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Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53.
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 w...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
1994
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2033684/ https://www.ncbi.nlm.nih.gov/pubmed/7981072 |
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author | Birch, J. M. Heighway, J. Teare, M. D. Kelsey, A. M. Hartley, A. L. Tricker, K. J. Crowther, D. Lane, D. P. Santibáñez-Koref, M. F. |
author_facet | Birch, J. M. Heighway, J. Teare, M. D. Kelsey, A. M. Hartley, A. L. Tricker, K. J. Crowther, D. Lane, D. P. Santibáñez-Koref, M. F. |
author_sort | Birch, J. M. |
collection | PubMed |
description | 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 Rb1 and BRCA1 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 theta 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. IMAGES: |
format | Text |
id | pubmed-2033684 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 1994 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-20336842009-09-10 Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53. Birch, J. M. Heighway, J. Teare, M. D. Kelsey, A. M. Hartley, A. L. Tricker, K. J. Crowther, D. Lane, D. P. Santibáñez-Koref, M. F. Br J Cancer Research Article 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 Rb1 and BRCA1 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 theta 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. IMAGES: Nature Publishing Group 1994-12 /pmc/articles/PMC2033684/ /pubmed/7981072 Text en https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Research Article Birch, J. M. Heighway, J. Teare, M. D. Kelsey, A. M. Hartley, A. L. Tricker, K. J. Crowther, D. Lane, D. P. Santibáñez-Koref, M. F. Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53. |
title | Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53. |
title_full | Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53. |
title_fullStr | Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53. |
title_full_unstemmed | Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53. |
title_short | Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53. |
title_sort | linkage studies in a li-fraumeni family with increased expression of p53 protein but no germline mutation in p53. |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2033684/ https://www.ncbi.nlm.nih.gov/pubmed/7981072 |
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