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Please see: J Med Genet 2014;51:214

J Med Genet doi:10.1136/jmedgenet-2012-101455
  • Cancer genetics
  • Original Article

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

Open Access
  1. Anders Molven1,21
  1. 1Section for Pathology, The Gade Institute, University of Bergen, Bergen, Norway
  2. 2Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  3. 3Western Norway Familial Cancer Center, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
  4. 4Department of Dermatology, Haukeland University Hospital, Bergen, Norway
  5. 5AP-HP, Hôpital Cochin-Tarnier, Université Paris Descartes, Paris, France
  6. 6AP-HP, Genetic Department, Bichat Hospital and INSERM U976, Cutaneous Research Center, Paris 7 University, Saint Louis Hospital, Paris, France
  7. 7Department of Dermatologic Oncology, San Gallicano Dermatologic Institute, IRCCS, Rome, Italy
  8. 8Unit of Dermatology, Université Claude Bernard Lyon 1, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Lyon, France
  9. 9Department of Dermatology, Rouen University Hospital, Rouen, France
  10. 10Department of Internal Medicine, University of Genoa and Laboratory of Genetics of Rare Hereditary Cancers, San Martino-IST Research Hospital, Genoa, Italy
  11. 11Medical Genetics, Molecular Medicine Department, Sapienza University, S. Camillo-Forlanini Hospital, Rome, Italy
  12. 12Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Leeds Cancer Research UK Centre, St James's University Hospital, Leeds, UK
  13. 13Queensland Institute of Medical Research, Brisbane, Queensland, Australia
  14. 14Unité de Cancérologie Cutanée, Service de Dermatologie, Bordeaux, France
  15. 15Latvian Biomedical Research and Study Centre, Riga, Latvia
  16. 16Dermato-Oncology Unit, Department of Dermatology, University of Athens Medical School, Andreas Sygros Hospital, Athens, Greece
  17. 17Department of Genetics, Rouen University Hospital, Rouen, France
  18. 18Department of Dermatology, Wellman Center for Photomedicine, MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA
  19. 19Service de Génétique, Département de Biopathologie, Institut de Cancérologie Gustave Roussy, Villejuif and INSERM U946, Bâtiment IGM, Fondation Jean Dausset, Paris, France
  20. 20Centre for Cancer Biomarkers, The Gade Institute, University of Bergen, Bergen, Norway
  21. 21Department of Pathology, Haukeland University Hospital, Bergen, Norway
  1. Correspondence to Professor Anders Molven, Section for Pathology, The Gade Institute, University of Bergen, Haukeland University Hospital, N-5021 Bergen, Norway; anders.molven{at}
  • Received 29 November 2012
  • Revised 21 December 2012
  • Accepted 24 December 2012
  • Published Online First 5 February 2013


Background 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.

Methods 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.

Results 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).

Conclusion 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.

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