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    Genetic and functional studies of a germline TP53 splicing mutation in a Li-Fraumeni-like family.

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    Authors
    Varley, Jennifer
    Chapman, P
    McGown, Gail
    Thorncroft, Mary R
    White, Gavin R M
    Greaves, M J
    Scott, David
    Spreadborough, Anne R
    Tricker, K J
    Birch, Jillian M
    Evans, D Gareth R
    Reddel, R
    Camplejohn, R S
    Burn, J
    Boyle, John M
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    Affiliation
    CRC Section of Molecular Genetics, Paterson Institute for Cancer Research, Manchester, UK.
    Issue Date
    1998-06-25
    
    Metadata
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    Abstract
    We report an extensive Li-Fraumeni-like family in which there is an unusual spectrum of tumours at relatively late onset. A germline TP53 splice donor mutation in exon 4 is present in all affected family members available for testing. The mutation abolishes correct splicing of intron 4 and techniques of RT-PCR have identified three different aberrant transcripts from the mutant TP53 allele. Using the yeast functional assay to analyse transcripts in cells from a number of family members with the mutant allele, TP53 appears wild-type. Functional studies have been carried out on cells from patients with and without cancer who carry the germline mutation, and on cells from unaffected individuals from the same family who do not carry the mutation. Using a number of functional endpoints known to distinguish between cells carrying mutant or wild-type TP53 alleles, we were unable to discriminate normal (wt/wt) from heterozygous (wt/mut) cells by lymphocyte apoptosis and fibroblast survival following low dose rate ionising radiation exposure. However germline mutation carriers show increased sensitivity to radiation-induced chromosome damage in the G2 phase of the cell cycle, and decreased transient and permanent G1 arrest. These studies demonstrate the importance of fully characterising the effects of TP53 germline mutations, and may explain some of the phenotypic features of this family.
    Citation
    Genetic and functional studies of a germline TP53 splicing mutation in a Li-Fraumeni-like family. 1998, 16 (25):3291-8 Oncogene
    Journal
    Oncogene
    URI
    http://hdl.handle.net/10541/92734
    DOI
    10.1038/sj.onc.1201878
    PubMed ID
    9681828
    Type
    Article
    Language
    en
    ISSN
    0950-9232
    ae974a485f413a2113503eed53cd6c53
    10.1038/sj.onc.1201878
    Scopus Count
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