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Liu D, Abbosh P, Keliher D, Reardon B, Miao D, Mouw K, Weiner-Taylor A, Wankowicz S, Han G, Teo MY, Cipolla C, Kim J, Iyer G, Al-Ahmadie H, Dulaimi E, Chen DY, Alpaugh RK, Hoffman-Censits J, Garraway LA, Getz G, Carter SL, Bellmunt J, Plimack ER, Rosenberg JE, Van Allen EM
Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer
Nat Commun (2017) 8:2193.
Abstract
Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts worse overall survival, and further observe alterations in cell-cycle and immune checkpoint regulation genes in post-treatment tumors. These results provide insight into the clinical and genomic dynamics of tumor evolution with cisplatin-based chemotherapy, suggest mechanisms of clinical resistance, and inform development of clinically relevant biomarkers and trials of combination therapies.
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Publication Date: 2017-12-19.
PMCID: PMC5736752
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