Melanoma is the malignancy of the skin with the highest mortality rates of all skin cancers with strongly increasing incidence rates. Apart from environmental factors, genetic risk factors play a causal role for melanoma, especially in familial melanoma, which constitutes about 10% of all cases. CDKN2A is the most prominent familial melanoma gene, with mutations occurring in up to 40% of the families. The aim of this thesis was to identify genetic risk factors in high risk melanoma patients in Austria. First, high risk melanoma patients were examined for copy number variations likely to be responsible for their risk of melanoma. Ten high risk melanoma patients were analyzed using Affymetrix SNP 6.0 genome-wide arrays. Second, germline variants in CDKN2A were determined in 700 individuals (136 from melanoma families, 164 with multiple primary melanomas, 200 with single primary melanomas and 200 healthy individuals). They were Sanger sequenced for CDKN2A exon 1[alpha], 1[beta] and 2. For interpretation of the variants found, a series of computational prediction methods was used in order to estimate pathogenicity of the new mutations. The search for CNVs yielded only limited results, but suggested deletions in intronic regions of the AKT signaling cascade as interesting candidates.
In CDKN2A however, the disease associated variants p.R24P (8x), p.N71T (1x), p.G101W (1x) and p.V126D (1x) in the melanoma families and p.R24P (2x) in the multiple primary melanoma group were discovered.
Furthermore, 6 variants of unknown significance, 2 of which were novel, were identified: p.A34V and c.151-4 G>C. Computational effect prediction tools predicted p.A34V as conferring intermediate risk for melanoma whereas c.151-4 G>C was predicted to be a splice site mutation by MutationTaster, suggesting detrimental effects on gene expression. In summary, p.R24P is the most common high risk variant in Austria.
Furthermore, two new variants, conferring potential risk for melanoma, in the context of familial melanoma, p.A34V and c.151-4 G>C, could be uncovered.