美国纪念斯隆-凯特琳癌症中心Barry S. Taylor等研究人员的最新研究，揭示了肿瘤谱系对BRCA基因介导的表型的影响。相关论文于2019年7月25日发表于国际顶尖学术期刊《自然》杂志上。

该课题组表明，在晚期癌症患者中，2.7%的患者群体携带生殖系BRCA1/2基因突变，1.8%的患者群体BRCA1/2基因存在功能缺失性改变，这两类BRCA1/2基因异常的群体中，诸如双等位基因失活，接合性依赖性表型外显率和对聚腺苷二磷酸核糖聚合酶抑制的敏感性的选择性压力仅存在于那些与BRCA1/2携带者（BRCA相关癌症类型）中可遗传的癌症风险增加相关的肿瘤类型中。相反,在BRCA非相关肿瘤患者中，尽管携带有BRCA1/2基因突变，但是他们的肿瘤发生机制与这类突变没有直接联系。总之,尽管在某些肿瘤中，BRCA基因突变是不可或缺的驱动因素,但在相当比例的其他癌症类型中,这类突变似乎是受肿瘤谱系影响的中性生物学差异，从而对疾病发病机制研究，癌症筛查，临床试验设计和治疗决策有提示意义。

据了解，BRCA1和BRCA2基因突变使个体易患某些癌症，通过疾病特异性筛查和预防策略已经降低了受影响患者的癌症死亡率。这些经典的肿瘤抑制基因与体细胞双等位基因失活相关，从而表现出致瘤作用，尽管单倍体不足也可能促进肿瘤的形成和发展。此外,BRCA1/2基因突变的肿瘤类型往往缺乏基于同源重组修复DNA双链断裂的能力,因此提升了对铂类药物化疗和聚腺苷二磷酸核糖聚合酶抑制剂的敏感性。然而,在大多数癌症类型中，BRCA1或BRCA2基因突变的表型和治疗相关性的研究仍然缺乏。

附：英文原文

Title: Tumour lineage shapes BRCA-mediated phenotypes

Author: Philip Jonsson, Chaitanya Bandlamudi, Michael L. Cheng, Preethi Srinivasan, Shweta S. Chavan, Noah D. Friedman, Ezra Y. Rosen, Allison L. Richards, Nancy Bouvier, S. Duygu Selcuklu, Craig M. Bielski, Wassim Abida, Diana Mandelker, Ozge Birsoy, Liying Zhang, Ahmet Zehir, Mark T. A. Donoghue, Jos Baselga, Kenneth Offit, Howard I. Scher, Eileen M. OReilly, Zsofia K. Stadler, Nikolaus Schultz, Nicholas D. Socci, Agnes Viale, Marc Ladanyi, Mark E. Robson, David M. Hyman, Michael F. Berger, David B. Solit, Barry S. Taylor

Issue&Volume: Volume 571 Issue 7766

Abstract: Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers, and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients. These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours. Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination, and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)-polymerase (PARP). However, the phenotypic and therapeutic relevance of mutations in BRCA1 or BRCA2 remains poorly defined in most cancer types. Here we show that in the 2.7% and 1.8% of patients with advanced-stage cancer and germline pathogenic or somatic loss-of-function alterations in BRCA1/2, respectively, selective pressure for biallelic inactivation, zygosity-dependent phenotype penetrance, and sensitivity to PARP inhibition were observed only in tumour types associated with increased heritable cancer risk in BRCA1/2 carriers (BRCA-associated cancer types). Conversely, among patients with non-BRCA-associated cancer types, most carriers of these BRCA1/2 mutation types had evidence for tumour pathogenesis that was independent of mutant BRCA1/2. Overall, mutant BRCA is an indispensable founding event for some tumours, but in a considerable proportion of other cancers, it appears to be biologically neutrala difference predominantly conditioned by tumour lineagewith implications for disease pathogenesis, screening, design of clinical trials and therapeutic decision-making.

DOI: 10.1038/s41586-019-1382-1

Source: https://www.nature.com/articles/s41586-019-1382-1