Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer

Area of Science:

• Oncology
• Genomics
• Cancer Research

Background:

• Cisplatin-based chemotherapy is widely used for muscle-invasive bladder cancer.
• The genomic impact of cisplatin and its effect on subsequent treatments are not fully understood.

Purpose of the Study:

• To analyze the genomic changes in bladder tumors before and after cisplatin-based chemotherapy.
• To investigate the relationship between chemotherapy-induced genomic alterations, tumor heterogeneity, and patient survival.

Main Methods:

• Whole exome sequencing of matched pre- and post-chemotherapy tumor samples from 30 bladder cancer patients.
• Analysis of tumor mutational burden, subclonal mutations, and mutational signatures.
• Correlation of genomic findings with overall survival and gene expression alterations.

Main Results:

• No overall increase in tumor mutational burden post-chemotherapy was observed.
• Significant chemotherapy-induced and spatial tumor heterogeneity was identified.
• A novel cisplatin damage and repair mutational signature was validated in post-treatment tumors.
• Post-treatment tumor heterogeneity predicted worse overall survival.
• Alterations in cell-cycle and immune checkpoint regulation genes were found in post-treatment tumors.

Conclusions:

• Cisplatin chemotherapy induces genomic heterogeneity and specific mutational signatures in bladder tumors.
• Tumor heterogeneity post-cisplatin is associated with poorer survival outcomes.
• These findings offer insights into cisplatin resistance mechanisms and inform biomarker development and combination therapy trials.