Liu, DavidAbbosh, PhilipKeliher, DanielReardon, BrendanMiao, DianaMouw, KentWeiner-Taylor, AmaroWankowicz, StephanieHan, GaramTeo, Min YuenCipolla, CatharineKim, JaegilIyer, GopaAl-Ahmadie, HikmatDulaimi, EsselChen, David Y. T.Alpaugh, R. KatherineHoffman-Censits, JeanGarraway, LeviGetz, GadCarter, ScottBellmunt, JoaquimPlimack, Elizabeth R.Rosenberg, Jonathan E.Van Allen, Eliezer2018-01-182017Liu, D., P. Abbosh, D. Keliher, B. Reardon, D. Miao, K. Mouw, A. Weiner-Taylor, et al. 2017. “Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer.” Nature Communications 8 (1): 2193. doi:10.1038/s41467-017-02320-7. http://dx.doi.org/10.1038/s41467-017-02320-7.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34651944Despite 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.en-USJournal Article2018-01-1810.1038/s41467-017-02320-7