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Liu D , Abbosh P , Keliher D , Reardon B , Miao D , Mouw K , Weiner-Taylor A , Wankowicz S , Han G , Teo MY , Cipolla C , Kim J , Iyer G , Al-Ahmadie H , Dulaimi E , Chen DYT , Alpaugh RK , Hoffman-Censits J , Garraway LA , Getz G , Carter SL , Bellmunt J , Plimack ER , Rosenberg JE , Van Allen EM
Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer
Nat Commun. 2017 Dec 19;8(1) :2193
PMID: 29259186    PMCID: PMC5736752   
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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.
2041-1723 Liu, David ORCID: http://orcid.org/0000-0003-0346-5033 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 ORCID: http://orcid.org/0000-0002-5093-6099 Al-Ahmadie, Hikmat Dulaimi, Essel Chen, David Y T Alpaugh, R Katherine Hoffman-Censits, Jean Garraway, Levi A Getz, Gad ORCID: http://orcid.org/0000-0002-0936-0753 Carter, Scott L Bellmunt, Joaquim Plimack, Elizabeth R ORCID: http://orcid.org/0000-0002-7618-0744 Rosenberg, Jonathan E Van Allen, Eliezer M ORCID: http://orcid.org/0000-0002-0201-4444 K08 CA188615/CA/NCI NIH HHS/United States P30 CA006927/CA/NCI NIH HHS/United States P30 CA008748/CA/NCI NIH HHS/United States Journal Article England Nat Commun. 2017 Dec 19;8(1):2193. doi: 10.1038/s41467-017-02320-7.