Journal
CANCER DISCOVERY
Volume 4, Issue 10, Pages 1140-1153Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-14-0623
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Funding
- Dana-Barber Leadership Council
- American Cancer Society
- Conquer Cancer Foundation
- NIH/National Human Genome Research Institute [U54HG003067]
- Cycle for Survival
- Geoffrey Beene Cancer Research Center
- Starr Cancer Consortium
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Cisplat in-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 pretreatment 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+ nonresponders) 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 nonresponders (q < 0.01). Expression of representative ERCC2 mutants in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared with wild-type ERCC2. The 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. SIGNIFICANCE: Somatic ERCC2 mutations correlate with complete response to cisplatin-based chemosensitivity in muscle-invasive urothelial carcinoma, and clinically identified mutations lead to cisplatin sensitivity in vitro. Nucleotide excision repair pathway defects may drive exceptional response to conventional chemotherapy. (C) 2014 AACR.
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