Low frequency of MTAP co‐deletion with CDKN2A in peritoneal mesothelioma suggests an independent diagnostic role for MTAP

Aims Loss of MTAP expression by immunohistochemistry (IHC) is widely used as a surrogate for CDKN2A homozygous deletion (HD) in pleural mesothelioma (PM), but its diagnostic value in peritoneal mesothelioma (PeM) is less well defined. We investigated whether the observed limited reliability of MTAP IHC in PeM reflects a lower frequency of MTAP/CDKN2A co‐deletion. Methods and results Twenty‐four PeMs selected from a previously characterized cohort according to CDKN2A and MTAP status underwent MTAP fluorescence in situ hybridization (FISH) using a custom‐made probe. Twenty‐five PMs and 10 reactive mesothelial proliferations (RMPs) were included as external controls. MTAP IHC, CDKN2A FISH and MTAP FISH were evaluated, and concordance was assessed using Cohen's kappa. In PM, MTAP IHC showed perfect concordance with MTAP FISH (kappa = 1.00; p < 0.001) and good concordance with CDKN2A FISH, as did MTAP FISH (kappa = 0.613; p = 0.002). MTAP IHC and FISH showed 100% specificity and 68.8% sensitivity for CDKN2A HD by FISH. In PeM, MTAP IHC remained highly concordant with MTAP FISH (kappa = 0.83; p = 0.001), whereas concordance with CDKN2A FISH was poor and not significant for both MTAP IHC (kappa = 0.21; p = 0.36) and MTAP FISH (kappa = 0.33; p = 0.17). In PeM, MTAP FISH showed 75% specificity and 62.5% sensitivity, MTAP IHC showed 75% specificity and 50% sensitivity for CDKN2A HD by FISH. All RMPs showed complete agreement and full specificity and sensitivity across all assays. Conclusions Our findings indicate that in PeM, MTAP, although a less reliable surrogate for CDKN2A status, may serve as an independent adjunct diagnostic marker. The low concordance between MTAP and CDKN2A alterations suggests a lower rate of co‐deletion and points to potential site‐specific molecular differences.