CDKN2 EXPLAINS PART OF THE CLINICAL PHENOTYPE IN DUTCH FAMILIAL ATYPICAL MULTIPLE-MOLE MELANOMA (FAMMM) SYNDROME FAMILIES

Combined multi-point linkage analysis in seven Dutch families with FAM MM syndrome confirmed the location of a melanoma susceptibility (MLM) gene in the 9p21 area. The occurrence of a shared high-risk haplotype in six of the families strongly suggests a founder effect in the Leide n region. No indication for locus heterogeneity was observed. Recently , the CDKN2 (p16) gene, an important regulator of the cell cycle, was isolated from the 9p21 region. A 19-bp germline deletion in the CDKN2 gene was detected in the high-risk haplotype, suggesting CDKN2 to be i dentical to MLM. Loss of heterozygosity studies in melanoma and pancre atic carcinoma from gene carriers strongly support the view that CDKN2 is a general tumour suppressor gene predisposing not only to melanoma but also to other malignancies. Interestingly, the occurrence of appa rent clinical FAMMM cases with melanoma but without the high-risk dele tion haplotype suggests the necessity of additional (naevus) genes to explain the complete FAMMM phenotype.