Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer.

Authors

David Liu, Dana-Farber Cancer Institute; Broad Institute of Harvard and MIT
Philip Abbosh, Fox Chase Cancer Center
Daniel Keliher, Dana-Farber Cancer Institute; Broad Institute of Harvard and MIT
Brendan Reardon, Dana-Farber Cancer Institute; Broad Institute of Harvard and MIT
Diana Miao, Dana-Farber Cancer Institute; Broad Institute of Harvard and MIT
Kent Mouw, Dana-Farber Cancer Institute
Amaro Weiner-Taylor, Broad Institute of Harvard and MIT
Stephanie Wankowicz, Dana-Farber Cancer Institute; Broad Institute of Harvard and MIT
Garam Han, Dana-Farber Cancer Institute; Broad Institute of Harvard and MIT
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 CenterFollow
David Y.T. Chen, Fox Chase Cancer Center
R. Katherine Alpaugh, Fox Chase Cancer CenterFollow
Jean Hoffman-Censits, Thomas Jefferson UniversityFollow
Levi A. Garraway, Dana-Farber Cancer Institute; Broad Institute of Harvard and MIT
Gad Getz, Dana-Farber Cancer Institute; Broad Institute of Harvard and MIT
Scott L. Carter, Dana-Farber Cancer Institute; Broad Institute of Harvard and MIT
Joaquim Bellmunt, Dana-Farber Cancer Institute; Broad Institute of Harvard and MIT
Elizabeth R. Plimack, Broad Institute of Harvard and MIT; Fox Chase Cancer Center
Jonathan E. Rosenberg, Memorial Sloan Kettering Cancer Center; Thomas Jefferson University
Eliezer M. Van Allen, Dana-Farber Cancer Institute; Broad Institute of Harvard and MIT

Document Type

Article

Publication Date

12-1-2017

Comments

This article has been peer reviewed. It is the author’s final published version in Nature Communications

Volume 8, Issue 1, December 2017, Article number 2193

The published version is available at DOI: 10.1038/s41467-017-02320-7. Copyright © Liu et al.

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.

Recommended Citation

Liu, David; Abbosh, Philip; Keliher, Daniel; Reardon, Brendan; Miao, Diana; Mouw, Kent; Weiner-Taylor, Amaro; Wankowicz, Stephanie; Han, Garam; Teo, Min Yuen; Cipolla, Catharine; Kim, Jaegil; Iyer, Gopa; Al-Ahmadie, Hikmat; Dulaimi, Essel; Chen, David Y.T.; Alpaugh, R. Katherine; Hoffman-Censits, Jean; Garraway, Levi A.; Getz, Gad; Carter, Scott L.; Bellmunt, Joaquim; Plimack, Elizabeth R.; Rosenberg, Jonathan E.; and Van Allen, Eliezer M., "Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer." (2017). Department of Medical Oncology Faculty Papers. Paper 73.
https://jdc.jefferson.edu/medoncfp/73

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

29259186