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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MSK Authors
  1. Dean Bajorin
    416 Bajorin
  2. David Solit
    440 Solit
  3. Gopakumar Vasudeva Iyer
    129 Iyer
  4. Bernard Bochner
    327 Bochner
  5. Victor Reuter
    922 Reuter
  6. Philip Hyunwoo Kim
    39 Kim
  7. Jonathan Eric Rosenberg
    227 Rosenberg
  8. Richard Bambury
    29 Bambury