Tumor Predisposing Post-Zygotic Chromosomal Alterations in Bladder Cancer-Insights from Histologically Normal...

Area of Science:

• Oncology
• Genetics
• Cancer Research

Background:

• Bladder urothelial carcinoma (BLCA) is a prevalent cancer with poor survival and a male predominance.
• Field cancerization, the presence of pre-neoplastic changes in histologically normal tissue surrounding a tumor, is implicated in BLCA development.

Purpose of the Study:

• To investigate early autosomal chromosomal alterations and loss of chromosome Y (LOY) in histologically normal urothelium from BLCA patients.
• To identify genomic hotspots associated with BLCA development and assess the prevalence of LOY in different tissue types.

Main Methods:

• Utilized a multi-sample, multi-tissue-per-patient approach analyzing 277 normal urothelium samples, 145 tumors, and 63 blood samples from 52 males and 15 females.
• Employed the Mosaic Chromosomal Alterations (MoChA) pipeline for sensitive detection of post-zygotic chromosomal aberrations and LOY.

Main Results:

• Detected at least one chromosomal alteration in normal urothelium samples from 45% of BLCA patients.
• Identified 16 genomic hotspots with gains, deletions, and copy number neutral loss of heterozygosity (CN-LOH), including known and novel BLCA driver genes.
• Observed significant prevalence of LOY-cells: 29% in tumors, 27% in blood, and 18% in normal urothelium.

Conclusions:

• The study demonstrates the capability to characterize early genomic alterations in urothelium preceding BLCA.
• Frequent LOY in both tumor and normal urothelium-derived tissues suggests its potential involvement in the pathogenesis of bladder cancer.