CDKN2a/p16INK4a mutations and lack of p19ARF involvement in familial melanoma kindreds

Germline mutations in the cyclin-dependent kinase inhibitor 2a (CDKN2a) gene, which maps to the 9p21 chromosomal region and encodes the cyclin-dependent kinase inhibitor p16INK4a, have been detected in a proportion of familial melanoma kindreds, suggesting that it is the putative 9p21-linked melanoma susceptibility gene. The p19ARF transcript, an alternative spliced form of the CDKN2a gene, has recently been shown to inhibit, like the p16INK4a protein, cell cycle progression, raising the possibility that it might constitute an additional melanoma tumor suppressor gene at the 9p21 locus. To determine the contribution of these candidate genes to familial melanoma genetic predisposition, we screened 10 such kindreds for germline mutations in the p16INK4a and p19ARF genes. Four independent germline missense mutations, mapping in exon 1α (Gly23Asp; Arg24Pro) and exon 2 (Asn71Ileu; Pro114Leu) of the CDKN2a gene, were identified. Two previously described polymorphisms were also detected, Ala148Thr in exon 2 and a base change in the 3′ untranslated region of exon 3. No disease-associated mutations in exon 1β of the p19ARF gene were found. Our data support the hypothesis that the CDKN2a is a melanoma susceptibility gene in familial melanoma, whereas the p19ARF gene does not seem to play a significant role.