Exposure to ultraviolet radiation (UVR) and the familial melanoma susceptibility gene p16 (CDKN2A) are among the major risk factors which have been identified to contribute to the development of melanoma, and also significantly contribute to squamous cell carcinoma.
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.
Finally, the high rate of p16 mutations in squamous cell carcinomas and the association of p16 with familial melanoma propose p16 as an ideal candidate gene predisposing to familial squamous cell carcinomas.
The clinical utility of genetic testing for hereditary melanoma families is debatable because CDKN2A status may not impact medical management in patients with 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.
Heritable alterations in CDKN2A account for a subset of familial melanoma cases although no robust method exists to identify those at risk of being a mutation carrier.
These data suggest that large deletions/duplications in the CDKN2A locus are infrequently involved in the development of familial melanoma in the Italian population.
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.
This mutation was seen in a patient belonging to a previously reported kindred with hereditary melanoma where this particular germline CDKN2A mutation had been identified.
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.
We compared the gene expression profile of SFs from FM individuals with two distinct CDKN2A/p16 mutations (V126D-p16 and R87P-p16) with the gene expression profile of SFs from age-matched individuals without p16 mutations and with no family history of melanoma.
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.
Little is known about the impact of knowledge of CDKN2A and MC1R genotype on melanoma prevention behaviors like sun avoidance and skin examination in the context of familial melanoma.
Germline CDKN2A mutations affecting p16(INK4a) were detected in 8 unrelated probands (13.6 %), including 7 familial cases and one patient with multiple melanomas; 4 out of 8 mutation carriers met the criteria for familial melanoma and had multiple primary lesions.