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.
Highlights
Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized
We examined a cohort of muscle invasive bladder cancer (MIBC) patients who underwent cisplatin-based neoadjuvant chemotherapy followed by cystectomy and analyzed genomic tumor changes in matched pre- and post-treatment bladder tumor samples
From two prospective clinical trials and a previously published cohort[7,8,9], we identified a cohort of MIBC patients who underwent neoadjuvant cisplatinbased chemotherapy (gemcitabine and cisplatin (GC); or methotrexate, vinblastine, adriamycin, and cisplatin (MVAC)) and subsequent cystectomy
Summary
The genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. We find that posttreatment 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. To further dissect chemotherapy-induced mutations, we perform a mutational signature analysis and discover a novel signature in post-cisplatin-based-chemotherapy tumor samples sharing features with a pre-clinical experimentally derived cisplatininduced mutational signature, and consistent with known characteristics of cisplatin damage and repair We validate this signature in an additional independent cohort of preand post-cisplatin therapy matched urothelial carcinomas. We 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 a Germline DNA
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