Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer Journal Article

   


Authors: Liu, D.; Abbosh, P.; Keliher, D.; Reardon, B.; Miao, D.; Mouw, K.; Weiner-Taylor, A.; Wankowicz, S.; Han, G.; Teo, M. Y.; Cipolla, C.; Kim, J.; Iyer, G.; Al-Ahmadie, H.; Dulaimi, E.; Chen, D. Y. T.; Alpaugh, R. K.; Hoffman-Censits, J.; Garraway, L. A.; Getz, G.; Carter, S. L.; Bellmunt, J.; Plimack, E. R.; Rosenberg, J. E.; Van Allen, E. M.
Article Title: Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer
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. © 2017 The Author(s).
Keywords: mutation; chemotherapy; protein; genomics; tumor; heterogeneity; cells and cell components; cancer
Journal Title: Nature Communications
Volume: 8
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2017-12-19
Start Page: 2193
Language: English
DOI: 10.1038/s41467-017-02320-7
PROVIDER: scopus
PMCID: PMC5736752
PUBMED: 29259186
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85038622849&doi=10.1038%2fs41467-017-02320-7&partnerID=40&md5=543a840ab6d07048f951bdb2402d54a9
Notes: Article -- Export Date: 2 January 2018 -- Source: Scopus
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MSK Authors
  1. Gopakumar Vasudeva Iyer
    345 Iyer
  2. Hikmat Al-Ahmadie
    661 Al-Ahmadie
  3. Jonathan Eric Rosenberg
    513 Rosenberg
  4. Min Yuen Teo
    105 Teo
  5. Catharine Kline Cipolla
    7 Cipolla
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