P16(INK4A) EXPRESSION IS FREQUENTLY DECREASED AND ASSOCIATED WITH 9P21 LOSS OF HETEROZYGOSITY IN SPORADIC MELANOMA

The product of the p16/INK4a/CDKN2/MTS1 tumor-suppressor gene acts as a negative cell cycle regulator by inhibiting G(1) cyclin-dependent ki nases that phosphorylate the retinoblastoma protein. p16 is inactivate d in a wide range of human malignancies, including familial melanoma. However, its expression and function in sporadic melanoma has not been extensively investigated. We studied p16 expression in 62 archival me lanomas and 30 archival nevi and lentigines by immunohistochemistry. E ighteen of 26 (69%) superficial spreading melanomas, 17 of 28 (61%) no dular melanomas, all of three lentigo maligna melanomas, and all of fi ve melanoma metastases were found to harbor less than 10 % p16-positiv e tumor cells. In contrast, only six of 24 (25%) nevi had less than 10 % positive cells. No correlation between tumor thickness and loss of p 16 expression was found. Using DNA from micro-dissected tumor and matc hed normal tissues, five of seven (71%) p16-negative melanoma cases ha d 9p21 loss of heterozygosity (LOH), and one of these 9p21 LOH cases h ad promoter region hypermethylation of the remaining p16 allele. These data demonstrate that partial or complete loss of p16 expression is p revalent in sporadic melanoma and is frequently associated with 9p21 L OH.