title: Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma.
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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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authors.initials: EM
authors.lastname: Van Allen
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Harvard Radiation Oncology Program, Boston, Massachusetts.
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authors.initials: KW
authors.lastname: Mouw
authors.affiliation: Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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authors.initials: P
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Gopa
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Nikhil
authors.initials: N
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authors.affiliation: Weill Cornell Medical College, Cornell University, New York, New York. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Hikmat
authors.initials: H
authors.lastname: Al-Ahmadie
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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authors.initials: C
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authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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authors.lastname: Ostrovnaya
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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authors.initials: GV
authors.lastname: Kryukov
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: O'Connor
authors.affiliation: Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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authors.lastname: Sfakianos
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Rochester Medical Center School of Medicine and Dentistry, Rochester, New York.
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authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Angela
authors.initials: A
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authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sabina
authors.initials: S
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authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Justine A
authors.initials: JA
authors.lastname: Barletta
authors.affiliation: Weill Cornell Medical College, Cornell University, New York, New York. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Victor
authors.initials: V
authors.lastname: Reuter
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Jesse
authors.initials: J
authors.lastname: Boehm
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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authors.lastname: Lawrence
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Massachusetts General Hospital Cancer Center and Department of Pathology, Boston, Massachusetts.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Philip
authors.initials: P
authors.lastname: Kantoff
authors.affiliation: Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, Cornell University, New York, New York.
authors.forename: Bernard H
authors.initials: BH
authors.lastname: Bochner
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: 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.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Bajorin
authors.affiliation: 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.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Harvard Radiation Oncology Program, Boston, Massachusetts.
authors.forename: Alan
authors.initials: A
authors.lastname: D'Andrea
authors.affiliation: 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.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: 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.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use*; D017124:Conserved Sequence; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011487:Protein Conformation; D012307:Risk Factors; D016896:Treatment Outcome; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000473:pathology*; D051759:Xeroderma Pigmentosum Group D Protein / Q000737:chemistry / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D051759:Xeroderma Pigmentosum Group D Protein; D002945:Cisplatin
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