BRCA1 Mutations in Cancer: Coordinating Deficiencies in Homologous Recombination with Tumorigenesis.
BRCA1 Mutations in Cancer: Coordinating Deficiencies in Homologous Recombination with Tumorigenesis.
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DOI：
10.1158/0008-5472.can-20-1830
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发表时间：
2020-11-01
期刊：
影响因子：
11.2
通讯作者：
Johnson N
中科院分区：
文献类型：
--
作者：
Krais JJ;Johnson N
由BRCA1种系突变引起的癌症缺乏同源重组（HR） DNA修复，并且对DNA损伤剂如铂和PARP抑制剂（PARPi）敏感。在脊椎动物中，敲除包括BRCA1和BRCA2在内的关键HR基因是致命的，因为HR是基因组复制所必需的。因此，癌症必须制定策略来应对HR活动的丧失。此外，由于已建立的肿瘤对化疗选择压力有反应，额外的遗传适应将癌症转变为hr精通状态。在这篇综述中，我们讨论了影响brca1突变癌症执行HR能力的生物学机制。此外，我们考虑从肿瘤起始到治疗难治性疾病的发展，在整个癌症生命过程中，HR状态是如何波动的。
Cancers that arise from BRCA1 germline mutations are deficient for homologous recombination (HR) DNA repair and are sensitive to DNA damaging agents such as platinum and PARP inhibitors (PARPi). In vertebrate organisms, knockout of critical HR genes including BRCA1 and BRCA2 is lethal because HR is required for genome replication. Thus, cancers must develop strategies to cope with loss of HR activity. Furthermore, as established tumors respond to chemotherapy selection pressure, additional genetic adaptations transition cancers to an HR-proficient state. In this review, we discuss biological mechanisms that influence the ability of BRCA1-mutant cancers to perform HR. Furthermore, we consider how the HR status fluctuates throughout the cancer life course, from tumor initiation to the development of therapy refractory disease.