Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition

Karin A W Wadt; Lauren G Aoude; Lotte Krogh; Lone Sunde; Anders Bojesen; Karen Grønskov; Nine Wartacz; Jakob Ek; Morten Tolstrup-Andersen; Mette Klarskov-Andersen; Åke Borg; Steffen Heegaard; Jens F Kiilgaard; Thomas V O Hansen; Kerenaftali Klein; Göran Jönsson; Krzysztof T Drzewiecki; Morten Dunø; Nicholas K Hayward; Anne-Marie Gerdes

doi:10.1371/journal.pone.0122662

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.

Authors

Karin A W Wadt¹, Lauren G Aoude², Lotte Krogh³, Lone Sunde⁴, Anders Bojesen⁵, Karen Grønskov⁶, Nine Wartacz¹, Jakob Ek¹, Morten Tolstrup-Andersen¹, Mette Klarskov-Andersen¹, Åke Borg⁷, Steffen Heegaard⁸, Jens F Kiilgaard⁹, Thomas V O Hansen¹⁰, Kerenaftali Klein², Göran Jönsson⁷, Krzysztof T Drzewiecki¹¹, Morten Dunø¹, Nicholas K Hayward², Anne-Marie Gerdes¹

Affiliations

¹ Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark.
² QIMR Berghofer Medical Research Institute, Brisbane, Australia.
³ Department of Clinical Genetics, University hospital of Odense, Odense, Denmark.
⁴ Department of Clinical Genetics, University hospital of Århus, Århus, Denmark.
⁵ Department of Clinical Genetics, Vejle hospital, Lillebaelt Hospital, Vejle, Denmark.
⁶ Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark; Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
⁷ Department of Oncology, Lund University and Skåne University Hospital, Lund, Sweden.
⁸ Department of Ophthalmology, Glostrup Hospital, University of Copenhagen, Denmark; Eye Pathology Institute, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
⁹ Department of Ophthalmology, Glostrup Hospital, University of Copenhagen, Denmark.
¹⁰ Center for Genomic Medicine, Rigshospitalet, Copenhagen University hospital, Copenhagen, Denmark.
¹¹ Department of Plastic Surgery, Breast Surgery and Burns, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Abstract

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

Substances

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

Grants and funding

The Nordic Cancer Union provided funds to KW and GJ (http://www.ncu.nu/). Rigshospitalet funded KW with a PhD scholarship. Fight for sight funded KW (http://www.vos.dk/). Aase and Ejnar Danielsens Fund funded KW (http://www.danielsensfond.dk). Fonden til lægevidenskabens fremme funded KW (http://www.apmollerfonde.dk/). 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.