title: Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors: Section for Pathology, The Gade Institute, University of Bergen, Haukeland University Hospital, N-5021 Bergen, Norway.
authors: Hanne Eknes
authors: HE
authors: Puntervoll
authors: Xiaohong R
authors: XR
authors: Yang
authors: Hildegunn Høberg
authors: HH
authors: Vetti
authors: Ingeborg M
authors: IM
authors: Bachmann
authors: Marie Françoise
authors: MF
authors: Avril
authors: Meriem
authors: M
authors: Benfodda
authors: Caterina
authors: C
authors: Catricalà
authors: Stéphane
authors: S
authors: Dalle
authors: Anne B
authors: AB
authors: Duval-Modeste
authors: Paola
authors: P
authors: Ghiorzo
authors: Paola
authors: P
authors: Grammatico
authors: Mark
authors: M
authors: Harland
authors: Nicholas K
authors: NK
authors: Hayward
authors: Hui-Han
authors: HH
authors: Hu
authors: Thomas
authors: T
authors: Jouary
authors: Tanguy
authors: T
authors: Martin-Denavit
authors: Aija
authors: A
authors: Ozola
authors: Jane M
authors: JM
authors: Palmer
authors: Lorenza
authors: L
authors: Pastorino
authors: Dace
authors: D
authors: Pjanova
authors: Nadem
authors: N
authors: Soufir
authors: Solrun J
authors: SJ
authors: Steine
authors: Alexander J
authors: AJ
authors: Stratigos
authors: Luc
authors: L
authors: Thomas
authors: Julie
authors: J
authors: Tinat
authors: Hensin
authors: H
authors: Tsao
authors: Ruta
authors: R
authors: Veinalde
authors: Margaret A
authors: MA
authors: Tucker
authors: Brigitte
authors: B
authors: Bressac-de Paillerets
authors: Julia A
authors: JA
authors: Newton-Bishop
authors: Alisa M
authors: AM
authors: Goldstein
authors: Lars A
authors: LA
authors: Akslen
authors: Anders
authors: A
authors: Molven
mesh_terms: D000328:Adult; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005091:Exons; D005260:Female; D018095:Germ-Line Mutation; D006200:Hair Color / Q000235:genetics*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D010641:Phenotype; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4
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