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

Melanoma Res. 2013 Jun;23(3):221-6. doi: 10.1097/CMR.0b013e3283608695.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cyclin-Dependent Kinase 4 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Female
  • Founder Effect
  • Genes, p16*
  • Genetic Predisposition to Disease
  • Genotype
  • Germ-Line Mutation*
  • Humans
  • Latvia
  • Male
  • Melanoma / enzymology
  • Melanoma / genetics*
  • Middle Aged
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / genetics*


  • Cyclin-Dependent Kinase Inhibitor p16
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4