Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer

David Liu, Philip Abbosh, Daniel Keliher, Brendan Reardon, Diana Miao, Kent Mouw, Amaro Weiner-Taylor, Stephanie Wankowicz, Garam Han, Min Yuen Teo, Catharine Cipolla, Jaegil Kim, Gopa Iyer, Hikmat Al-Ahmadie, Essel Dulaimi, David Y. T. Chen, R. Katherine Alpaugh, Jean Hoffman-Censits, Levi A. Garraway, Gad Getz, Scott L. Carter, Joaquim Bellmunt, Elizabeth R. Plimack (), Jonathan E. Rosenberg () and Eliezer M. Van Allen ()
Additional contact information
David Liu: Dana-Farber Cancer Institute
Philip Abbosh: Fox Chase Cancer Center
Daniel Keliher: Dana-Farber Cancer Institute
Brendan Reardon: Dana-Farber Cancer Institute
Diana Miao: Dana-Farber Cancer Institute
Kent Mouw: Dana-Farber Cancer Institute
Amaro Weiner-Taylor: Broad Institute of Harvard and MIT
Stephanie Wankowicz: Dana-Farber Cancer Institute
Garam Han: Dana-Farber Cancer Institute
Min Yuen Teo: Memorial Sloan Kettering Cancer Center
Catharine Cipolla: Memorial Sloan Kettering Cancer Center
Jaegil Kim: Broad Institute of Harvard and MIT
Gopa Iyer: Memorial Sloan Kettering Cancer Center
Hikmat Al-Ahmadie: Memorial Sloan Kettering Cancer Center
Essel Dulaimi: Fox Chase Cancer Center
David Y. T. Chen: Fox Chase Cancer Center
R. Katherine Alpaugh: Fox Chase Cancer Center
Jean Hoffman-Censits: Thomas Jefferson University Hospital
Levi A. Garraway: Dana-Farber Cancer Institute
Gad Getz: Broad Institute of Harvard and MIT
Scott L. Carter: Dana-Farber Cancer Institute
Joaquim Bellmunt: Dana-Farber Cancer Institute
Elizabeth R. Plimack: Fox Chase Cancer Center
Jonathan E. Rosenberg: Memorial Sloan Kettering Cancer Center
Eliezer M. Van Allen: Dana-Farber Cancer Institute

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02320-7

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