Cells with TP53 mutations in low grade astrocytic tumors evolve clonally to malignancy and are an unfavorable prognostic factor

It is important to understand how lon grade tumors recur and progress to ma lignant lesions since this dramatically shortens patient survival. Here, we evaluated the concept that malignant progression and poor prognosis of low grade astrocytic tumors are TP53 dependent through clonal expansion of mut ated cells. TP53 status was established in primary and recurrent tumors fro m 36 patients with WHO grade II astrocytic tumors and two tumor types were found. Tumors from 14 patients (39%; type 1) had TP53 mutated cells, and 92 % of these recurred with 57% progressing to malignancy. The evolution of TP 53 mutated cells before and after progression was examined using a clonal a nalysis procedure in yeast. Malignant progression was accompanied by an inc reased percentage of mutant TP53 (red) yeast colonies resulting from monocl onal expansion of cells with mutated TP53. The presence of TP53 mutations i n WHO grade II astrocytic tumors was associated with malignant progression (P = 0.034, chi(2) test) and shorter progression-free survival (PFS; 47.6+/ -9.6 months for TP53-mutated tumors vs 67.8+/-8.2 months for TP53-wild type tumors, P<0.05, log-rank test). Tumors from 22 patients (61%; type 2) were without TP53 mutations, and 64% of these recurred without a change in TP53 status, although 41% progressed to malignancy. This suggests that TP53 mut ation is not an initiating or progression event in the majority of low grad e astrocytic tamers. Our study also indicates that irradiation for WHO grad e II astrocytic tumors might be associated with Door outcome (P<0.0001) and this was independent of TP53 status. These findings have important implica tions in the clinical management of patients with low grade astocytoma and provide new support to the clonal evolution model for tumor progression.