RARE MUTATIONS OF THE GROWTH SUPPRESSOR GENES INVOLVED IN NEGATIVE REGULATION OF THE CELL-CYCLE - P15, P16 AND P18 GENES IN ORAL SQUAMOUS-CELL CARCINOMA

The growth suppressing activity of the retinoblastoma susceptibility g ene product, pRb, is down regulated by cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) whose activity is negatively regulated by CDK inhibi tors of the p16 family. We have previously reported point mutations of the p16/CDKN2 gene in 4 (57%) of 7 oral squamous cell carcinoma (SCC) cell lines. In the current study, we examined the mutational status o f CDK inhibitors, including 3 genes of the p16 family (p16, p15 and p1 8), in 50 human oral SCCs, and also additional results concerning thei r loss of heterozygosity in the regions of the p16, p15 and p18 genes. Our results demonstrated that 2 of 50 (4%) primary oral SCCs had nons ense mutations of the p16 gene, and 2 of 50 (4%) showed frameshift mut ations of the p18 gene. However, we detected no mutation of the p15 ge ne in any of the 50 oral SCCs. In addition, no evidence of hypermethyl ation of the p16 gene was found in our series. To better understand th e extent of alterations affecting chromosomes 9p21 (location of the p1 5/p16 genes) and 1p32 (location of the p18 gene), loss of heterozysity (LOH) on these locations was examined. LOH was detected in 16 of 34 ( 47%) informative samples that had no detectable mutation of the p15/p1 6 genes on 9p21, but we found no LOH at 1p32. These results strongly s uggest that a putative tumor suppressor gene for oral SCC may be prese nt on chromosome 9p21-22, while the p16, p15 and p18 genes play a mino r role in the oncogenesis of this cancer.