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

S. Ali Shahnavaz, G. Bradley, J. A. Regezi, N. Thakker, L. Gao, D. Hogg, R. C K Jordan

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The CDKN2A gene locus encodes two different proteins derived from alternative splicing, p16 (exons 1α, 2, and 3) acts as a G1 cell cycle regulator, and p14ARF (exons 1β, 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-micro-dissected lesional tissue, and exons 1α, 1β, and 2 were analyzed by duplex PCR. Immunohistochemistry was done to identify p16 and p14ARF protein expression. Two adjacent polymorphic microsatellite markers were used for allelotyping. Homozygous deletion of exon 1α was identified in 2 of 17 (12%) precancerous lesions. Loss of either exon 1α, exon 2, or both was seen in seven of nine (78%) carcinomas. In five of these carcinomas, there was loss of only exon 1α. No case showed deletion of exon 1β. 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 1α of the CDKN2A gene is common but that deletion of exon 2 and 1β 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.
    Original languageEnglish
    Pages (from-to)2371-2375
    Number of pages4
    JournalCancer Research
    Volume61
    Issue number6
    Publication statusPublished - 15 Mar 2001

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