué)科學(xué)院北京協(xié)和醫(yī)學(xué)院附屬腫瘤醫(yī)院中國癌癥中心王佳玉和徐兵河、廣州拓普基因科技、解放軍總醫(yī)院第五醫(yī)學(xué)中心黃焰、遼寧省腫瘤醫(yī)院孫濤、湖南省人民醫(yī)院范培芝、四川大學(xué)華西醫(yī)院呂青、南昌市第三醫(yī)院雷秋模、廣東省人民醫(yī)院廖寧、中國醫(yī)科大學(xué)附屬第一醫(yī)院金鋒、四川省腫瘤醫(yī)院李卉、華中科技大學(xué)同濟醫(yī)學(xué)院附屬協(xié)和醫(yī)院黃韜、蚌埠醫(yī)學(xué)院第一附屬醫(yī)院錢軍、中山大學(xué)附屬佛山醫(yī)院龐丹梅、中山大學(xué)附屬腫瘤醫(yī)院王樹森、中南大學(xué)湘雅醫(yī)院唐利立、湖北省腫瘤醫(yī)院吳新紅、中山大學(xué)附屬第一醫(yī)院林穎等學(xué)者的研究報告，對中國家族性乳腺癌患者22個乳腺癌或卵巢癌易感基因種系突變譜進行了測序分析。

　　結(jié)果發(fā)現(xiàn)，中國28家醫(yī)院481例女性乳腺癌患者其中攜帶致病或可能致病突變患者135例（28.1%），對應(yīng)12種不同的癌癥易感基因（BRCA1基因70例占14.6%，BRCA2基因24例占5.0%，非BRCA基因突變41例占8.5%）。此外，未知意義突變119例占24.7%。

　　最常見的致病突變?yōu)?例BRCA1基因c.5470_5477缺失伴BRIP1基因2392位點胞嘧啶→胸腺嘧啶。所有檢測到的突變主要見于同源重組修復(fù)通路。BRCA1突變與BRCA2突變相比，年輕女性患者發(fā)生率顯著較高（P<0.01）。

　　既往無腫瘤病史的患者家族成員檢出一些致病突變，其中新突變92個（BRCA基因突變31個，包括致病突變2個、可能致病突變16個、未知意義突變13個；非BRCA基因突變61個，包括可能致病突變9個、未知意義突變52個）。家族癌癥成員≥3個與1～2個的患者相比，BRCA突變檢出率較高，不過無顯著統(tǒng)計學(xué)意義。

　　因此，該研究結(jié)果表明，多基因組檢測可以提高乳腺癌高風(fēng)險患者的突變檢出率，詳細的家族史有助于對新突變進行分類。

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