FANCM, RAD1, CHEK1 and TP53I3 act as BRCA-like tumor suppressors and are mutated in hereditary ovarian cancer
FANCM, RAD1, CHEK1 and TP53I3 act as BRCA-like tumor suppressors and are mutated in hereditary ovarian cancer
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DOI：
10.1016/j.cancergen.2019.04.061
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发表时间：
2019-06-01
期刊：
影响因子：
1.9
通讯作者：
Tainsky, Michael A.
中科院分区：
文献类型：
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作者：
Lopes, Jaime L.;Chaudhry, Sophia;Tainsky, Michael A.
虽然25%的卵巢癌病例是由于遗传因素，但大多数遗传风险仍然无法解释。我们先前通过BRCA 1/BRCA 2阴性的有家族风险的卵巢癌患者的生殖系全外显子组测序确定了候选基因。在这里，我们进行了功能评估，以确定它们是否作为BRCA样肿瘤抑制因子。7个候选的风险基因被siRNA靶向mRNA耗竭，然后进行克隆生存，DNA损伤剂的细胞毒性，并参与同源重组修复的功能测定。BRCA 1和BRCA 2作为功能丧失结果的标准，在BRCA 1/BRCA 2缺陷细胞中也观察到各种候选基因的敲除导致肿瘤抑制表型。CHEK 1、FANCM和TP 53 I3的缺失导致同源重组修复效率降低。敲除RAD 1、CHEK 1或FANCM导致细胞活力下降，CHEK 1、RAD 1或TP 53 I3缺陷的细胞显示出对顺铂的敏感性增加。这项研究的结果表明，在遗传性卵巢癌中发现的突变基因FANCM、RAD 1、CHEK 1和TP 53 I3起BRCA样肿瘤抑制因子的作用。
Although 25% of ovarian cancer cases are due to inherited factors, most of the genetic risk remains unexplained. We previously identified candidate genes through germline whole exome sequencing of BRCA1/BRCA2 negative ovarian cancer patients with familial risk. Here, we per-formed functional assessment to determine whether they act as BRCA-like tumor suppressors.Seven candidate risk genes were targeted by siRNA for mRNA depletion followed by functional assays for clonogenic survival, cytotoxicity to DNA damaging agents, and involvement in homologous recombination repair. BRCA1 and BRCA1 were targeted as standards for loss of function outcome.Knockdown of various candidate genes led to tumor suppressor phenotypes also observed in BRCA1/BRCA2 deficient cells. Deficiency of CHEK1, FANCM and TP53I3 led to reduced homologous recombination repair efficiency. Knockdown of RAD1, CHEK1 or FANCM led to a decrease in cellular viability and cells deficient in CHEK1, RAD1 or TP53I3 displayed increased sensitivity to cisplatin.Functional studies of candidate genes identified by whole exome sequencing complements bioinformatics techniques and aid the implication of novel risk loci. The results of this study suggest that genes found mutated in hereditary ovarian cancer, FANCM, RAD1, CHEK1 and TP53I3, act as BRCA-like tumor suppressors.