Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors.
Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors.
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DOI：
10.1038/ng.3557
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发表时间：
2016-06
期刊：
影响因子：
30.8
通讯作者：
Getz G
中科院分区：
文献类型：
--
作者：
Kim J;Mouw KW;Polak P;Braunstein LZ;Kamburov A;Kwiatkowski DJ;Rosenberg JE;Van Allen EM;D'Andrea A;Getz G
DNA修复途径的改变在肿瘤中很常见，并可导致特征性的突变特征；然而，与核苷酸切除修复(NER)途径中的体细胞改变相关的特定突变特征尚未确定。在这里，我们研究了尿路上皮癌的突变过程，这是一种核心NER基因ERCC2显著突变的肿瘤类型。对三个独立的尿路上皮肿瘤队列的分析显示，体细胞ERCC2突变与以广泛碱基变化为特征的突变特征的活性之间存在很强的相关性。此外，我们注意到该信号的活性与吸烟之间的关联，这种关联独立于ERCC2突变状态，提供了与烟草相关的尿路上皮癌突变的基因组证据。总之，这些分析确定了第一个与NER相关的突变特征，并强调了DNA损伤和随后的DNA修复在塑造肿瘤突变格局中的相关作用。
Alterations in DNA repair pathways are common in tumors and can result in characteristic mutational signatures; however, a specific mutational signature associated with somatic alterations in the nucleotide excision repair (NER) pathway has not yet been identified. Here, we examine the mutational processes operating in urothelial cancer, a tumor type in which the core NER gene ERCC2 is significantly mutated. Analysis of three independent urothelial tumor cohorts reveals a strong association between somatic ERCC2 mutations and activity of a mutational signature characterized by a broad spectrum of base changes. In addition, we note an association between activity of this signature and smoking that is independent of ERCC2 mutation status, providing genomic evidence of tobacco-related mutagenesis in urothelial cancer. Together, these analyses identify the first NER-related mutational signature and highlight the related roles of DNA damage and subsequent DNA repair in shaping the tumor mutational landscape.