Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma.
Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma.
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DOI：
10.1158/2159-8290.cd-14-0623
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发表时间：
2014-10
期刊：
影响因子：
28.2
通讯作者：
Rosenberg JE
中科院分区：
文献类型：
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作者：
Van Allen EM;Mouw KW;Kim P;Iyer G;Wagle N;Al-Ahmadie H;Zhu C;Ostrovnaya I;Kryukov GV;O'Connor KW;Sfakianos J;Garcia-Grossman I;Kim J;Guancial EA;Bambury R;Bahl S;Gupta N;Farlow D;Qu A;Signoretti S;Barletta JA;Reuter V;Boehm J;Lawrence M;Getz G;Kantoff P;Bochner BH;Choueiri TK;Bajorin DF;Solit DB;Gabriel S;D'Andrea A;Garraway LA;Rosenberg JE
以顺铂为基础的化疗是肌肉浸润性尿路上皮癌患者的标准治疗方法。新辅助顺铂化疗后病理降期至pT0/pTis与生存率提高相关，尽管顺铂反应的分子决定因素尚未完全明确。我们对50例接受新辅助顺铂化疗后行膀胱切除术的肌肉浸润性尿路上皮癌患者的治疗前肿瘤和生殖系DNA进行了全外显子组测序（25例为pT0/pTis“反应者”，25例为pT2 +“无反应者”），以识别在反应者中优先出现的体细胞突变。与无反应者相比，核苷酸切除修复基因ERCC2是在顺铂反应者中唯一显著富集突变的基因（q < 0.01）。在ERCC2缺陷细胞系中表达具有代表性的ERCC2突变，与野生型ERCC2相比，未能恢复对顺铂和紫外线的敏感性。ERCC2正常功能的缺失可能有助于尿路上皮癌对顺铂的敏感性，并且体细胞ERCC2突变状态可能为肌肉浸润性尿路上皮癌中含顺铂方案的使用提供参考。
Cisplatin-based chemotherapy is the standard of care for patients with muscle invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, although molecular determinants of cisplatin response are incompletely understood. We performed whole exome sequencing on pre-treatment tumor and germline DNA from 50 patients with muscle invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (25 pT0/pTis “responders”, 25 pT2+ “non-responders”) to identify somatic mutations that occurred preferentially in responders. ERCC2, a nucleotide excision repair gene, was the only significantly mutated gene enriched in the cisplatin responders compared with non-responders (q < 0.01). Expression of representative ERCC2 mutations in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared to wild-type ERCC2. Lack of normal ERCC2 function may contribute to cisplatin sensitivity in urothelial cancer and somatic ERCC2 mutation status may inform cisplatin-containing regimen usage in muscle invasive urothelial carcinoma.