MUTATIONAL STATE OF P16 CDKN2 AND VHL GENES IN SQUAMOUS-CELL CARCINOMA OF THE ORAL CAVITY/

Two new tumor-suppressor genes, the cyclin dependent kinase 4 inhibito r gene (p16/CDKN2) and the von Hippel-Lindau disease gene (VHL), have been cloned and mapped on chromosomes 9p and 3p respectively, where pu tative tumor-suppressor genes of the oral squamous-cell carcinoma (SCC ) may be present. In order to elucidate whether abnormalities of these genes could contribute to the tumorigenesis of oral SCC, genomic DNAs from 62 tissue samples of tumors (32 primary SCCs and 30 pre-cancerou s lesions) and from 7 oral SCC cell lines were examined by polymerase chain reaction-single strand conformation polymorphism analysis and di rect DNA sequencing. Four of 7 (57%) cell lines contained nonsense mut ations or missense mutations in the p16/CDKN2 gene and 2 of 32 (6%) pr imary oral SCCs had nonsense mutations. Particularly, 3 of 4 nonsense mutations detected in the present study were found in codon 80 (CGA--> TGA; Arg-->Stop), suggesting that codon 80 was a mutational hot spot o f the p16/CDKN2 gene. No VHL gene mutation was found in any subject. T hese results suggest that mutation of the VHL gene is not a common fac tor in the development of human oral SCC. In contrast, the p16/CDKN2 g ene may be correlated with the progression of a subtype of this cancer .