Role of Spatial Heterogeneity in Muscle-Invasive Bladder Cancer on Overall Survival and Immunotherapy Response

Tumor location influences survival in bladder cancer, potentially due to genetic heterogeneity driven by distinct embryological origins and structural compositions. We investigate location-specific somatic gene alterations (GAs) and their potential clinical implications in muscle-invasive bladder cancer (MIBC).

We explored the role of the intra-bladder tumor location in determining survival and underlying genetic alterations in MIBC patients using multiple large independent databases. We analyzed the tumor location's impact on survival using the Surveillance, Epidemiology, and End Results (SEER) database and validated these findings using cBioPortal (CBP), which also contains gene sequencing data, enabling a comparison of GA frequency by tumor location. We investigated GA combinations to identify potential synthetic lethal (SL) combinations and co-occurrence signatures for survival prediction. Using the ROC Plotter database, we explored how significantly altered genes affect the response to immune checkpoint inhibitors (ICI).

An analysis of 6712 SEER and 570 CBP patients revealed significant (p < 0.001) differences in overall survival stratified by tumor location, with trigone tumors showing the worst survival. Genomic analysis identified 35 genes with location-specific alteration frequencies. Three of these genes, CDKN2A, SPTAN1, and BIRC6, were significantly predictive of ICI response, and three genes were uniquely associated with a specific location: BPTF (anterior wall), RYR1, and OBSCN (dome). Furthermore, we identified 349 SL pairs from the 35 significantly altered genes, and a co-occurrence analysis revealed two novel gene pairs associated with improved survival.

Intra-bladder tumor location determines survival and distinct genetic profiles in MIBC. These location-specific alterations predict ICI response and identify novel synthetic lethal targets, guiding precision oncology.