Molecular Genetics

The first identified melanoma susceptibility gene, located on chromosome 9p21-p13, has been known by many different names: MTS1, INK4A, CDKN2. The currently accepted gene nomenclature is CDKN2A, which stands for cyclin-dependent kinase inhibitor 2A. This locus was mapped by linkage analysis in families in which melanoma was considered the sole phenotype, rather than including a nevus phenotype as well.[13] By using different first exons, exon 1a and 1p, respectively, CDKN2A encodes for two proteins, p16INK4A (commonly referred to as p16) and p14ARF (alternative reading frame). Both proteins are tumor suppressors involved in cell cycle regulation. p16 inhibits phosphorylation (and thereby activation) of the retinoblastoma gene product (pRb) by CDK4 and CDK6. p14ARF inhibits HDM2 degradation of p53. Thus, loss of function of either protein drives cell cycle progression through deregulation of either the pRb or p53 pathways (Fig. 2).

Most germline mutations in CDKN2A are missense mutations found in exons 1 a and exon 2, some of which are recurrent. Because of the low frequency of mutations detected in familial melanoma, mutation analysis has been extended and has led to the finding of mutations in the 5' untranslated region and intronic regions, where they affect splicing (e.g., Refs. [14-16]). Where analyzed, all but one of the recurring mutations within CDKN2A have been shown to be founder mutations. The exception to this rule is a 24-base-pair duplication at the beginning of the coding region, which results in the addition (or in some cases the deletion) of one repeat unit of a naturally occurring 24-base-pair tandem repeat. Haplotype analysis of families carrying this duplication has indicated that the mutation has arisen multiple times, presumably as a result of replication slippage.

Because of the sharing of exon 2, many mutations affecting p16INK4A also affect p14ARF. However, gene defects affecting only p14ARF have been described in some melanoma families[7] thus indicating that the ARF locus is a melanoma susceptibility gene in its own right.

A candidate gene search led to the finding of a second melanoma susceptibility gene, CDK4, on chromosome 12q14.[17] CDK4 mutations have been reported in only three families worldwide, but whereas its role in familial melanoma overall is low, mutations of this gene have similar impact to those in CDKN2A.[18] Phenotypic characteristics of the families carrying CDK4 germline mutations do not differ from CDKN2A-affected families, similarly showing a high penetrance for melanoma in p16

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