ANALYSIS OF P53 MUTATION AND EPIDERMAL GROWTH-FACTOR RECEPTOR AMPLIFICATION IN RECURRENT GLIOMAS WITH MALIGNANT PROGRESSION

Genomic alterations and expression of the p53 tumor suppressor gene an d the epidermal growth factor receptor gene (EGFR) were investigated i n 22 patients with primary World Health Organization (WHO) grade II gl iomas that on recurrence had progressed to malignant gliomas of WHO gr ades III or IV. Mutations of the p53 gene (exons 5 to 8) were found in 12 of 22 primary tumors (10 of 13 astrocytomas, 1 of 7 oligodendrogli omas, 1 of 2 oligoastrocytomas). In each of these cases identical p53 mutations were present in the respective malignant recurrences. In all instances in which the p53 mutation was associated with p53 protein a ccumulation (10 of 12 cases) the percentage of p53 immunopositive tumo r cells had increased from the primary to the recurrent tumor. None of the primary low-grade and none of the recurrent high-grade tumors (7 anaplastic astrocytomas, 10 anaplastic oligodendrogliomas, 4 anaplasti c oligoastrocytomas, and 5 glioblastomas) showed evidence of EGFR gene amplification. Our results thus demonstrate that p53 is mutated in a high fraction of low-grade astrocytomas with progression to anaplastic astrocytomas and glioblastomas and that progression in such cases is frequently associated with an increase in the fraction of p53 immunopo sitive tumor cells. The general absence of EGFR amplification in our t umor series supports the hypothesis that the significance of p53 mutat ion and EGFR amplification may be different in glioblastomas that deve loped by progression from low-grade astrocytomas (secondary glioblasto mas) compared to glioblastomas that developed rapidly in a de novo man ner without a history of previous low-grade tumor (primary glioblastom as).