Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma Journal Article
| Authors: | Van Allen, E. M.; Mouw, K. W.; Kim, P.; Iyer, G.; Wagle, N.; Al-Ahmadie, H.; Zhu, C.; Ostrovnaya, I.; Kryukov, G. V.; O'Connor, K. W.; Sfakianos, J.; Garcia Grossman, I.; Kim, J.; Guancial, E. A.; Bambury, R.; Bahl, S.; Gupta, N.; Farlow, D.; Qu, A.; Signoretti, S.; Barletta, J. A.; Reuter, V.; Boehm, J.; Lawrence, M.; Getz, G.; Kantoff, P.; Bochner, B. H.; Choueiri, T. K.; Bajorin, D. F.; Solit, D. B.; Gabriel, S.; D'Andrea, A.; Garraway, L. A.; Rosenberg, J. E. |
| Article Title: | Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma |
| Abstract: | Cisplatin-based chemotherapy is the standard of care for patients with muscle-invasive urothelial carcinoma. Pathologic downstaging to pTO/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 pTO/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 identifi ed mutations lead to cisplatin sensitivity in vitro . Nucleotide excision repair pathway defects may drive exceptional response to conventional chemotherapy. |
| Journal Title: | Cancer Discovery |
| Volume: | 4 |
| Issue: | 10 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2014-10-01 |
| Start Page: | 1140 |
| End Page: | 1153 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-14-0623 |
| PROVIDER: | scopus |
| PUBMED: | 25096233 |
| PMCID: | PMC4238969 |
| DOI/URL: | |
| Notes: | Export Date: 3 November 2014 -- Source: Scopus |
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