{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T01:15:41Z","timestamp":1788311741983,"version":"build-2803163510"},"reference-count":25,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2016,8,1]],"date-time":"2016-08-01T00:00:00Z","timestamp":1470009600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Marie-Jos\u00e9e and Henry R. Kravis Center for Molecular Oncology"},{"name":"National Cancer Institute Cancer Center Core","award":["P30 CA008748"],"award-info":[{"award-number":["P30 CA008748"]}]},{"name":"Cycle for Survival"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>The authors characterized the genetic landscape of chemoradiation\u2010treated urothelial carcinoma of the bladder (UCB) with the objective of identifying potential correlates of response.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Primary tumors with (n\u2009=\u20098) or without (n\u2009=\u200940) matched recurrent tumors from 48 patients who had non\u2010metastatic, high\u2010grade UCB and received treatment primarily with chemoradiation were analyzed using a next\u2010generation sequencing assay enriched for cancer\u2010related 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>The profile of alterations approximated that of prior UCB cohorts. Within 5 pairs of matched primary\u2010recurrent tumors, a median of 92% of somatic mutations were shared. A median 33% of mutations were shared between 3 matched bladder\u2010metastasis 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; <jats:italic>P<\/jats:italic>\u2009=\u2009.070) or any recurrence (hazard ratio, 0.37; <jats:italic>P<\/jats:italic>\u2009=\u2009.070). The most common of these alterations, <jats:italic>ERCC2<\/jats:italic> (excision repair cross\u2010complementation group 2) mutations, were associated with significantly lower 2\u2010year metastatic recurrence (0% vs 43%; log\u2010rank <jats:italic>P<\/jats:italic>\u2009=\u2009.044). No impact of MRE11 protein expression on outcome was detected.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>A similar mutation profile between primary and recurrent tumors suggests that pre\u2010existing, resistant clonal populations represent the primary mechanism of chemoradiation treatment failure. Deleterious DDR genetic alterations, particularly recurrent alterations in <jats:italic>ERCC2<\/jats:italic>, may be associated with improved chemoradiation outcomes in patients with UCB. A small sample size necessitates independent validation of these observations. <jats:bold><jats:italic>Cancer<\/jats:italic> 2016;122:3715\u201023.<\/jats:bold> \u00a9 <jats:italic>2016 American Cancer Society<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.30219","type":"journal-article","created":{"date-parts":[[2016,8,2]],"date-time":"2016-08-02T14:04:59Z","timestamp":1470146699000},"page":"3715-3723","source":"Crossref","is-referenced-by-count":57,"title":["Genomic characterization of response to chemoradiation in urothelial bladder cancer"],"prefix":"10.1002","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6287-3427","authenticated-orcid":false,"given":"Neil B.","family":"Desai","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology University of Texas Southwestern Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sasinya N.","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Pathology Memorial Sloan Kettering Cancer Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily C.","family":"Zabor","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene K.","family":"Cha","sequence":"additional","affiliation":[{"name":"Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center New York New York"},{"name":"Weill Cornell Medical College Cornell University New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Hreiki","sequence":"additional","affiliation":[{"name":"Department of Pathology Memorial Sloan Kettering Cancer Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Sfakianos","sequence":"additional","affiliation":[{"name":"Department of Urology Icahn School of Medicine at Mount Sinai New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Weill Cornell Graduate School of Medical Science Cornell University New York New York"},{"name":"Marie\u2010Jos\u00e9e and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditya","family":"Bagrodia","sequence":"additional","affiliation":[{"name":"Weill Cornell Medical College Cornell University New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan E.","family":"Rosenberg","sequence":"additional","affiliation":[{"name":"Weill Cornell Medical College Cornell University New York New York"},{"name":"Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean F.","family":"Bajorin","sequence":"additional","affiliation":[{"name":"Weill Cornell Medical College Cornell University New York New York"},{"name":"Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael F.","family":"Berger","sequence":"additional","affiliation":[{"name":"Department of Pathology Memorial Sloan Kettering Cancer Center New York New York"},{"name":"Marie\u2010Jos\u00e9e and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center New York New York"},{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard H.","family":"Bochner","sequence":"additional","affiliation":[{"name":"Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center New York New York"},{"name":"Weill Cornell Medical College Cornell University New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Zelefsky","sequence":"additional","affiliation":[{"name":"Weill Cornell Medical College Cornell University New York New York"},{"name":"Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa A.","family":"Kollmeier","sequence":"additional","affiliation":[{"name":"Weill Cornell Medical College Cornell University New York New York"},{"name":"Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Ostrovnaya","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hikmat A.","family":"Al\u2010Ahmadie","sequence":"additional","affiliation":[{"name":"Department of Pathology Memorial Sloan Kettering Cancer Center New York New York"},{"name":"Weill Cornell Medical College Cornell University New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Solit","sequence":"additional","affiliation":[{"name":"Weill Cornell Medical College Cornell University New York New York"},{"name":"Marie\u2010Jos\u00e9e and Henry R. 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