Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma
Eliezer M Van Allen, Kent W Mouw, Philip Kim, Gopa Iyer, Nikhil Wagle, Hikmat Al-Ahmadie, Cong Zhu, Irina Ostrovnaya, Gregory V Kryukov, Kevin W O'Connor, John Sfakianos, Ilana Garcia-Grossman, Jaegil Kim, Elizabeth A Guancial, Richard Bambury, Samira Bahl, Namrata Gupta, Deborah Farlow, Angela Qu, Sabina Signoretti, Justine A Barletta, Victor Reuter, Jesse Boehm, Michael Lawrence, Gad Getz, Philip Kantoff, Bernard H Bochner, Toni K Choueiri, Dean F Bajorin, David B Solit, Stacey Gabriel, Alan D'Andrea, Levi A Garraway, Jonathan E Rosenberg, Eliezer M Van Allen, Kent W Mouw, Philip Kim, Gopa Iyer, Nikhil Wagle, Hikmat Al-Ahmadie, Cong Zhu, Irina Ostrovnaya, Gregory V Kryukov, Kevin W O'Connor, John Sfakianos, Ilana Garcia-Grossman, Jaegil Kim, Elizabeth A Guancial, Richard Bambury, Samira Bahl, Namrata Gupta, Deborah Farlow, Angela Qu, Sabina Signoretti, Justine A Barletta, Victor Reuter, Jesse Boehm, Michael Lawrence, Gad Getz, Philip Kantoff, Bernard H Bochner, Toni K Choueiri, Dean F Bajorin, David B Solit, Stacey Gabriel, Alan D'Andrea, Levi A Garraway, Jonathan E Rosenberg
Abstract
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 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.
Conflict of interest statement
Conflict of Interest Statement: Dr. Rosenberg is a consultant for Boerhinger Ingelheim, Bristol Myers Squib, Oncogenex, Onyx, Johnson and Johnson, and Dendreon. Dr. Garraway and Dr. Wagle are equity holders in and consultants to Foundation Medicine. Dr. Garraway is a consultant to Novartis, Millenium/Takeda, and Boehringer Ingelheim, and a recipient of a sponsored research grant from Novartis. Drs. Rosenberg, Garraway, Van Allen, Mouw, Wagle, and D’Andrea have a patent pending for the relationship between somatic ERCC2 mutations and cisplatin response.
©2014 American Association for Cancer Research.
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Source: PubMed