TY - JOUR
T1 - Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer
AU - Liu, David
AU - Abbosh, Philip
AU - Keliher, Daniel
AU - Reardon, Brendan
AU - Miao, Diana
AU - Mouw, Kent
AU - Weiner-Taylor, Amaro
AU - Wankowicz, Stephanie
AU - Han, Garam
AU - Teo, Min Yuen
AU - Cipolla, Catharine
AU - Kim, Jaegil
AU - Iyer, Gopa
AU - Al-Ahmadie, Hikmat
AU - Dulaimi, Essel
AU - Chen, David Y.T.
AU - Alpaugh, R. Katherine
AU - Hoffman-Censits, Jean
AU - Garraway, Levi A.
AU - Getz, Gad
AU - Carter, Scott L.
AU - Bellmunt, Joaquim
AU - Plimack, Elizabeth R.
AU - Rosenberg, Jonathan E.
AU - Van Allen, Eliezer M.
N1 - Funding Information:
This work was funded by the Starr Cancer Consortium (J.R., E.V.A.), NIH 3P30CA006927-50SD (E.R.P.), NIH/NCI P30 CA008748 (Memorial Sloan Kettering Cancer Center Support Grant), NIH/NCI P30 CEA006927 (Fox Chase Cancer Center Support Grant), K08 CA188615 (E.V.A.), and the Damon Runyon Foundation (E.V.A.).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-02320-7
DO - 10.1038/s41467-017-02320-7
M3 - Article
C2 - 29259186
AN - SCOPUS:85038622849
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2193
ER -