Unravelling bladder cancer in Uganda: insights from the discrepancies in TP53 assessment between immunohistochemistry and whole exome sequencing

Abstract

Background: Bladder cancer (urothelial carcinoma) is highly heterogeneous. Despite several cutting-edge treatment practices, the prognosis of muscle-invasive urothelial carcinoma (MIUC) remains very poor. Immunohistochemistry (IHC) and whole exome sequencing (WES) have been used to understand the heterogeneous nature of this aggressive cancer. Unfortunately, TP53, the guardian of the genome, is the most mutated gene in MIUC. Overexpression of its gene products is a predictor of poor prognosis in urothelial carcinoma. This study assessed TP53 gene mutations and their protein expression using IHC and WES techniques.

Methods: We conducted a cross-sectional study where 50 formalin-fixed paraffin-embedded (FFPE) tissue blocks, processed from biopsy specimens from patients admitted to Mulago National Referral Hospital (MNRH) with MIUC, were consecutively selected and re- examined. TP53 IHC and WES were done according to standard protocols.

Results: All patients presented with haematuria and a bladder mass. The female-to-male ratio was 1:1.5. The mean age of the participants was 59.3 years (standard deviation [SD] 12.9). Using IHC, 26 (52%) of the 50 samples stained positive for TP53, yet only one had a TP53 missense gene mutation at WES.

Conclusion: In this sample of Ugandan patients, mutations in the TP53 gene do not drive MIUC as they do in various parts of the world. The overexpressed TP53 proteins seen at IHC are possibly from the wild-type gene. Therefore, regarding clinical practice, this high discordance between TP53 immunopositivity and TP53 gene mutations for MIUC makes IHC (a cheaper and readily available option in our setting) a poor surrogate for TP53 WES.