CDKN2a/p16(INK4a) mutations and lack of 0p19(ARF) involvement in familial melanoma kindreds

Germline mutations in the cyclin-dependent kinase inhibitor 2a (CDKN2a) gen e, which maps to the 9p21 chromosomal region and encodes the cyclin-depende nt kinase inhibitor p16(INK4a), have been detected in a proportion of famil ial melanoma kindreds, suggesting that it is the putative 9p21-linked melan oma susceptibility gene. The p19(ARF) transcript, an alternative spliced fo rm of the CDKN2a gene, has recently been shown to inhibit, like the p16(INK 4a) 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 mutation s in the p16(INK4a) and p19(ARF) genes. Four independent germline missense mutations, mapping in exon 1 alpha (Gly23Asp; Arg24Pro) and exon 2 (Asn71Il eu; Pro114Leu) of the CDKN2a gene, were identified. Two previously describe d polymorphisms were also detected, Ala148Thr in exon 2 and a base change i n the 3' untranslated region of exon 3, No disease-associated mutations in exon 1 beta of the p19(ARF) gene were found. Our data support the hypothesi s that the CDKN2a is a melanoma susceptibility gene in familial melanoma, w hereas the p19(ARF) gene does not seem to play a significant role.