ERCC2 helicase domain mutations confer nucleotide excision repair deficiency and drive cisplatin sensitivity in muscle-invasive bladder cancer Journal Article

Authors: Li, Q.; Damish, A. W.; Frazier, Z.; Liu, D.; Reznichenko, E.; Kamburov, A.; Bell, A.; Zhao, H.; Jordan, E. J.; Gao, S. P.; Ma, J.; Abbosh, P. H.; Bellmunt, J.; Plimack, E. R.; Lazaro, J. B.; Solit, D. B.; Bajorin, D.; Rosenberg, J. E.; D'Andrea, A. D.; Riaz, N.; Van Allen, E. M.; Iyer, G.; Mouw, K. W.
Article Title: ERCC2 helicase domain mutations confer nucleotide excision repair deficiency and drive cisplatin sensitivity in muscle-invasive bladder cancer
Abstract: Purpose: DNA-damaging agents comprise the backbone of systemic treatment for many tumor types; however, few reliable predictive biomarkers are available to guide use of these agents. In muscle-invasive bladder cancer (MIBC), cisplatin-based chemotherapy improves survival, yet response varies widely among patients. Here, we sought to define the role of the nucleotide excision repair (NER) gene ERCC2 as a biomarker predictive of response to cisplatin in MIBC. Experimental Design: Somatic missense mutations in ERCC2 are associated with improved response to cisplatin-based chemotherapy; however, clinically identified ERCC2 mutations are distributed throughout the gene, and the impact of individual ERCC2 variants on NER capacity and cisplatin sensitivity is unknown. We developed a microscopy-based NER assay to profile ERCC2 mutations observed retrospectively in prior studies and prospectively within the context of an institution-wide tumor profiling initiative. In addition, we created the first ERCC2-deficient bladder cancer preclinical model for studying the impact of ERCC2 loss of function. Results: We used our functional assay to test the NER capacity of clinically observed ERCC2 mutations and found that most ERCC2 helicase domain mutations cannot support NER. Furthermore, we show that introducing an ERCC2 mutation into a bladder cancer cell line abrogates NER activity and is sufficient to drive cisplatin sensitivity in an orthotopic xeno-graft model. Conclusions: Our data support a direct role for ERCC2 mutations in driving cisplatin response, define the functional landscape of ERCC2 mutations in bladder cancer, and provide an opportunity to apply combined genomic and functional approaches to prospectively guide therapy decisions in bladder cancer. © 2018 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 25
Issue: 3
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2019-02-01
Start Page: 977
End Page: 988
Language: English
DOI: 10.1158/1078-0432.Ccr-18-1001
PUBMED: 29980530
PROVIDER: scopus
Notes: Source: Scopus
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MSK Authors
  1. Dean Bajorin
    411 Bajorin
  2. David Solit
    435 Solit
  3. Nadeem Riaz
    210 Riaz
  4. Gopakumar Vasudeva Iyer
    126 Iyer
  5. Sizhi Gao
    29 Gao
  6. Jonathan Eric Rosenberg
    225 Rosenberg
  7. Jennifer Ma
    34 Ma
  8. Emmet John Jordan
    29 Jordan
  9. Qiang   Li
    8 Li
  10. HuiYong   Zhao
    7 Zhao
  11. Andrew Carmen Bell
    11 Bell