PATTERN OF MUTANT P53 EXPRESSION IN HUMAN ASTROCYTOMAS SUGGESTS THE EXISTENCE OF ALTERNATE PATHWAYS OF TUMORIGENESIS

Background. Clinical observations suggest that malignant astrocytomas may arise from well-differentiated, low-grade tumors that have undergo ne anaplastic progression or may develop de novo. Mutations that alter the function of the p53 gene product are thought to play a critical r ole in astrocytoma tumorigenesis. The authors studied the pattern of m utant p53 expression in astrocytomas to define its role in the formati on of malignant tumors by these different pathways. Methods. Tissues f rom 44 astrocytomas corresponding to Grades I-IV of the World Health O rganization (WHO) classification were analyzed for the presence of mut ations in exons 5, 7, and 8 of the p53 gene using single strand confor mation polymorphism (SSCP) and sequence analysis of DNA amplified by t he polymerase chain reaction. Immunostaining for mutant p53 proteins w as performed on tissues fixed in formaldehyde solution and embedded in paraffin; the tissues were from these 44 astrocytomas and another 103 astrocytomas obtained from archival material. Results. Tumors with mu tant p53 genes were reliably identified by immunostaining for mutant p 53 proteins. A higher percentage of astrocytomas of histologic Grades II-IV stained positively for p53 than were identified by mutational an alysis. The average ages of patients with Grade III/IV astrocytomas wi th prominent (>10%) p53 staining and those with sparse (<10%) or no p5 3 staining were 44.5, 64.3, and 67.9 years, respectively (P < 0.0001). Conclusions. The pattern of mutant p53 expression is consistent with a role in driving the progression of low-grade astrocytomas to more ma lignant tumors. These results provide a genetic basis for the clinical observation that malignant astrocytomas resulting from anaplastic pro gression occur in a younger patient population than do malignant astro cytomas arising de novo.