Methylthioadenosine Phosphorylase (MTAP) and p16 Expression in Melanocytic Nevi and Melanoma with Molecular Correlation.

Abstract: Homozygous deletion of CDKN2A in melanoma is common, but loss of p16 expression by immunohistochemistry is an imperfect surrogate marker for CDKN2A deletion. Methylthioadenosine phosphorylase (MTAP), located at the same chromosomal locus as CDKN2A (9p21.3), is frequently codeleted. Recently, protein arginine methyltransferase 5 (PRMT5), a downstream effector of MTAP, has emerged as a therapeutic target, and loss of MTAP expression may both inform and enhance the use of PRMT5 inhibitors. We evaluate the expression of MTAP in nevi and melanomas, comparing it with p16 as a diagnostic surrogate for CDKN2A deletion, and evaluating its utility as a marker for MTAP locus deletion. We included 45 nevi and 70 melanomas, with correlation of p16 and MTAP expression to CDKN2A and MTAP locus status in 63 melanoma cases. Most nevi (71%) showed a mosaic pattern of p16 expression, whereas 100% of nevi showed retained expression of MTAP. In melanoma, 59% of cases showed loss of p16, and 10% showed loss of MTAP. p16 had a moderate sensitivity (82%) and negative predictive value (NPV; 87%) and low specificity (43%) and positive predictive value (PPV; 35%) for detection of CDKN2A homozygous deletion. In contrast, MTAP loss was 100% specific for homozygous deletion of CDKN2A, with a PPV of 100%, sensitivity of 41%, and NPV of 82%. Complete loss of p16 expression was seen in 90% of melanomas with single copy CDKN2A deletion, whereas MTAP showed retained or mosaic expression in 100% of these cases. These findings support the use of MTAP as a surrogate marker for the homozygous deletion of CDKN2A in melanoma. Furthermore, loss of MTAP expression also strongly correlates with homozygous deletion of the MTAP locus with 100% specificity, 70% sensitivity, and a PPV of 100% and NPV of 93%. This finding may have implications for the susceptibility of melanoma to PRMT5 and related inhibitors. Methylthioadenosine Phosphorylase (MTAP) and p16 Expression in Melanocytic Nevi and Melanoma with Molecular Correlation.