Vijai Joseph, Topka Sabine, Villano Danylo, Ravichandran Vignesh, Maxwell Kara N, Maria Ann, Thomas Tinu, Gaddam Pragna, Lincoln Anne, Kazzaz Sarah, Wenz Brandon, Carmi Shai, Schrader Kasmintan A, Hart Steven N, Lipkin Steve M, Neuhausen Susan L, Walsh Michael F, Zhang Liying, Lejbkowicz Flavio, Rennert Hedy, Stadler Zsofia K, Robson Mark, Weitzel Jeffrey N, Domchek Susan, Daly Mark J, Couch Fergus J, Nathanson Katherine L, Norton Larry, Rennert Gad, Offit Kenneth
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Cancer Discov. 2016 Nov;6(11):1267-1275. doi: 10.1158/2159-8290.CD-16-0487. Epub 2016 Sep 21.
Known gene mutations account for approximately 50% of the hereditary risk for breast cancer. Moderate and low penetrance variants, discovered by genomic approaches, account for an as-yet-unknown proportion of the remaining heritability. A truncating mutation c.325C>T:p.Arg109* (R109X) in the ATP-dependent helicase ERCC3 was observed recurrently among exomes sequenced in BRCA wild-type, breast cancer-affected individuals of Ashkenazi Jewish ancestry. Modeling of the mutation in ERCC3-deficient or CRISPR/Cas9-edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair-deficient phenotype. Comparison of frequency of this recurrent mutation in over 6,500 chromosomes of breast cancer cases and 6,800 Ashkenazi controls showed significant association with breast cancer risk (OR = 1.53, OR = 1.73), particularly for the estrogen receptor-positive subset (P < 0.007).
A functionally significant recurrent ERCC3 mutation increased the risk for breast cancer in a genetic isolate. Mutated cell lines showed lower survival after in vitro exposure to DNA-damaging agents. Thus, similar to tumors arising in the background of homologous repair defects, mutations in nucleotide excision repair genes such as ERCC3 could constitute potential therapeutic targets in a subset of hereditary breast cancers. Cancer Discov; 6(11); 1267-75. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1197.
已知基因突变约占乳腺癌遗传风险的50%。通过基因组学方法发现的中度和低度外显率变异，在其余遗传度中所占比例尚不清楚。在对阿什肯纳兹犹太血统、BRCA野生型且患乳腺癌个体的外显子组测序中，反复观察到ATP依赖解旋酶ERCC3中的截断突变c.325C>T:p.Arg109*（R109X）。在ERCC3缺陷或经CRISPR/Cas9编辑的细胞系中对该突变进行建模，结果显示，当受到紫外线C照射或用DNA烷化剂Illudin S处理时，该蛋白表达降低且功能亚态性随之出现，呈现出一致的模式。在ERCC3缺陷细胞中过表达突变蛋白只能部分挽救其DNA修复缺陷表型。对6500多条乳腺癌病例染色体和6800名阿什肯纳兹对照者染色体中该反复突变频率进行比较，结果显示其与乳腺癌风险存在显著关联（比值比=1.53，比值比=1.73），尤其是雌激素受体阳性亚组（P<0.007）。
一种具有功能意义的反复出现的ERCC3突变增加了一个遗传隔离群体患乳腺癌的风险。突变细胞系在体外暴露于DNA损伤剂后存活率较低。因此，与同源修复缺陷背景下产生的肿瘤类似，ERCC3等核苷酸切除修复基因中的突变可能构成一部分遗传性乳腺癌的潜在治疗靶点。癌症发现；6(11)；1267 - 75。©2016美国癌症研究协会。本文在本期特刊第1197页重点介绍。
