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

Oncogene volume 18, pages 5870–5878 (1999)Cite this article

Abstract

It is important to understand how low grade tumors recur and progress to malignant 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 mutated cells. TP53 status was established in primary and recurrent tumors from 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 TP53 mutated cells before and after progression was examined using a clonal analysis procedure in yeast. Malignant progression was accompanied by an increased percentage of mutant TP53 (red) yeast colonies resulting from monoclonal expansion of cells with mutated TP53. The presence of TP53 mutations in WHO grade II astrocytic tumors was associated with malignant progression (P=0.034, χ2 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 mutation is not an initiating or progression event in the majority of low grade astrocytic tumors. Our study also indicates that irradiation for WHO grade II astrocytic tumors might be associated with poor outcome (P<0.0001) and this was independent of TP53 status. These findings have important implications in the clinical management of patients with low grade astocytoma and provide new support to the clonal evolution model for tumor progression.

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Acknowledgements

We would like to thank Y Sawamura and H Abe for providing resources and continuous encouragement, Dr RD Iggo and Dr A Estreicher for assistance with the setup of the yeast assay, A-C Diserens for excellent technical assistance, and Drs C Calkins, D Phelps, L Matthews, and JJ Olson for critically reading the manuscript. This work was made possible by grants 4037-044729 and 31-49194.96 from the Swiss National Science Foundation (to EG Van Meir) and grant KFS 172-9-1995 from the Swiss Cancer Research Foundation (to EG Van Meir), the Théodore Ott Foundation (to K Meagher-Villemure), the Irène Nada Andrée Chuard-Schmidt Foundation (to K Meagher-Villemure) and support from MBNA, N.A. (to the Laboratory of Molecular Neuro-Oncology).

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Authors and Affiliations

  1. Department of Neurosurgery, Laboratory of Tumor Biology and Genetics, University Hospital (CHUV), Lausanne, 1011, Switzerland

    Nobuaki Ishii, Marie-France Hamou, Kathleen Meagher-Villemure, Nicolas de Tribolet & Erwin G Van Meir

  2. Department of Neurosurgery, University of Hokkaido School of Medicine, Sapporo, 060, Japan

    Nobuaki Ishii & Mitsuhiro Tada

  3. Division of Neuropathology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, CH-1011, Switzerland

    Robert C Janzer & Kathleen Meagher-Villemure

  4. Department of Neuropathology, University of Bonn Medical Center, Bonn, D-53105, Germany

    Otmar D Wiestler

  5. Department of Neurological Surgery and Winship Cancer Center, Laboratory of Molecular Neuro-Oncology, Emory University, Atlanta, 30322, Georgia, GA, USA

    Erwin G Van Meir

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  1. Nobuaki Ishii
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Ishii, N., Tada, M., Hamou, MF. et al. Cells with TP53 mutations in low grade astrocytic tumors evolve clonally to malignancy and are an unfavorable prognostic factor. Oncogene 18, 5870–5878 (1999). https://doi.org/10.1038/sj.onc.1203241

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