MDM-2 ONCOPROTEIN OVEREXPRESSION IN LARYNGEAL SQUAMOUS-CELL CARCINOMA- ASSOCIATION WITH WILD-TYPE P53 ACCUMULATION

The MDM-2 gene encodes for a nuclear phosphoprotein that binds p53 and inhibits its ability to activate transcription by concealing the p53 activation domain. It has been suggested that MDM-2 overexpression mig ht represent an alternative mechanism by which p53-mediated pathways a re inactivated in human tumors. MDM-2 overexpression can be detected b y immunohistochemical analysis as a result of gene amplification and/o r increased mRNA expression. We studied MDM-2 gene amplification and p rotein overexpression in 46 and 50 cases, respectively, of laryngeal s quamous cell carcinomas previously analyzed for p53 gene alterations. Not one of the cases showed MDM-2 gene amplification, whereas MDM-2 nu clear immunoreactivity was found in 17 tumors (34%). In 10 of these, c oexpression of p53 protein was detectable in the absence of gene mutat ions in exons 5 through 9 (P = .03). Likewise, MDM-2 was also overexpr essed in 18 (46%) of 39 morphologically normal mucosa samples, 15 (50% ) of 30 preneoplastic lesions, and 9 (40%) of 22 cases of severe dyspl asia. Finally, we found no significant correlations between MDM-2 expr ession (neither yet se nor in association with wild-type or mutated p5 3), and the evaluated clinicopathologic parameters of histologic grade , lymph node status, or clinical stage. Our results suggest that MDM-2 gene amplification might not occur in laryngeal carcinomas and that M DM-2 protein overexpression might represent an alternative mechanism b y which p53 is inactivated in the early stages of laryngeal cancer tum origenesis.