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Reduced latency but no increased brain tumor penetrance in mice with astrocyte specific expression of a human p53 mutant

Oncogene volume 19, pages 5329–5337 (2000)Cite this article

Abstract

p53-germline mutations located in the core DNA-binding domain have been associated with a more dominant tumor penetrance especially for breast cancer and brain tumors. We previously reported an unusual accumulation of CNS tumors associated with a unique p53 germline mutation, Y236Δ (deletion of codon 236). To test whether this tissue-specific tumor predisposition reflects a gain-of-function activity of Y236Δ, we generated transgenic mice expressing Y236Δ in astrocytes using the regulatory elements of the glial fibrillary acidic protein (GFAP) gene. After transplacental exposure to N-ethyl-N-nitrosourea (25 mg/kg BW) brain tumors developed in 18% (7/39) of GFAP-Y236Δ transgenic p53+/− mice, while in p53+/− mice the incidence was 28% (11/40) (P>0.3). However, the mean tumor latency for GFAP-Y236Δ/p53+/− mice was significantly shorter than for p53+/− mice, with 19.9 weeks vs 31.6 weeks (P=0.039), respectively. Taken together, cell specific expression of Y236Δ results in an acceleration of tumor progression but does not confer a higher tumor penetrance. Conceivably, the transdominant effect of Y236Δ provided a growth advantage early in the progression of neoplastic cells, since the endogenous p53 wild-type allele was lost in all brain tumors independent of the genotype. This reflects well observations from human astrocytic neoplasms with p53 mutations.

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Acknowledgements

We are indebted to L Donehower for providing the p53-deficient mice and to L Mucke for the GFAP-promoter construct. We thank M König, B Pfister, L Vlk, B Odermatt, S Trepey and M-F Hamou for histology, and Ch El-Ariss for technical assistance. We appreciated the helpful discussions with J Hainfellner and P Kleihues. We thank E Van Meir and N de Tribolet for their support, and S Marino, and R Iggo for critical reading of this manuscript. This project was supported by grants of the Swiss National Science Foundation (to ME Hegi and A Aguzzi, and to E Van Meir and ME Hegi), the Swiss Cancer League (to ME Hegi and N de Tribolet), the Swiss Cancer League/Cancer League of the Canton of Aargau (to A Aguzzi), and the Deutsche Forschungsgemeinschaft (DFG) (to MA Klein).

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  1. Daniela Rüedi

    Present address: Catalys AG, Wallisellen, 8340, Switzerland

Authors and Affiliations

  1. Institute of Neuropathology, University Hospital of Zurich, 8091 Zurich, Switzerland, University Hospital, Lausanne, 1011, Switzerland

    Michael A Klein, Daniela Rüedi, Adriano Aguzzi & Monika E Hegi

  2. Department of Neurosurgery, Laboratory of Tumor Biology and Genetics, University Hospital, Lausanne, 1011, Switzerland

    Michimasa Nozaki, Elizabeth W Dell, Annie-Claire Diserens & Monika E Hegi

  3. Institute of Pathology, University Hospital, 1011, Lausanne, Switzerland

    Walter Seelentag & Robert C Janzer

  4. Division of Neuropathology, University Hospital, Lausanne, 1011, Switzerland

    Robert C Janzer

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Klein, M., Rüedi, D., Nozaki, M. et al. Reduced latency but no increased brain tumor penetrance in mice with astrocyte specific expression of a human p53 mutant. Oncogene 19, 5329–5337 (2000). https://doi.org/10.1038/sj.onc.1203941

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