Birch, J.M., Heighway, J., Teare, M.D. orcid.org/0000-0003-3994-0051 et al. (6 more authors) (1994) Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53. British Journal of Cancer, 70 (6). pp. 1176-1181. ISSN 0007-0920
Abstract
We report a family with the Li-Fraumeni syndrome (LFS) in whom we have been unable to detect a mutation in the coding sequence of the p53 gene. Analysis of linkage to three polymorphic markers within p53 enabled direct involvement of p53 to be excluded. This is the first example of a LFS family in whom exclusion of p53 has been possible. Four affected members of the family with sarcoma or premenopausal breast cancer showed increased expression of p53 protein in their normal tissues as detected by immunohistochemistry. It therefore appears that the LFS phenotype has been conferred by an aberrant gene, showing a dominant pattern of inheritance, which may be acting to compromise normal p53 function rather than by a mutation in p53 itself. In order to try to determine the chromosomal location of this putative gene, we have carried out studies of linkage to candidate loci. By these means we have excluded involvement of RbN and BRCAJ on chromosomes 13q and 17q respectively. The MDM2 oncogene on chromosome 12q was considered to be the prime candidate as MDM2 is amplified in sarcomas and the MDM2 product binds to p53. Furthermore, p53 mutation and amplification of MDM2 have been shown to be mutually exclusive events in tumour development. Linkage analysis to two polymorphic markers within MDM2 yielded a three-point LOD score of - 5.4 at a recombination fraction equal to zero. Therefore MDM2 could be excluded. It is possible that the gene which is responsible for cancer susceptibility in this family, possibly via interaction with p53, will be important in the histogenesis of breast cancer in general. We are now carrying out further studies to locate and identify this gene.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 1994 Macmillan Press Ltd. Reproduced in accordance with the publisher's self-archiving policy. |
Keywords: | Soft-Tissue-Sarcoma; Cancer Family; Breast-Cancer; Gene; Amplification; Tumors; Polymorphism; Spectrum; Children; Oncogene |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Health and Related Research (Sheffield) > ScHARR - Sheffield Centre for Health and Related Research |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 07 Oct 2016 12:38 |
Last Modified: | 07 Oct 2016 12:38 |
Published Version: | http://dx.doi.org/10.1038/bjc.1994.468 |
Status: | Published |
Publisher: | Cancer Research UK |
Refereed: | Yes |
Identification Number: | 10.1038/bjc.1994.468 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:105453 |