NOVEL MUTATIONS IN THE P16 CDKN2A BINDING REGION OF THE CYCLIN-DEPENDENT KINASE-4 GENE/

Mutations in genes that lie in the retinoblastoma pathway have been im plicated in the pathogenesis of many tumor types, Two critical compone nts that determine progression from G(1) to S include p16/CDKN2A and C DK4 Alterations in p16/CDKN2A have been well documented in multiple ca ncers, including melanoma, However, changes in CDK4 are apparently mor e rare. Only two alterations, both at codon 24, have been identified i n CDK4: an activating arginine-to-cysteine transition and a germ-line arginine-to-histidine substitution in one French kindred, In a survey of 20 neuroblastomas, 17 uncultured metastatic melanomas, 33 unculture d primary uveal melanomas, 8 colon cancer cell lines, and 20 primary c olon cancer samples, we found no evidence of mutations in exon 2 of CD K4. From our cell lines derived from metastatic melanomas, we detected two alterations in the functionally critical exon 2 of CDK4: a lysine -to-glutamine transition at codon 22 and the arginine-to-histidine mut ation at codon 24. These findings document several novel changes in th e p16-binding region of CDK4.