Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53.

2.50
Hdl Handle:
http://hdl.handle.net/10541/96548
Title:
Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53.
Authors:
Birch, Jillian M; Heighway, Jim; Teare, M Dawn; Kelsey, Anna M; Hartley, Ann L; Tricker, K J; Crowther, Derek; Lane, D P; Santibanez-Koref, Mauro F
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 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.
Affiliation:
University of Manchester, CRC Paediatric & Familial Cancer Research Group, Christie Hospital, UK.
Citation:
Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53. 1994, 70 (6):1176-81 Br. J. Cancer
Journal:
British Journal of Cancer
Issue Date:
Dec-1994
URI:
http://hdl.handle.net/10541/96548
PubMed ID:
7981072
PubMed Central ID:
2033684
Type:
Article
Language:
en
ISSN:
0007-0920
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorBirch, Jillian Men
dc.contributor.authorHeighway, Jimen
dc.contributor.authorTeare, M Dawnen
dc.contributor.authorKelsey, Anna Men
dc.contributor.authorHartley, Ann Len
dc.contributor.authorTricker, K Jen
dc.contributor.authorCrowther, Dereken
dc.contributor.authorLane, D Pen
dc.contributor.authorSantibanez-Koref, Mauro Fen
dc.date.accessioned2010-04-14T11:39:10Z-
dc.date.available2010-04-14T11:39:10Z-
dc.date.issued1994-12-
dc.identifier.citationLinkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53. 1994, 70 (6):1176-81 Br. J. Canceren
dc.identifier.issn0007-0920-
dc.identifier.pmid7981072-
dc.identifier.urihttp://hdl.handle.net/10541/96548-
dc.description.abstractWe 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.en
dc.language.isoenen
dc.subjectTumour Suppressor Protein p53-
dc.subject.meshBase Sequence-
dc.subject.meshDNA Primers-
dc.subject.meshFemale-
dc.subject.meshGenes, p53-
dc.subject.meshGenetic Markers-
dc.subject.meshHumans-
dc.subject.meshLi-Fraumeni Syndrome-
dc.subject.meshLinkage (Genetics)-
dc.subject.meshMale-
dc.subject.meshMolecular Sequence Data-
dc.subject.meshNuclear Proteins-
dc.subject.meshPedigree-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshProto-Oncogene Proteins c-mdm2-
dc.subject.meshTumor Suppressor Protein p53-
dc.titleLinkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53.en
dc.typeArticleen
dc.contributor.departmentUniversity of Manchester, CRC Paediatric & Familial Cancer Research Group, Christie Hospital, UK.en
dc.identifier.journalBritish Journal of Canceren
dc.identifier.pmcid2033684-

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