Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.

2.50
Hdl Handle:
http://hdl.handle.net/10541/92046
Title:
Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.
Authors:
Birch, Jillian M; Blair, Val; Kelsey, Anna M; Evans, D Gareth R; Harris, Martin; Tricker, K J; Varley, Jennifer
Abstract:
The 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.
Affiliation:
CRC Paediatric and Familial Cancer Research Group and Department of Histopathology, Royal Manchester Children's Hospital, UK.
Citation:
Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. 1998, 17 (9):1061-8 Oncogene
Journal:
Oncogene
Issue Date:
3-Sep-1998
URI:
http://hdl.handle.net/10541/92046
DOI:
10.1038/sj.onc.1202033
PubMed ID:
9764816
Type:
Article
Language:
en
ISSN:
0950-9232
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.authorBlair, Valen
dc.contributor.authorKelsey, Anna Men
dc.contributor.authorEvans, D Gareth Ren
dc.contributor.authorHarris, Martinen
dc.contributor.authorTricker, K Jen
dc.contributor.authorVarley, Jenniferen
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.en
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

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