Comprehensive mutational analysis of CDKN2A and CDK4 in Greek patients with cutaneous melanoma.

BACKGROUND: The penetrance of CDKN2A mutations is subject to geographical and latitudinal variation and is presumably dictated by ultraviolet radiation exposure and possibly other co-inherited genetic factors. The frequency of mutations increases with the number of family members affected and the number of primary tumours, and also fluctuates with geography. To date, little is known about the prevalence of CDKN2A mutations in patients with melanoma from Greece. OBJECTIVE: To characterize the frequency of CDKN2A and CDK4 mutations in a hospital-based population of Greek patients with melanoma. METHODS: Three hundred and four consecutive single primary melanoma (SPM), nine familial melanoma (FM) and seven multiple primary melanoma cases (MPM) were assessed for sequence variants in exons 1α, 1ß and 2 of CDKN2A and exon 2 of CDK4. RESULTS: Germline CDKN2A mutations were detected in 10 of 304 SPM (3·3%), in four of seven MPM (57%) and in two of nine FM (22%) cases. The most common mutation was a Northern European allele (p16 p.R24P) detected in eight individuals. Five previously unreported CDKN2A variants were also identified: -34G>C, c.41_43delins20bp, c.301G>C (p.G101R), c.301G>A (p.G101E) and c.296_297insGACC. We also describe the first report of a CDK4 p.R24H substitution in a Greek family. CONCLUSIONS: The Greek population appears to harbour a higher prevalence of the CDKN2A mutation than other reported cohorts. This supports the notion that genetic susceptibility may play a stronger influence in a country with a relatively low incidence of melanoma. Furthermore, the identification of Northern European alleles suggests that gene migration may be responsible, in part, for the observed cases in Greece.

Effect of the histone deacetylase inhibitor trichostatin a in human peripheral blood lymphocytes as a function of donor age.

The histone deacetylase inhibitor trichostatin A (TSA) is a promising agent for the treatment of certain types of cancers alone or in synergistic combination with other anticancer agents. One of the advantages of the use of histone deacetylase inhibitors, such as TSA, is that its effects have been found to be more potent toward cancer cells compared to normal cells. The effect of anticancer agents on the immune system, and on lymphocytes in particular, is of major importance to the success of anticancer regimens. In this respect, information documenting the effect of such agents on normal lymphocytes compared to malignant cells may be of significant value for the successful designing of clinical protocols. Moreover, the parameter of age may be a factor in the differential effects of such protocols. Histone deacetylase inhibitors lead to the accumulation of acetylated histones and, depending on the cell type, may induce either apoptosis, cell cycle arrest, or differentiation. Previous work from our lab has shown that TSA induces the accumulation of histone H4 acetylation and apoptosis in human peripheral blood lymphocytes. In light of the above, we have extended our investigation of the effects of TSA on human lymphocytes to include the parameter of age, which has not been previously studied. Our results show that TSA induces apoptosis of lymphocytes from donors of all age groups, but no age-related changes in the levels of apoptosis are observed.