Poor Prognosis among Radiation-Associated Bladder Cancer Is Defined by Clinicogenomic Features.

Area of Science:

• Oncology
• Genomics
• Radiation Oncology

Background:

• Prostate cancer radiotherapy (RT) is linked to a higher incidence of secondary bladder cancer.
• Understanding the genomic underpinnings of RT-associated bladder cancer is crucial for risk stratification and prevention.

Purpose of the Study:

• To integrate clinical and genomic data to elucidate the development of bladder cancer following prostate RT.
• To identify specific genetic alterations and mutational signatures associated with RT-induced bladder tumors.

Main Methods:

• Retrospective analysis of 82 patients (41 RT-associated bladder cancer, 41 controls).
• Integration of genomic sequencing data and clinical variables.
• Mutational signature analysis.

Main Results:

• RT-associated tumors showed enrichment for KDM6A and ATM alterations, while control tumors had CDKN2A mutations.
• Increased variant numbers were observed in RT tumors, with lower variant allele frequencies.
• Three predominant mutational signatures were identified, linked to APOBEC3A, smoking/ERCC2, and mismatch repair (MMR).
• Poor prognostic factors included short tumor latency, smoking, specific mutational signatures, and CDKN2A copy number loss.

Conclusions:

• Two potential pathways for RT-associated bladder cancer: field cancerization (smoking/genetic predisposition) leading to aggressive tumors, and RT initiating oncogenesis in healthy urothelium causing less aggressive disease with longer latency.
• Clinicogenomic features can help identify patients at high risk for aggressive bladder cancer post-prostate RT.