LOSS OF EXPRESSION OF THE P16 CYCLIN-DEPENDENT KINASE INHIBITOR 2 TUMOR-SUPPRESSOR GENE IN MELANOCYTIC LESIONS CORRELATES WITH INVASIVE STAGE OF TUMOR PROGRESSION/

Sporadic and familial malignant melanoma susceptibility has been linke d to defects in the chromosomal region 9p21. Recently, a putative 9p21 tumor suppressor gene, the cyclin dependent kinase inhibitor 2 (CDKN2 ) or pld gene, has been shown to be deleted, mutated, or rearranged in a high percentage of sporadic melanoma cell lines, as well as mutated in the germline of a proportion of familial melanoma patients. CDKN2 encodes a M(r) 16,000 protein (p16) that plays a key role in cell cycl e control by binding to the cyclin-dependent kinase 4 enzyme and inhib iting its ability to phosphorylate critical substrates necessary for t ransition past the G(1) phase of the cell cycle. Thus, mutations or de letions of the CDKN2 gene could result in abnormal proliferation via d efective cell cycle control. The correlation of 9p21 cytogenetic and m olecular alterations with the clinical stages of melanoma progression suggests that dysfunction of a gene within this chromosomal region is critical to the evolution of melanoma. However, it remains unclear whe ther this gene is the CDKN2 gene. If so, then loss of p16 is potential ly an initiating or early event in melanoma progression To address the issues of what is the potential involvement of the CDKN2 gene in spor adic melanoma and precisely when during the clinically evident stages of melanoma progression defects in CDKN2, occur, we have evaluated by immunohistochemistry the expression of p16 protein in 103 melanocytic lesions representing all stages in the progression of melanoma. Our re sults suggest that loss of p16 protein expression is (a) not necessary for tumor initiation in malignant melanoma because all melanomas in s itu and the majority of primary invasive melanomas retain expression o f this protein; and (b) potentially more related to invasiveness or th e ability to metastasize, because 52% of primary invasive tumors and 7 2% of metastatic lesions show partial or complete loss of expression o f p16.