Track

Clinical Studies

Abstract

Deletion of the tumor suppressor gene CDKN2A and subsequent loss of its protein, p16, are pivotal events in melanoma progression. The MTAP gene, adjacent to CDKN2A on chromosome 9p21.3, encodes methylthioadenosine phosphorlase, an enzyme vital for adenine and methionine salvage. Both genes are often co-deleted in cancer. Targeted therapies for MTAP-deficient tumors highlight the need for accurate identification of MTAP deficiency. We performed immunohistochemical analyses to assess p16 and MTAP co-expression in 110 melanomas and 57 benign melanocytic nevi using tissue microarrays. Complete loss of p16 expression was observed in 15% (14 of 94) of evaluable melanoma cases, while complete loss of MTAP expression was found in 5% (5 of 106) of cases. All MTAP-deficient melanomas with evaluable p16-stained cores also exhibited p16 loss (n=4). All benign nevi retained p16 and MTAP expression. Notably, both p16 and MTAP levels were significantly lower in higher-stage (pT3 and pT4) compared to lower-stage (pT1 and pT2) melanomas (p=0.005 for p16 and p=0.03 for MTAP). Loss of p16 expression was significantly correlated with metastatic progression (p=0.0005) and decreased disease-specific survival in primary melanoma (p=0.007). In contrast, loss of MTAP expression did not show significant prognostic value, which may be attributed to the limited sample size. Our study indicates that MTAP is lost in only a subset of p16-deficient melanomas and suggests that p16 loss is not a reliable surrogate marker for MTAP deficiency. The different expression patterns of p16 and MTAP may reflect the complexity of 9p21 gene deletions in melanoma.