title: Genomic characterization of response to chemoradiation in urothelial bladder cancer.
abstract: BACKGROUND
  The authors characterized the genetic landscape of chemoradiation-treated urothelial carcinoma of the bladder (UCB) with the objective of identifying potential correlates of response.
  
  
  METHODS
  Primary tumors with (n = 8) or without (n = 40) matched recurrent tumors from 48 patients who had non-metastatic, high-grade UCB and received treatment primarily with chemoradiation were analyzed using a next-generation sequencing assay enriched for cancer-related and canonical DNA damage response (DDR) genes. Protein expression of meiotic recombination 11 homolog (MRE11), a previously suggested biomarker, was assessed in 44 patients. Recurrent tumors were compared with primary tumors, and the clinical impact of likely deleterious DDR gene alterations was evaluated.
  
  
  RESULTS
  The profile of alterations approximated that of prior UCB cohorts. Within 5 pairs of matched primary-recurrent tumors, a median of 92% of somatic mutations were shared. A median 33% of mutations were shared between 3 matched bladder-metastasis pairs. Of 26 patients (54%) who had DDR gene alterations, 12 (25%) harbored likely deleterious alterations. In multivariable analysis, these patients displayed a trend toward reduced bladder recurrence (hazard ratio, 0.32; P = .070) or any recurrence (hazard ratio, 0.37; P = .070). The most common of these alterations, ERCC2 (excision repair cross-complementation group 2) mutations, were associated with significantly lower 2-year metastatic recurrence (0% vs 43%; log-rank P = .044). No impact of MRE11 protein expression on outcome was detected.
  
  
  CONCLUSIONS
  A similar mutation profile between primary and recurrent tumors suggests that pre-existing, resistant clonal populations represent the primary mechanism of chemoradiation treatment failure. Deleterious DDR genetic alterations, particularly recurrent alterations in ERCC2, may be associated with improved chemoradiation outcomes in patients with UCB. A small sample size necessitates independent validation of these observations. Cancer 2016;122:3715-23. © 2016 American Cancer Society.
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern, Dallas, Texas.
authors.forename: Neil B
authors.identifier: http://orcid.org/0000-0002-6287-3427
authors.initials: NB
authors.lastname: Desai
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sasinya N
authors.initials: SN
authors.lastname: Scott
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Zabor
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: Eugene K
authors.initials: EK
authors.lastname: Cha
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Joseph
authors.initials: J
authors.lastname: Hreiki
authors.affiliation: Department of Urology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: John P
authors.initials: JP
authors.lastname: Sfakianos
authors.affiliation: Weill Cornell Graduate School of Medical Science, Cornell University, New York, New York.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ramirez
authors.affiliation: Weill Cornell Medical College, Cornell University, New York, New York.
authors.forename: Aditya
authors.initials: A
authors.lastname: Bagrodia
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: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
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: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, 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: Michael F
authors.initials: MF
authors.lastname: Berger
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: Weill Cornell Medical College, Cornell University, New York, New York.|Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zelefsky
authors.affiliation: Weill Cornell Medical College, Cornell University, New York, New York.|Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Marisa A
authors.initials: MA
authors.lastname: Kollmeier
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovnaya
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, Cornell University, New York, New York.
authors.forename: Hikmat A
authors.initials: HA
authors.lastname: Al-Ahmadie
authors.affiliation: Weill Cornell Medical College, Cornell University, New York, New York.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, 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: 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
authors.initials: G
authors.lastname: Iyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D059248:Chemoradiotherapy / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D023281:Genomics / Q000379:methods; D006801:Humans; D000076228:MRE11 Homologue Protein; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000628:therapy; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000628:therapy*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D000076228:MRE11 Homologue Protein; D051759:Xeroderma Pigmentosum Group D Protein
keywords: DNA damage response; bladder chemoradiation; bladder preservation; excision repair cross-complementation group 2 (ERCC2); radiation resistance