Amplification and Overexpression of MDM2 in Primary (de novo) Glioblastomas

Abstract

Glioblastoma multiforme (WHO Grade IV), the most malignant neoplasm of the human nervous system, develops rapidly de novo (primary glioblastoma) or through progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). We recently reported that mutations of the p53 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 screened by immunohistochemistry for MDM2 overexpression and by differential PCR for gene amplification. Tumor cells immunoreactive to MDM2 were found in 15 of 29 primary glioblastomas (52%), but in only 3 of 27 secondary glioblastomas (11%; P=0.0015). MDM2 amplification occurred in 2 primary (7%) glioblastomas but in none of the secondary glioblastomas. Only one out of 15 primary glioblastomas overexpressing MDM2 contained a p53 mutation. These results suggest that MDM2 overexpression with or without gene amplification constitutes a molecular mechanism of escape from p53-regulated growth control, operative in the evolution of primary glioblastomas that typically lack p53 mutations.