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Nat Commun DOI:10.1038/s41467-017-02320-7

Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer.

Publication TypeJournal Article
Year of Publication2017
AuthorsLiu, D, Abbosh, P, Keliher, D, Reardon, B, Miao, D, Mouw, K, Weiner-Taylor, A, Wankowicz, S, Han, G, Teo, MYuen, Cipolla, C, Kim, J, Iyer, G, Al-Ahmadie, H, Dulaimi, E, Chen, DYT, R Alpaugh, K, Hoffman-Censits, J, Garraway, LA, Getz, G, Carter, SL, Bellmunt, J, Plimack, ER, Rosenberg, JE, Van Allen, EM
JournalNat Commun
Date Published2017 Dec 19

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.


Alternate JournalNat Commun
PubMed ID29259186
PubMed Central IDPMC5736752
Grant ListK08 CA188615 / CA / NCI NIH HHS / United States
P30 CA006927 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States