The recent detection of p16INK4 (MTS1) mutations in familial melanoma kindreds, many human tumour cell lines, and primary tumours is consistent with this idea.
A deletion in the second exon of the CDK4I gene was found in one germline allele of a familial melanoma patient from a family with eight affected first degree relatives.
A locus for familial melanoma, MLM, has been mapped within the same interval on chromosome 9p21 as the gene for a putative cell cycle regulator, p16INK4 (CDKN2) MTS1.
Together with other recent reports, these findings provide support for CDKN2 as a susceptibility locus for familial melanoma but suggest that other loci are involved in some hereditary melanoma kindreds.
Germ-line mutations in the cyclin-dependent kinase (CDK) inhibitor p16 have been reported in a subset of melanoma pedigrees, but their prevalence is unknown in more common cases of familial melanoma that do not involve large families with multiple affected members.
Inactivation of the CDKN2A gene (also known as p16INK4A and MTS1) attracted considerable interest after it was mapped to 9p21, a locus for familial melanoma.
Although germline mutations and deletions of the p16INK4 gene located at 9p21 have been reported in familial melanoma, the relative contributions of mutation and deletion in sporadic melanoma are at present unclear.
Moreover, a CDK4 gene mutation, responsible for a functional resistance of CDK4 kinase to p16 inhibitory activity, has been described to occur in some cases of familial melanoma.
In this study, we examined whether two other potential tumor suppressors, CDKN2B and p19ARF, which also map within the 9p21 region, play a role in the development of familial melanoma.
In summary, our results show frequent involvement of the p16 gene in familial melanoma and confirm the role of the CDK4 gene as a melanoma-predisposing gene.
In this article the evidence for the role of CDKN2A in the genesis of familial melanoma is reviewed and the implications of genetic testing in families with this disease are discussed.
The product of the p16/INK4a/CDKN2/MTS1 tumor-suppressor gene acts as a negative cell cycle regulator by inhibiting G1 cyclin-dependent kinases that phosphorylate the retinoblastoma protein. p16 is inactivated in a wide range of human malignancies, including familial melanoma.
Our data support the hypothesis that the CDKN2a is a melanoma susceptibility gene in familial melanoma, whereas the p19ARF gene does not seem to play a significant role.
While a proportion of familial melanoma kindreds exhibit germline mutations in the cell cycle regulatory gene CDKN2A (p16INK4a) or its protein target, cyclin-dependent kinase 4 (CDK4), the biochemical basis of most familial melanoma is unknown.
These recent advances open up the possibility of genetic testing for melanoma susceptibility in the setting of familial melanoma and suggest novel therapeutic strategies for melanoma based on gene therapy or small molecule mimicry targeted to the correction of defects in the p16 regulatory pathway.(J Am Acad Dermatol 2000;42:705-22.)
Additionally, we screened these samples for mutations in CDKN2A, a gene in which alterations are well documented in primary melanoma as well as in the germline of familial melanoma.