Abstract 869: Characterization of malignant melanoma families with CDK4 germ-line mutation

Background: CDKN2A (p16) and CDK4 are high-risk susceptibility genes for cutaneous melanoma. CDKN2A is the major identified high-risk gene and CDKN2A-mutated families have been extensively characterized. Melanoma families with CDK4 mutation are very rare. Only 10 such families have been published and a systematic investigation of their phenotype is lacking. Aim of study: We evaluated all known CDK4-mutated families with regard to phenotypic features of their melanocytic disease. We also examined if common variants of the melanocortin-1 receptor (MC1R) gene had an effect on age of melanoma onset. Methods: CDK4-melanoma families, previously ascertained by different research groups, were selected for this study either by contacting the authors of published papers or by requests via the GenoMEL Melanoma Genetics Consortium. Phenotypic data related to melanoma and pigmentation were collected via a standardized form. For all family members with available DNA, exon 2 of CDK4 and the complete coding region of the MC1R gene were sequenced. Results: Thirteen CDK4 families (including three unpublished) were enrolled in the study. Altogether, 83 subjects with malignant melanoma, having a total of 125 melanomas, were verified in the pedigrees. The mean and median age of melanoma diagnosis was 38.5 years and 36.5 years, respectively. Of the 83 melanoma-positive subjects, 29 (34.9%) had multiple primary melanoma. Superficially spreading melanoma was the most common histological diagnosis (52.2%). DNA was available from 198 members of the pedigrees, and 81 tested positive for either the CDK4 R24H or R24C mutation; 117 subjects including 39 spouses tested negative. Subjects with the CDK4 mutation or with verified melanoma had a much higher prevalence of atypical nevi (79.5% and 77.2%, respectively) than CDK4-negative family members (26.0%; p