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Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation

Oncogene volume 19, pages 4079–4083 (2000)Cite this article

Abstract

We have previously reported high-frequency microsatellite instability (MSI-H) and germ-line mismatch repair gene mutation in patients with unusually young onset of high-grade glioma. Some of these patients developed metachronous MSI-H colorectal cancer and conformed to the diagnosis of Turcot's syndrome. Frameshift mutation of TGFβRII was present in all the colorectal carcinomas but not in brain tumours. We further characterized the genetic pathways of tumour evolution in these metachronous gliomas and colorectal carcinomas. All MSI-H glioblastomas had inactivation of both alleles of the p53 gene and showed over-expression of the p53 protein while none of the colorectal carcinomas had p53 mutation or protein over-expression. Flow cytometry and comparative genomic hybridization revealed that all glioblastomas were chromosomal unstable with aneuploid DNA content, and with a variable number of chromosomal arm aberrations. In contrast, the colorectal carcinomas had diploid or near-diploid DNA content with few chromosomal arm aberrations. The pattern of chromosomal aberrations in the two organs was different. Loss of 9p was consistently observed in all glioblastomas but not in colorectal carcinomas. Epidermal growth factor receptor amplification was absent in all glioblastomas and colorectal carcinomas. Our results suggest that both the frequency of p53 mutation and its effects differ greatly in the two organs. Following loss of mismatch repair function, p53 inactivation and chromosomal instability are not necessary for development of colorectal carcinoma, but are required for genesis of glioblastoma.

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Acknowledgements

This work is supported by Committee on Research and Conference Grant from the University of Hong Kong; Grant number: 10202796; Croucher Foundation Research Grant; Grant number: 394/046/1238. We thank Ian Roberts and Despina Sanoudou Gibiol, University of Cambridge, UK, for their advice on the CGH work, Ivan SH Ho for excellent technical assistance.

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Authors and Affiliations

  1. Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong

    Suet Yi Leung, Siu Tsan Yuen, Tsun Leung Chan, Annie SY Chan & Lap Ping Chung

  2. Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong

    Judy WC Ho, Yiu Wah Fan & Kwan Ngai Hung

  3. Hereditary Gastrointestinal Cancer Registry, Queen Mary Hospital, The University of Hong Kong, Hong Kong

    Siu Tsan Yuen, Judy WC Ho, Kedo Kwan & Lap Ping Chung

  4. Department of Pathology, Cambridge University, Cambridge, UK

    Andrew H Wyllie

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Leung, S., Yuen, S., Chan, T. et al. Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation. Oncogene 19, 4079–4083 (2000). https://doi.org/10.1038/sj.onc.1203740

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