Incidence and timing of p53 mutations during astrocytoma progression in patients with multiple biopsies.

Abstract

Mutations of the p53 tumor suppressor gene are a genetic hallmark of human astrocytic neoplasms, but their predictive role in glioma progression is still poorly understood. We analyzed 144 biopsies from 67 patients with recurrent astrocytoma by single-strand conformation polymorphism and direct DNA sequencing. We found that 46 of 67 patients (69%) had a p53 mutation in at least one biopsy. In 41 of these (89%), the mutation was already present in the first biopsy, indicating that p53 mutations are early events in the evolution of diffuse astrocytomas. Double mutations of the p53 gene were observed in three tumors and also present from the first biopsy. Of 28 low-grade astrocytomas with a p53 mutation, 7 (25%) showed loss of the normal allele in the first biopsy. The allele status remained the same in 95% of the cases, irrespective of whether the recurrent lesion had the same or a higher grade of malignancy. Progression of low-grade astrocytomas to anaplastic astrocytoma or glioblastoma occurred at a similar frequency in lesions with (79%) and without (63%) p53 mutations (P = 0.32), indicating that this genetic alteration is associated with tumor recurrence but not predictive of progression to a more malignant phenotype. However, the time interval until progression was shorter in patients with low-grade astrocytomas carrying a p53 mutation (P = 0.055).