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dc.contributor.authorBirch, Jillian M
dc.contributor.authorBlair, Val
dc.contributor.authorKelsey, Anna M
dc.contributor.authorEvans, D Gareth R
dc.contributor.authorHarris, Martin
dc.contributor.authorTricker, K J
dc.contributor.authorVarley, Jennifer
dc.date.accessioned2010-02-12T16:31:34Z
dc.date.available2010-02-12T16:31:34Z
dc.date.issued1998-09-03
dc.identifier.citationCancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. 1998, 17 (9):1061-8 Oncogeneen
dc.identifier.issn0950-9232
dc.identifier.pmid9764816
dc.identifier.doi10.1038/sj.onc.1202033
dc.identifier.urihttp://hdl.handle.net/10541/92046
dc.description.abstractThe Li-Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li-Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed significantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a significantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations.
dc.language.isoenen
dc.subjectTumour Suppressor Protein p53en
dc.subjectCanceren
dc.subject.meshAdolescent
dc.subject.meshAdult
dc.subject.meshAge Factors
dc.subject.meshAged
dc.subject.meshAged, 80 and over
dc.subject.meshChi-Square Distribution
dc.subject.meshChild
dc.subject.meshChild, Preschool
dc.subject.meshCohort Studies
dc.subject.meshDNA Mutational Analysis
dc.subject.meshFamily
dc.subject.meshFamily Health
dc.subject.meshFemale
dc.subject.meshGenotype
dc.subject.meshGerm-Line Mutation
dc.subject.meshHumans
dc.subject.meshInfant
dc.subject.meshInfant, Newborn
dc.subject.meshLi-Fraumeni Syndrome
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshNeoplasms
dc.subject.meshPedigree
dc.subject.meshPhenotype
dc.subject.meshTumor Suppressor Protein p53
dc.titleCancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.en
dc.typeArticleen
dc.contributor.departmentCRC Paediatric and Familial Cancer Research Group and Department of Histopathology, Royal Manchester Children's Hospital, UK.en
dc.identifier.journalOncogeneen
html.description.abstractThe Li-Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li-Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed significantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a significantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations.


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