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Patterns of CDKN2A Gene Loss in Sequential Oral Epithelial Dysplasias and Carcinomas¹

Faculty of Dentistry [S. A. S., G. B.], and Faculty of Medicine [L. G., D. H.], University of Toronto, Toronto, Ontario M5G1G6, Canada; Department of Stomatology, University of California San Francisco, San Francisco, California 94143 [J. A. R., R. C. K. J.]; and University of Manchester, Manchester M13 9PL, United Kingdom [N. T.]

The CDKN2A gene locus encodes two different proteins derived from alternative splicing. p16 (exons 1, 2, and 3) acts as a G₁ cell cycle regulator, and p14^ARF (exons 1ß, 2, and 3) acts to modulate MDM2-mediated degradation of p53. Inactivation of p16 is a common finding in many cancers; however, there is little data on CDKN2A gene abnormalities in oral precancer. In this longitudinal study, we examined changes in the CDKN2A gene locus in sequential epithelial dysplasias and oral carcinomas from 11 patients. Genomic DNA was extracted from laser-microdissected lesional tissue, and exons 1, 1ß, and 2 were analyzed by duplex PCR. Immunohistochemistry was done to identify p16 and p14^ARF protein expression. Two adjacent polymorphic microsatellite markers were used for allelotyping. Homozygous deletion of exon 1 was identified in 2 of 17 (12%) precancerous lesions. Loss of either exon 1, exon 2, or both was seen in seven of nine (78%) carcinomas. In five of these carcinomas, there was loss of only exon 1. No case showed deletion of exon 1ß. In 5 of 11 patients, microsatellite markers showed differing patterns of allelic imbalance in the precancerous lesions and the subsequent carcinoma, suggesting a complex genetic pattern of progression from dysplasia to carcinoma. We conclude that during oral carcinogenesis homozygous deletion of exon 1 of the CDKN2A gene is common but that deletion of exon 2 and 1ß 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 carcinogenesis.

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