TIMING OF P53 MUTATIONS DURING ASTROCYTOMA TUMORIGENESIS

Using a combination of polymerase chain reaction and single-strand con formation polymorphism techniques (PCR-SSCP) we have analyzed 78 brain tumor samples (70 primary and 8 metastatic) for the presence of mutat ions in the conserved regions of the Tp53 (tumor p53) gene. We have fo und that only two groups, gliomas (exclusively in astrocytomas) and me tastases, displayed Tp53 mutations. Three of eight (37.5%) metastases showed a mutant Tp53 allele accompanied by loss of the normal one. In contrast, the frequency of Tp53 mutations in the primary brain tumors examined was lower (5.7%). Although we have examined different types o f primary brain tumors, Tp53 mutations were exclusively observed in bo th, low and high-grade astrocytomas (four of 24). The Tp53 mutations d etected in astrocytic tumors appear to be correlated with the malignan cy grade. The low-grade astrocytomas were heterozygous for the mutatio n, whereas the high-grade astrocytomas had affected the two Tp53 allel es, suggesting a two-steps model for inactivation of the p53 gene in a strocytomas. Thus, single p53 mutation seems to occur in initial stage s of astrocytoma tumorigenesis; the later lost of the remaining wild-t ype allele appears associated with the progression towards a more mali gnant stage.