Familial melanoma genes, melanocyte immortalization, and melanoma initiation

Abstract

The most common types of pigmented lesions have been classified by Clark and colleagues into a series of increasingly malignant types. We have proposed a general model for the genetic events underlying this series of lesions and progression from one lesion type to another. The current form of this model, the evidence that gave rise to it, and the areas of uncertainty that remain are presented here. In particular, evidence for the following is discussed: 1. Involvement of the process of cell senescence in the proliferative arrest seen in nevi. 2. A role for apoptosis and keratinocyte-dependence in the flat growth pattern of radial growth-phase melanomas. 3. The genetic suppression of both senescence and apoptosis in more advanced melanomas. The protein p16, encoded by the familial melanoma locus cyclin-dependent kinase inhibitor 2A (CDKN2A), appears to play a central role in the senescence of nevi and probably also in the keratinocyte-dependence of thin melanomas, in interaction with two other key tumor suppressors, retinoblastoma (RB)-1 and p53. © 2006 Humana Press Inc.