Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer. Academic Article uri icon

Overview

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.

publication date

  • December 19, 2017

Research

keywords

  • Antineoplastic Combined Chemotherapy Protocols
  • Carcinoma
  • Clonal Evolution
  • Drug Resistance, Neoplasm
  • Urinary Bladder
  • Urinary Bladder Neoplasms

Identity

PubMed Central ID

  • PMC5736752

Scopus Document Identifier

  • 85038622849

Digital Object Identifier (DOI)

  • 10.1093/bioinformatics/btp543

PubMed ID

  • 29259186

Additional Document Info

volume

  • 8

issue

  • 1