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dc.contributor.authorVarley, Jennifer
dc.contributor.authorMcGown, Gail
dc.contributor.authorThorncroft, Mary R
dc.contributor.authorJames, Louise A
dc.contributor.authorMargison, Geoffrey P
dc.contributor.authorForster, Gill
dc.contributor.authorEvans, D Gareth R
dc.contributor.authorHarris, Martin
dc.contributor.authorKelsey, Anna M
dc.contributor.authorBirch, Jillian M
dc.date.accessioned2010-02-08T15:39:21Z
dc.date.available2010-02-08T15:39:21Z
dc.date.issued1999-10
dc.identifier.citationAre there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors. 1999, 65 (4):995-1006 Am. J. Hum. Genet.en
dc.identifier.issn0002-9297
dc.identifier.pmid10486318
dc.identifier.doi10.1086/302575
dc.identifier.urihttp://hdl.handle.net/10541/91399
dc.description.abstractWe have analyzed a panel of 14 cases of childhood adrenocortical tumors unselected for family history and have identified germline TP53 mutations in >80%, making this the highest known incidence of a germline mutation in a tumor-suppressor gene in any cancer. The spectrum of germline TP53 mutations detected is remarkably limited. Analysis of tumor tissue for loss of constitutional heterozygosity, with respect to the germline mutant allele and the occurrence of other somatic TP53 mutations, indicates complex sequences of genetic events in a number of tumors. None of the families had cancer histories that conformed to the criteria for Li-Fraumeni syndrome, but, in some families, we were able to demonstrate that the mutation had been inherited. In these families there were gene carriers unaffected in their 40s and 50s, and there were others with relatively late-onset cancers. These data provide evidence that certain TP53 alleles confer relatively low penetrance for predisposition to the development of cancer, and they imply that deleterious TP53 mutations may be more frequent in the population than has been estimated previously. Our findings have considerable implications for the clinical management of children with andrenocortical tumors and their parents, in terms of both genetic testing and the early detection and treatment of tumors.
dc.language.isoenen
dc.subjectAdrenal Cortex Canceren
dc.subjectCancer Proteinsen
dc.subject.meshAdaptor Proteins, Signal Transducing
dc.subject.meshAdolescent
dc.subject.meshAdrenal Cortex Neoplasms
dc.subject.meshAdult
dc.subject.meshAge of Onset
dc.subject.meshAged
dc.subject.meshAlleles
dc.subject.meshCarrier Proteins
dc.subject.meshChild
dc.subject.meshChild, Preschool
dc.subject.meshDNA Mutational Analysis
dc.subject.meshDNA-Binding Proteins
dc.subject.meshFemale
dc.subject.meshGenes, p53
dc.subject.meshGenetic Predisposition to Disease
dc.subject.meshGenetic Testing
dc.subject.meshGerm-Line Mutation
dc.subject.meshHumans
dc.subject.meshImmunohistochemistry
dc.subject.meshLi-Fraumeni Syndrome
dc.subject.meshLoss of Heterozygosity
dc.subject.meshMale
dc.subject.meshMicrosatellite Repeats
dc.subject.meshMiddle Aged
dc.subject.meshMolecular Sequence Data
dc.subject.meshMutS Homolog 2 Protein
dc.subject.meshNeoplasm Proteins
dc.subject.meshNuclear Proteins
dc.subject.meshPenetrance
dc.subject.meshPolymorphism, Single-Stranded Conformational
dc.subject.meshProto-Oncogene Proteins
dc.titleAre there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors.en
dc.typeArticleen
dc.contributor.departmentCancer Research Campaign, Section of Molecular Genetics, Paterson Institute for Cancer Research, Manchester, United Kingdom. jvarley@picr.man.ac.uken
dc.identifier.journalAmerican Journal of Human Geneticsen
html.description.abstractWe have analyzed a panel of 14 cases of childhood adrenocortical tumors unselected for family history and have identified germline TP53 mutations in >80%, making this the highest known incidence of a germline mutation in a tumor-suppressor gene in any cancer. The spectrum of germline TP53 mutations detected is remarkably limited. Analysis of tumor tissue for loss of constitutional heterozygosity, with respect to the germline mutant allele and the occurrence of other somatic TP53 mutations, indicates complex sequences of genetic events in a number of tumors. None of the families had cancer histories that conformed to the criteria for Li-Fraumeni syndrome, but, in some families, we were able to demonstrate that the mutation had been inherited. In these families there were gene carriers unaffected in their 40s and 50s, and there were others with relatively late-onset cancers. These data provide evidence that certain TP53 alleles confer relatively low penetrance for predisposition to the development of cancer, and they imply that deleterious TP53 mutations may be more frequent in the population than has been estimated previously. Our findings have considerable implications for the clinical management of children with andrenocortical tumors and their parents, in terms of both genetic testing and the early detection and treatment of tumors.


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