Melanoma

The frequency of p53 mutations detected in melanoma has been generally reported to be lower than in other tumor types. The most common mechanism determining alterations in the p53 pathway in melanoma is represented by the homozygous deletion of the alternative reading frame (ARF) and p16 genes as the result of CDKN2A locus injury. Since ARF preserves the functional activity of p53, whereas p16 is more relevant for retinoblastoma (RB), deletions involving CDKN2A exons can theoretically disrupt both regulatory pathways. But if homozygous deletions of exons 1 and 1 (or 1 and 2) of CDKN2A affect both p16 and ARF, the effects of point mutations occurring in exon 2 are less clear, since few of them have been functionally characterized for their effect on ARF, thus leaving doubts on the real need of p53 pathway inactivation. Nonetheless, concomitant mutations in TP53 and p16 genes have been reported in some melanoma cell lines and, in a recent study, we found TP53 mutations either concomitant or alternative with respect to those of the CDKN2A locus, the latter always being associated with BRAF mutations. Of note, this mutational profile is preferentially found in poorly surviving patients .

The role of the p53 pathway in melanoma; mutations at the TP53 gene are confirmed in 25% of melanomas, as also reported in other studies. Several other findings suggest a role for p53 in melanoma: (a) animal studies showing that p53 and BRAF pathways interact genetically to produce melanoma, (b) human melanocytes in which both RB and p53 pathways are inactivated along with induction of hTERT constitutive activity, are prone to transformation by activated RAS and show invasive growth in human skin transplanted in mice, and (c) the analysis of TP53 polymorphism at codon 72 indicates p53 gene involvement in melanoma risk.

As a note of caution, we should mention that since studies have been performed on melanoma cell lines and mutated TP53 is known to facilitate the in vitro establishment of cell lines from tumor specimens, an overestimation of the reported frequencies of TP53 alterations in these studies cannot be ruled out. What about the 15%–20% melanomas not showing these patterns of genetic alterations? An obvious answer is that since p16 is generally not expressed, these samples may require more detailed analysis in the p53 gene or, alternatively, the assessment of ARF methylation status.