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

## TL;DR

This study shows that the location of a bladder tumor affects survival and treatment response, with specific genetic mutations linked to tumor regions and potential for personalized therapies.

## Contribution

The study identifies location-specific genetic alterations in bladder cancer that predict immunotherapy response and reveal new drug targets.

## Key findings

- Tumors in the trigone region of the bladder are associated with the worst survival outcomes.
- Three genes (CDKN2A, SPTAN1, BIRC6) predict response to immunotherapy based on tumor location.
- Location-specific genetic alterations reveal 349 synthetic lethal gene pairs for potential drug targeting.

## Abstract

Bladder cancer is a complex disease, and our study demonstrates that the specific physical location of a tumor within the bladder (such as the dome or trigone) significantly impacts a patient’s survival and treatment response. By analyzing data from over 7000 patients across large national databases, we found that patients with tumors in the “trigone” region of the bladder had the lowest overall survival rates. Furthermore, we discovered that bladder cancers harbor distinct genetic mutations depending on their anatomical location. Importantly, we found that three of these location-specific altered genes can predict whether a patient is likely to benefit from immunotherapy. By mapping these regional genetic differences, we also identified novel genetic vulnerabilities—known as synthetic lethal combinations—that could be targeted with emerging drugs. Ultimately, considering exactly where a tumor is located inside the bladder can help doctors provide more personalized, effective therapies for patients with muscle-invasive bladder cancer.

Purpose: 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). Methods: 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). Results: 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. Conclusions: 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.