RT Journal Article
SR Electronic
T1 Melanoma prone families with <em>CDK4</em> germline mutation: phenotypic profile and associations with <em>MC1R</em> variants
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 264
OP 270
DO 10.1136/jmedgenet-2012-101455
VO 50
IS 4
A1 Hanne Eknes Puntervoll
A1 Xiaohong R Yang
A1 Hildegunn Høberg Vetti
A1 Ingeborg M Bachmann
A1 Marie Françoise Avril
A1 Meriem Benfodda
A1 Caterina Catricalà
A1 Stéphane Dalle
A1 Anne B Duval-Modeste
A1 Paola Ghiorzo
A1 Paola Grammatico
A1 Mark Harland
A1 Nicholas K Hayward
A1 Hui-Han Hu
A1 Thomas Jouary
A1 Tanguy Martin-Denavit
A1 Aija Ozola
A1 Jane M Palmer
A1 Lorenza Pastorino
A1 Dace Pjanova
A1 Nadem Soufir
A1 Solrun J Steine
A1 Alexander J Stratigos
A1 Luc Thomas
A1 Julie Tinat
A1 Hensin Tsao
A1 Rūta Veinalde
A1 Margaret A Tucker
A1 Brigitte Bressac-de Paillerets
A1 Julia A Newton-Bishop
A1 Alisa M Goldstein
A1 Lars A Akslen
A1 Anders Molven
YR 2013
UL http://jmg.bmj.com/content/50/4/264.abstract
AB 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&lt;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.