Molecular Profiling of Bladder Adenocarcinoma Using a National Genomics Repository

Background: Bladder adenocarcinoma (BA) is a rare malignancy, accounting for up to 2% of bladder cancers. Its molecular drivers remain poorly defined, limiting therapeutic options and prognostic assessment. This study characterizes the genomic landscape of BA using a large, multi-institutional sequencing database to identify recurrent alterations and potential therapeutic targets. Methods: Clinical and genomic data for BA were extracted from the AACR Project GENIE® database (accessed July 2025). Samples underwent targeted next-generation sequencing (50–555 genes, >500× coverage). Analyses included somatic mutation frequency, copy number alterations (CNAs), tumor mutational burden (TMB), and stratification by sex, race, and tumor site (primary vs. metastatic). Statistical comparisons used chi-squared, Student’s t-test, or Mann–Whitney U with Benjamini–Hochberg correction. Results: A total of 206 tumor samples from 195 patients were an-alyzed. The cohort was predominantly male (61%) and White (43%). Common somatic point mutations included TP53 (65.0%), KRAS (35.4%), PIK3CA (17.0%), SMAD4 (16.5%), and ARID1A (11.2%). CNAs were frequently affected by CDKN2A (11.6%), CDKN2B (11.6%), and SMAD4 (7.0%). Sex-stratified analysis revealed male enrichment in ARFGAP3, PTEN, LATS2, TSC2, and PRKDC, while CD40, FOXQ1, and WEE1 were observed only in females. Race-based differences included FANCD2 and EGFR en-richment in Asian patients. Co-occurring somatic point mutations were identified between ARID1A–TERT, NSD1–KDM6A, and KRAS–SMAD4, while SMAD4 and KDM6A point mutations demonstrated mutual exclusivity. Discussion: Findings confirm TP53, KRAS, and PIK3CA as recurrently mutated drivers in BA and highlight FGFR3 as a novel re-currently mutated gene, as well as frequent copy number losses involving SMAD4, CDKN2A, and CDKN2B. Subgroup analyses highlight sex- and race-associated muta-tional differences, suggesting potential biologic underpinnings of demographic dispari-ties. Co-occurrence and exclusivity analyses reveal previously unreported interactions, underscoring pathway redundancy and cooperation in tumor progression. Conclusion: This study provides one of the most comprehensive genomic characterizations of BA to date, identifying recurrent drivers, subgroup-specific alterations, and mutational inter-actions. These insights highlight TP53, KRAS, and PIK3CA pathway disruption as central in BA biology and support the development of targeted therapeutics and prospective validation in independent cohorts.