title: Analysis of Latvian familial melanoma patients shows novel variants in the noncoding regions of CDKN2A and that the CDK4 mutation R24H is a founder mutation.
abstract: Hereditary cutaneous melanoma is associated with mutations in the high-risk CDKN2A gene in about 40% of melanoma-prone families. Mutations in the CDK4 gene are the cause in only a few pedigrees. In this study, we analyzed 20 Latvian familial melanoma probands and carried out a comprehensive analysis of CDKN2A including sequencing of its promoter/intronic regions and deletion screening. We also analyzed the critical second exon of the CDK4 gene. One novel intronic variant (IVS2+82C>T) of the CDKN2A gene and a small deletion (c.-20677_-20682delGTACGC) in its promoter region were found. Genotyping of the novel variants in larger melanoma and control groups indicated that the deletion increases the risk of melanoma (odds ratio=6.353, 95% confidence interval: 1.34-30.22, P=0.0168). The CDK4 gene analysis showed a Latvian melanoma family with the mutation R24H carried on the same haplotype as in two previously described Latvian CDK4-positive families. Our study suggests that the main risk gene in Latvian families with a strong family history of melanoma is CDK4 and that most of the other cases analyzed could be sporadic or associated with low-penetrance risk genes.
authors.affiliation: Latvian Biomedical Research and Study Centre, Riga LV-1067, Latvia. ruuta@biomed.lu.lv
authors.forename: Rūta
authors.initials: R
authors.lastname: Veinalde
authors.forename: Aija
authors.initials: A
authors.lastname: Ozola
authors.forename: Kristīne
authors.initials: K
authors.lastname: Azarjana
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
authors.forename: Lars A
authors.initials: LA
authors.lastname: Akslen
authors.forename: Simona
authors.initials: S
authors.lastname: Doniņa
authors.forename: Guna
authors.initials: G
authors.lastname: Proboka
authors.forename: Ingrīda
authors.initials: I
authors.lastname: Cēma
authors.forename: Ainārs
authors.initials: A
authors.lastname: Baginskis
authors.forename: Dace
authors.initials: D
authors.lastname: Pjanova
mesh_terms: D000368:Aged; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005260:Female; D018703:Founder Effect; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007844:Latvia; D008297:Male; D008545:Melanoma / Q000201:enzymology / Q000235:genetics*; D008875:Middle Aged; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4