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.
The risk of identifying a CDKN2A germline mutation increases with the number of primary melanomas and with the presence of familial history of melanoma.
Recently, the cyclin D-dependent kinase inhibitors (CDKIs) p16INK4a and p15INK4b have been localized within chromosome 9p21, and the presence of p16INK4a point mutations has been demonstrated in familial melanoma and melanoma cell lines in vitro.
MeWo cells, which alone expressed intrinsic wild-type p16 among six melanoma cell lines examined, showed higher radiosensitivity in comparison with the other five melanoma cells.
Rare high-penetrance factors are expressed in familial clustering of melanoma and include mutations in CDKN2A (encoding p16(INK4a) and p14(ARF)) and CDK4.
The combination of MMR gene mutations and abnormalities of p16 or other molecular pathways is needed to induce melanocytic carcinogenesis in a familial setting as well as in sporadic MM.
We identified five novel CDKN2A variants (Ala57Gly, Pro81Arg, Ala118Val, Leu130Val, and Arg131Pro) and four that previously have been reported in melanoma families (Glu27X, Met53Ile, Arg87Trp, and Ala127Pro).
The lack of complete concordance between p15 and p16 expression implies that the genes are not functionally redundant and that loss of either gene may be important in the pathogenesis of MM.
We identified germline mutations in highly CM-associated genes (CDKN2A and CDK4) and low/medium-penetrance variants (MC1R and MITF) in patients with multiple primary CMs or individuals with one or more CM and a positive family history for CM or pancreatic cancer among first- or second-degree relatives.
Expression of p16 protein, intragenic mutations of CDKN2A and hypermethylation of CDKN2A promoter region in 41 sporadic primary uveal melanomas were studied.
Similarly, copy number aberrations of CDKN2A by FISH were absent in Spitz nevi but were found in 2 (9.5%) of 21 ASTs and 4 (33%) of 12 spitzoid melanomas.
Diagnosis of melanoma occurred in three of eight kindreds with germline CDKN2A mutations, supporting that families with such mutations are at increased risk for melanoma development.
In Sweden, only a minor portion of such melanoma families carry a mutation in the known melanoma gene CDKN2A, and there is a need to identify additional melanoma susceptibility genes.