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