Nature 355, 846 - 847 (27 February 1992); doi:10.1038/355846a0

Clonal expansion of p53 mutant cells is associated with brain tumour progression

David Sidransky^*, Tom Mikkelsen^†, Karl Schwechheimer^‡, Mark L. Rosenblum^§, Web Cavanee^† & Bert Vogelstein^*

^*The Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
^†Ludwig Institute for Cancer Research, Montreal, Province of Quebec, H3A 1A1, Canada
^‡Abteilung Neuropatologi Pathologischer Institut, Albert Ludwigs Universitat, Frieberg, Germany
^§Brain Tumor Research Center, Department of Neurological Surgery, University of California Medical Center, San Francisco, California 94143, USA
To whom correspondence should be addressed.

TUMOUR progression is a fundamental feature of the biology of cancer¹. Cancers do not arise de novo in their final form, but begin as small, indolent growths, which gradually acquire characteristics associated with malignancy. In the brain, for example, low-grade tumours (astrocytomas) evolve into faster growing, more dysplastic and invasive high-grade tumours (glioblastomas)^2,3. To define the genetic events underlying brain tumour progression, we analysed the p53 gene in ten primary brain tumour pairs. Seven pairs consisted of tumours that were high grade both at presentation and recurrence (group A) and three pairs consisted of low-grade tumours that had progressed to higher grade tumours (group B). In group A pairs, four of the recurrent tumours contained a p53 gene mutation; in three of them, the same mutation was found in the primary tumour. In group B pairs, progression to high grade was associated with a p53 gene mutation. A subpopulation of cells were present in the low-grade tumours that contained the same p53 gene mutation predominant in the cells of the recurrent tumours that had progressed to glioblastoma. Thus, the histological progression of brain tumours was associated with a clonal expansion of cells that had previously acquired a mutation in the p53 gene, endowing them with a selective growth advantage. These experimental observations strongly support Nowell's clonal evolution model of tumour progression⁴.

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