Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer

• Published in: Nature communications Vol. 8; no. 1; pp. 2193 - 11
• Main Authors: 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., Van Allen, Eliezer M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.12.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/2329; 631/67/589/1336; 631/67/69; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers; Biomarkers, Tumor - genetics; Bladder; Bladder cancer; Cancer; Carcinoma - drug therapy; Carcinoma - genetics; Carcinoma - mortality; Carcinoma - pathology; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; Clinical trials; Clonal Evolution - drug effects; Cohort Studies; Cystectomy; DNA Mutational Analysis; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Female; Gene expression; Gene regulation; Heterogeneity; Humanities and Social Sciences; Humans; Immune checkpoint; Invasiveness; Male; Middle Aged; multidisciplinary; Muscles; Mutation; Neoadjuvant Therapy - methods; Neoplasm Invasiveness; Science; Science (multidisciplinary); Spatial heterogeneity; Survival Rate; Transcriptome - genetics; Treatment Outcome; Tumors; Urinary bladder; Urinary Bladder - pathology; Urinary Bladder - surgery; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - mortality; Urinary Bladder Neoplasms - surgery; Whole Exome Sequencing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02320-7

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. The impact of cisplatin-based chemotherapy on tumor genomes is complex. Here, the authors study matched pre- and post-chemotherapy primary samples in muscle-invasive bladder cancer, finding a cisplatin-based mutational signature, and highlighting the impact of intratumor heterogeneity on survival.