Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma.

Abstract

UNLABELLED:

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.

• Authors: 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
• Journal: Cancer discovery (Cancer Discov) Vol. 4 Issue 10 Pg. 1140-53 (Oct 2014) ISSN: 2159-8290 [Electronic] United States
• PMID: 25096233 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Xeroderma Pigmentosum Group D Protein
• Cisplatin

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cisplatin (administration & dosage, therapeutic use)
• Conserved Sequence
• DNA Repair
• Drug Resistance, Neoplasm (genetics)
• Female
• Humans
• Male
• Middle Aged
• Models, Molecular
• Mutation
• Neoadjuvant Therapy
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplasm Staging
• Protein Conformation
• Risk Factors
• Treatment Outcome
• Urologic Neoplasms (drug therapy, genetics, pathology)
• Urothelium (pathology)
• Xeroderma Pigmentosum Group D Protein (chemistry, genetics)