Mutations in the p53 gene occur in diverse human tumour types
Janice M. Nigro*, Suzanne J. Baker*, Antonette C. Preisinger*, J. Milburn Jessup†, Richard Hosteller†, Karen Cleary†, Sandra H. Signer‡, Nancy Davidson*, Stephen Baylin*, Peter Devilee§, Thomas Glover∥, Francis S. Collins∥, Ainsley Weslon¶, Rama Modali¶, Curtis C. Harris¶ & Bert Vogelstein*£
* The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore,
Maryland 21231, USA
† M. D. Anderson Hospital, Houston, Texas 77030, USA
‡ Department of Pathology, Duke University, Durham,
North Carolina 27710, USA
§ Department of Human Genetics, University of Leiden, Holland
∥ Department of Human Genetics, University of Michigan, Ann Arbor,
Michigan 48109, USA
¶ Laboratory of Human Carcinogenesis, National Cancer Institute,
Bethesda, Maryland 20892, USA
£ To whom correspondence should be addressed.
THE p53 gene has been a constant source of fascination since its discovery nearly a decade ago1,2. Originally considered to be an oncogene, several convergent lines of research have indicated that the wild-type gene product actually functions as a tumour suppressor gene3–9. For example, expression of the neoplastic phenotype is inhibited, rather than promoted, when rat cells are transfected with the murine wild-type p53 gene together with mutant p53 genes and/or other oncogenes3,4. Moreover, in human tumours, the short arm of chromosome 17 is often deleted (reviewed in ref. 10). In colorectal cancers, the smallest common region of deletion is centred at 17pl3.1 (ref. 9); this region harbours the p53 gene, and in two tumours examined in detail, the remaining (non-deleted) p53 alleles were found to contain mutations9. This result was provocative because allelic deletion coupled with mutation of the remaining allele is a theoretical hallmark of tumour-suppressor genes11. In the present report, we have attempted to determine the generality of this observation; that is, whether tumours with allelic deletions of chromosome 17p contain mutant p53 genes in the allele that is retained. Our results suggest that (1) most tumours with such allelic deletions contain p53 point mutations resulting in amino-acid substitutions, (2) such mutations are not confined to tumours with allelic deletion, but also occur in at least some tumours that have retained both parental 17p alleles, and (3) p53 gene mutations are clustered in four 'hot-spots' which exactly coincide with the four most highly conserved regions of the gene. These results suggest that p53 mutations play a role in the development of many common human malignancies.
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