Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition

PLoS One. 2015 Mar 24;10(3):e0122662. doi: 10.1371/journal.pone.0122662. eCollection 2015.


Both environmental and host factors influence risk of cutaneous melanoma (CM), and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations. Rare mutations were also seen in CDK4 and BAP1, while MC1R variants were common, occurring at more than twice the frequency compared to Danish controls. The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls. To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Denmark / epidemiology
  • Genes, Neoplasm / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing / standards*
  • Germ-Line Mutation / genetics
  • Humans
  • Melanoma / epidemiology*
  • Melanoma / genetics*
  • Microphthalmia-Associated Transcription Factor
  • Receptor, Melanocortin, Type 1
  • Skin Neoplasms / epidemiology*
  • Skin Neoplasms / genetics*
  • Tumor Suppressor Proteins
  • Ubiquitin Thiolesterase


  • BAP1 protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • Receptor, Melanocortin, Type 1
  • Tumor Suppressor Proteins
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4
  • Ubiquitin Thiolesterase

Grant support

The Nordic Cancer Union provided funds to KW and GJ ( Rigshospitalet funded KW with a PhD scholarship. Fight for sight funded KW ( Aase and Ejnar Danielsens Fund funded KW ( Fonden til lægevidenskabens fremme funded KW ( NH was supported by a fellowship from the National Health and Medical Research Council of Australia. LA was supported by a PhD scholarship from the Australia and New Zealand Banking Group Limited Trustees. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.