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

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
2
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Harvard Radiation Oncology Program, Boston, Massachusetts.
3
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Weill Cornell Medical College, Cornell University, New York, New York. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Weill Cornell Medical College, Cornell University, New York, New York. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
7
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
8
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
9
Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
10
Division of Hematology/Oncology, Department of Medicine, University of Rochester Medical Center School of Medicine and Dentistry, Rochester, New York.
11
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
12
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
13
Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Massachusetts General Hospital Cancer Center and Department of Pathology, Boston, Massachusetts.
14
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, Cornell University, New York, New York.
15
Weill Cornell Medical College, Cornell University, New York, New York. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
16
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts. rosenbj1@mskcc.org levi_garraway@dfci.harvard.edu.
17
Weill Cornell Medical College, Cornell University, New York, New York. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. rosenbj1@mskcc.org levi_garraway@dfci.harvard.edu.

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.

PMID:
25096233
PMCID:
PMC4238969
DOI:
10.1158/2159-8290.CD-14-0623
[Indexed for MEDLINE]
Free PMC Article

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