Tumour lineage shapes BRCA-mediated phenotypes
Tumour lineage shapes BRCA-mediated phenotypes
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DOI：
10.1038/s41586-019-1382-1
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发表时间：
2019-07-25
期刊：
影响因子：
64.8
通讯作者：
Taylor, Barry S.
中科院分区：
文献类型：
--
作者：
Jonsson, Philip;Bandlamudi, Chaitanya;Taylor, Barry S.
BRCA1和BRCA2的突变使个人易患某些癌症(1-3)，针对疾病的筛查和预防策略降低了受影响患者的癌症死亡率(4，5)。这些经典的肿瘤抑制基因具有与体细胞双等位基因失活相关的致瘤作用，尽管单倍性不足也可能促进肿瘤的形成和发展(6，7)。此外，BRCA1/2突变的肿瘤通常缺乏通过同源重组修复双链DNA断裂的能力(8-13)，因此对含铂治疗和多(ADP-核糖)聚合酶(PARP)抑制剂的治疗敏感性增加(14，15)。然而，在大多数癌症类型中，BRCA1或BRCA2突变的表型和治疗相关性仍然不明确。在这里，我们发现，在2.7%和1.8%的晚期癌症患者和BRCA1/2生殖系致病或躯体功能丧失改变的患者中，双等位基因失活的选择性压力、合子依赖的表型外显率和对PARP抑制的敏感性仅在BRCA1/2携带者(BRCA相关癌症类型)中与可遗传癌症风险增加相关的肿瘤类型中观察到。相反，在非BRCA相关癌症类型的患者中，这些BRCA1/2突变类型的大多数携带者都有独立于突变BRCA1/2的肿瘤发病机制的证据。总体而言，突变BRCA是某些肿瘤不可或缺的创始事件，但在相当大一部分其他癌症中，它似乎是生物学中性的--这种差异主要受肿瘤谱系的影响--对疾病发病机制、筛查、临床试验设计和治疗决策有影响。
Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers(1-3), and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients(4,5). These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours(6,7). Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination(8-13), and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)polymerase (PARP)(14,15). 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 neutral-a difference predominantly conditioned by tumour lineage-with implications for disease pathogenesis, screening, design of clinical trials and therapeutic decision-making.