MTAP Expression by Immunohistochemistry: A Novel Biomarker in NSCLC

INTRODUCTION: Loss of MTAP serves as a potential predictive marker of response to cooperative PRMT5 inhibitors and as a negative predictor of response to immune checkpoint inhibitors. We investigated the prevalence of MTAP deficiency by immunohistochemistry (IHC) in NSCLC as a surrogate for MTAP loss. METHODS: MTAP IHC was performed on 698 NSCLC samples. Data from routine next-generation sequencing, analyzed with the Oncomine Precision Assay (OPA-NGS, Thermo Fisher), were available in 426 cases, including CDKN2A copy number variation (CNV) data in 411 cases. Our findings were compared with data from The Cancer Genome Atlas (TCGA). RESULTS: MTAP deficiency by IHC was found in 18.2% of NSCLC. CDKN2A loss by OPA-NGS, used as a surrogate for MTAP loss, was significantly associated with MTAP deficiency by IHC, but it was found in only 28.4% of the MTAP-deficient NSCLC analyzed for CDKN2A CNV. In the TCGA cohort, only 72.9% of NSCLC with CDKN2A loss had a concurrent MTAP loss defined by CNV. CONCLUSION: MTAP IHC seems to be better suited than OPA-NGS to assess the MTAP status in NSCLC, especially as the MTAP gene is not specifically covered within this panel. CDKN2A loss is not a reliable MTAP loss surrogate, as it overestimates MTAP loss in more than 25% of the cases in the TCGA cohort.