Melanoma prone families with CDK4 germline mutation: Phenotypic profile and associations with MC1R variants

Hanne Eknes Puntervoll, Xiaohong R. Yang, Hildegunn Hoøberg Vetti, Ingeborg M. Bachmann, Marie Françoise Avril, Meriem Benfodda, Caterina Catricalá, Stéphane Dalle, Anne B. Duval-Modeste, Paola Ghiorzo, Paola Grammatico, Mark Harland, Nicholas K. Hayward, Hui Han Hu, Thomas Jouary, Tanguy Martin-Denavit, Aija Ozola, Jane M. Palmer, Lorenza Pastorino, Dace PjanovaNadem Soufir, Solrun J. Steine, Alexander J. Stratigos, Luc Thomas, Julie Tinat, Hensin Tsao, Ruta Veinalde, Margaret A. Tucker, Brigitte Bressac de Paillerets, Julia A. Newton-Bishop, Alisa M. Goldstein, Lars A. Akslen, Anders Molven

Research output: Contribution to journalArticlepeer-review

101 Citations (Scopus)


CDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma. Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a systematic investigation of their phenotype. All known families with CDK4 germline mutations (n=17) were recruited for the study by contacting the authors of published papers or by requests via the Melanoma Genetics Consortium (GenoMEL). Phenotypic data related to primary melanoma and pigmentation characteristics were collected. The CDK4 exon 2 and the complete coding region of the MC1R gene were sequenced. Eleven families carried the CDK4 R24H mutation whereas six families had the R24C mutation. The total number of subjects with verified melanoma was 103, with a median age at first melanoma diagnosis of 39 years. Forty-three (41.7%) subjects had developed multiple primary melanomas (MPM). A CDK4 mutation was found in 89 (including 62 melanoma cases) of 209 tested subjects. CDK4 positive family members (both melanoma cases and unaffected subjects) were more likely to have clinically atypical nevi than CDK4 negative family members ( p<0.001). MPM subjects had a higher frequency of MC1R red hair colour variants compared with subjects with one tumour (p=0.010). Our study shows that families with CDK4 germline mutations cannot be distinguished phenotypically from CDKN2A melanoma families, which are characterised by early onset of disease, increased occurrence of clinically atypical nevi, and development of MPM. In a clinical setting, the CDK4 gene should therefore always be examined when a melanoma family tests negative for CDKN2A mutation.

Original languageEnglish
Pages (from-to)264-270
Number of pages7
JournalJournal of Medical Genetics
Issue number4
Publication statusPublished - 2013
Externally publishedYes

Field of Science*

  • 1.6 Biological sciences
  • 3.1 Basic medicine

Publication Type*

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database


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