ANALYSIS OF THE CDKN2A, CDKN2B AND CDK4 GENES IN 48 AUSTRALIAN MELANOMA KINDREDS

Germline mutations within the cyclin-dependent kinase inhibitor 2A (CD KN2A) gene and one of its targets, the cyclin dependent kinase 4 (CDK4 ) gene, have been identified in a proportion of melanoma kindreds, In the case of CDK4, only one specific mutation, resulting in the substit ution of a cysteine for an arginine at codon 24 (R24C), has been found to be associated with melanoma. We have previously reported the ident ification of germline CDKN2A mutations in 7/18 Australian melanoma kin dreds and the absence of the R24C CDK4 mutation in 21 families lacking evidence of a CDKN2A mutation. The current study represents an expans ion of these efforts and includes a total of 48 melanoma families from Australia. All of these families have now been screened for mutations within CDKN2A and CDK4, as well as for mutations within the CDKN2A ho molog and 9p21 neighbor, the CDKN2B gene, and the alternative exon 1 ( E1 beta) of CDKN2A. Families lacking CDKN2A mutations, but positive fo r a polymorphism(s) within this gene, were further evaluated to determ ine if their disease was associated with transcriptional silencing of one CDKN2A allele, Overall, CDKN2A mutations were detected in 3/30 (10 %) of the new kindreds. Two of these mutations have been observed prev iously: a 24 bp duplication at the 5' end of the gene and a G to C tra nsversion in exon 2 resulting in an M53I substitution. A novel G to A transition in exon 2, resulting in a D108N substitution was also detec ted, Combined with our previous findings, we have now detected germlin e CDKN2A mutations in 10/48 (21%) of our melanoma kindreds, In none of the 'CDKN2A-negative' families was melanoma found to segregate with e ither an untranscribed CDKN2A allele, an R24C CDK4 mutation, a CDKN2B mutation, or an E1 beta mutation. The last three observations suggest that these other cell cycle control genes (or alternative gene product s) are either not involved at all, or to any great extent, in melanoma predisposition.