Patterns of CDKN2A gene loss in sequential oral epithelial dysplasias and carcinomas

The CDKN2A gene locus encodes two different proteins derived from alternati ve splicing. p16 (exons 1 alpha, 2, and 3) acts as a G(1) cell cycle regula tor, and p1(ARF) (exons 1 beta, 2, and 3) acts to modulate MDM2-mediated de gradation of p53, Inactivation of p16 is a common finding in many cancers; however, there is little data on CDKN2A gene abnormalities in oral precance r, In this longitudinal study, we examined changes in the CDKN2A gene locus in sequential epithelial dysplasias and oral carcinomas from II patients. Genomic DNA was extracted from laser-microdissected lesional tissue, and ex ons 1 alpha, 1 beta, and 2 were analyzed by duplex PCR, Immunohistochemistr y was done to identify p16 and p14(ARF) protein expression. Two adjacent po lymorphic microsatellite markers were used for allelotyping, Homozygous del etion of exon 1 alpha was identified in 2 of 17 (12%) precancerous lesions. Loss of either exon la, exon 2, or both was seen in seven of nine (78%) ca rcinomas. In five of these carcinomas, there was loss of only exon 1 alpha. No case showed deletion of exon 1 beta, In 5 of 11 patients, microsatellit e markers showed differing patterns of allelic imbalance in the precancerou s lesions and the subsequent carcinoma, suggesting a complex genetic patter n of progression from dysplasia to carcinoma. We conclude that during oral carcinogenesis homozygous deletion of exon la of the CDKN2A gene is common but that deletion of exon 2 and Ip is less frequent. Moreover, our results suggest that the progression from oral precancer to cancer, in some cases, is more complex genetically than predicted by linear models of carcinogenes is.