MTAP protein status is highly concordant with CDKN2A fluorescent in situ hybridization and allows stratification of the luminal subtype in muscle‐invasive bladder cancer

Aims Loss of heterozygosity in chromosome 9p21, common in urothelial carcinoma (UC), typically involves deletion of CDKN2A and MTAP genes. MTAP loss is emerging as a promising therapeutic target and predictive biomarker in UC. This single‐centrre retrospective study examined the incidence of CDKN2A deletions and MTAP loss in muscle‐invasive bladder cancer (MIBC) and metastatic urothelial carcinoma (mUC), investigating their correlations with clinical, pathological, and genomic features, as well as patient outcomes. Methods Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) were performed on 302 MIBC specimens and 63 biopsy‐proven metachronous urothelial metastases to assess CDKN2A deletions and MTAP protein expression. Results CDKN2A homozygous deletion (HD), identified in 30.3% of MIBCs, and MTAP loss, found in 28.8% of MIBCs, were both significantly associated with the luminal‐URO subtype, FGFR3 mutations, and normal/wildtype p53 IHC ( P < 0.05). Loss of MTAP expression was significantly correlated with CDKN2A HD, with 84.0% sensitivity, 92.3% negative predictive value (NPV), 96.3% specificity, and 91.9% positive predictive value (PPV). MTAP expression was 100% concordant between primary tumours and nodal metastases. Patients with MTAP loss had a higher incidence of visceral metastases (50%) compared to bone/soft tissue (35.7%) and nodes (14.3%). Mean progression‐free survival and overall survival were shorter for patients with MTAP loss, although not statistically significant. Conclusion Our findings highlight CDKN2A HD and MTAP loss as prevalent genetic alterations in MIBC and mUC, particularly within the luminal‐URO subtype and FGFR3 ‐mutated, p53‐normal/wildtype tumours. MTAP IHC can serve as a surrogate marker for 9p21.3 HD, highlighting its clinical relevance and potential as a therapeutic target and predictive biomarker in MIBC.