AMPLIFICATION AND OVEREXPRESSION OF MDM2 IN PRIMARY (DE-NOVO) GLIOBLASTOMAS

Glioblastoma multiforme (WHO Grade IV), the most malignant neoplasm of the human nervous system, develops rapidly de novo (primary glioblast oma) or through progression from low-grade or anaplastic astrocytoma ( secondary glioblastoma). We recently reported that mutations of the p5 3 gene are present in more than two-thirds of secondary glioblastomas but rarely occur in primary glioblastomas, suggesting the presence of different genetic pathways (Watanabe et al, Brain Pathol 1996;6:217-24 ). In the present study, primary and secondary glioblastomas were scre ened by immunohistochemistry for MDM2 overexpression and by differenti al PCR for gene amplification. Tumor cells immunoreactive to MDM2 were found in 15 of 29 primary glioblastomas (52%), but in only 3 of 27 se condary glioblastomas (11%; P=0.0015). MDM2 amplification occurred in 2 primary (7%) glioblastomas but in none of the secondary glioblastoma s. Only one out of 15 primary glioblastomas overexpressing MDM2 contai ned a p53 mutation. These results suggest that MDM2 overexpression wit h or without gene amplification constitutes a molecular mechanism of e scape From p53-regulated growth control, operative in the evolution of primary glioblastomas that typically lack p53 mutations.