MUTATIONS OF THE CDKN2 P16(INK4) GENE IN AUSTRALIAN MELANOMA KINDREDS/

The cyclin dependent kinase inhibitor 2 (CDKN2) gene on chromosome 9p2 1 is potentially involved in the genesis of many cancers and is curren tly under intense investigation as a possible melanoma susceptibility locus. We have analyzed 18 Australian melanoma kindreds for mutations within the coding and neighboring splice junction portions of the CDKN 2 gene. In seven kindreds (including our six largest), CDKN2 mutations were found to segregate with the putative melanoma chromosome previou sly assigned by 9p haplotype analysis. These changes included the dupl ication of a 24 bp repeat, a deleted C residue resulting in the introd uction of a premature stop codon, and four single basepair changes cau sing amino acid substitutions. Mutations segregated to 46 of 51 affect ed individuals in these seven kindreds, with three apparent sporadic c ases in one family and one in each of another two families. Penetrance was variable (55-100%) among the different mutations. These data prov ide additional strong support that the CDKN2 gene is the chromosome 9p 21 familial melanoma locus.