Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition.

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

doi:10.1371/journal.pone.0122662

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.

Highlights

Cutaneous melanoma (CM) accounts for 95% of melanoma cases and the incidence of CM in Denmark increased by 63.5% for males and 48.5% for females from 2003–2012 [1], makingPLOS ONE | DOI:10.1371/journal.pone.0122662 March 24, 2015Molecular Characterization of Melanoma Cases in DenmarkTrustees
To date there has been no large study of genetic alterations in Danish high-risk melanoma cases, and we were intrigued by a clinical observation of an apparently low frequency of CDKN2A mutations when testing was conducted in a clinical genetic setting
We identified CDKN2A mutations in 3.9% of unrelated high-risk Danish CM cases

Summary

Introduction

Cutaneous melanoma (CM) accounts for 95% of melanoma cases and the incidence of CM in Denmark increased by 63.5% for males and 48.5% for females from 2003–2012 [1], making. Familial melanoma accounts for around 5–10% of CM cases and several high-risk genes have been identified. Families with CDK4 and CDKN2A mutations have similar phenotypes regarding CM, with cases frequently having multiple primary melanoma (MPM), early onset CM, and high numbers of clinically atypical nevi [17]. To date there has been no large study of genetic alterations in Danish high-risk melanoma cases, and we were intrigued by a clinical observation of an apparently low frequency of CDKN2A mutations when testing was conducted in a clinical genetic setting. We examined the frequency of CDKN2A, CDK4, BAP1, MC1R and MITF (p.E318K) mutations in a large sample of Danish high-risk CM and UM cases

Material and Methods

Statistical methods

Results

Discussion