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

Cancer Discov. 2014 Oct;4(10):1140-53. doi: 10.1158/2159-8290.CD-14-0623. Epub 2014 Aug 5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cisplatin / administration & dosage
  • Cisplatin / 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*
  • Urologic Neoplasms / genetics*
  • Urologic Neoplasms / pathology
  • Urothelium / pathology*
  • Xeroderma Pigmentosum Group D Protein / chemistry
  • Xeroderma Pigmentosum Group D Protein / genetics*


  • Antineoplastic Agents
  • Xeroderma Pigmentosum Group D Protein
  • Cisplatin