REAPPRAISAL OF P53 MUTATIONS IN HUMAN-MALIGNANT ASTROCYTIC NEOPLASMS BY P53 FUNCTIONAL ASSAY - COMPARISON WITH CONVENTIONAL STRUCTURAL-ANALYSES

We previously reported clonal expansion of p53 mutations in malignant astrocytic tumors detected with a yeast p53 functional assay that meas ures mutant p53 alleles quantitatively and loss of p53 transcriptional competence qualitatively (Tada et al., Int J Cancer 67:447-450, 1996) . This method selectively detects inactivating mutations and is relati vely insensitive to contamination of tumor samples with normal tissue. To determine whether the mutation frequency and spectrum detected in this way differ from those seen with conventional techniques, 54 malig nant astrocytomas were tested with the yeast assay, and the abnormalit ies detected were characterized by DNA sequencing. Inactivating p53 mu tations were found in 67% of anaplastic astrocytomas and 41% of gliobl astomas. Overall, mutations were found in 48% of tumors, compared with only 29% in previous studies (P<0.005), a difference that probably re flects the greater sensitivity of the yeast assay than of conventional techniques. The frequency of mutations in anaplastic astrocytomas (in our study plus published studies) was significantly higher than in gl ioblastomas (39% vs 29%; P<0.05). This suggests that acquisition of p5 3 mutations is not rate limiting for progression to glioblastoma and t hat many glioblastomas develop by p53-independent pathways. Sequencing of mutant p53 cDNAs rescued from yeast showed that the mutation spect rum for functionally inactive mutants was nearly identical to the spec tra from previous studies on structural mutants, indicating that trans criptional activity is the critical biological target of p53 mutation in malignant astrocytomas. (C) 1997 Wiley-Liss, Inc.