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dc.contributor.authorBoyle, John M
dc.contributor.authorSpreadborough, Anne R
dc.contributor.authorGreaves, Martin J
dc.contributor.authorBirch, Jillian M
dc.contributor.authorVarley, Jennifer
dc.contributor.authorScott, David
dc.date.accessioned2009-10-12T11:56:21Z
dc.date.available2009-10-12T11:56:21Z
dc.date.issued2002-02
dc.identifier.citationDelayed chromosome changes in gamma-irradiated normal and Li-Fraumeni fibroblasts. 2002, 157 (2):158-65 Radiat. Res.en
dc.identifier.issn0033-7587
dc.identifier.pmid11835679
dc.identifier.urihttp://hdl.handle.net/10541/84038
dc.description.abstractKnockout mice with only one Trp53 allele (+/- genotype) are highly susceptible to radiation-induced cancers, possibly through numerical chromosome changes. Patients with the Li-Fraumeni syndrome, having heterozygous TP53 germline mutations (+/mut genotype), are also susceptible to spontaneous and radiogenic cancers. We have investigated the susceptibility of six Li-Fraumeni syndrome +/mut and six normal fibroblast strains to induced numerical and unstable structural aberrations at six population doublings after exposure to 3 or 6 Gy gamma rays. Four of the irradiated Li-Fraumeni syndrome strains showed small increases in both aberration types, similar to those seen in the normal strains. In two irradiated Li-Fraumeni syndrome strains, there were high levels of induced structural changes, and one of these showed a modest increase in hyperploidy. We suggest that enhanced sensitivity to delayed radiation-induced chromosome changes in Li-Fraumeni syndrome cells requires other genetic alterations in addition to TP53 heterozygosity, apparently in contrast to the situation in Trp53 heterozygous null mice. If such additional alterations occur in vivo in Li-Fraumeni syndrome patients, they may predispose them to radiogenic cancers, mainly through enhanced structural rather than numerical chromosome changes. Our findings raise questions about the validity of quantitative extrapolation of cytogenetic data from Trp53-defective mice to radiogenic cancer risk in humans.
dc.language.isoenen
dc.subject.meshAneuploidy
dc.subject.meshAnimals
dc.subject.meshCells, Cultured
dc.subject.meshChromosome Aberrations
dc.subject.meshChromosome Breakage
dc.subject.meshChromosomes, Human
dc.subject.meshDose-Response Relationship, Radiation
dc.subject.meshFibroblasts
dc.subject.meshGamma Rays
dc.subject.meshGenes, p53
dc.subject.meshGenetic Predisposition to Disease
dc.subject.meshGenotype
dc.subject.meshHumans
dc.subject.meshLi-Fraumeni Syndrome
dc.subject.meshLoss of Heterozygosity
dc.subject.meshMice
dc.subject.meshMice, Knockout
dc.subject.meshRadiation Tolerance
dc.subject.meshSpecies Specificity
dc.subject.meshTime Factors
dc.titleDelayed chromosome changes in gamma-irradiated normal and Li-Fraumeni fibroblasts.en
dc.typeArticleen
dc.contributor.departmentCRC Cancer Genetics Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 9BX, United Kingdom.en
dc.identifier.journalRadiation Researchen
html.description.abstractKnockout mice with only one Trp53 allele (+/- genotype) are highly susceptible to radiation-induced cancers, possibly through numerical chromosome changes. Patients with the Li-Fraumeni syndrome, having heterozygous TP53 germline mutations (+/mut genotype), are also susceptible to spontaneous and radiogenic cancers. We have investigated the susceptibility of six Li-Fraumeni syndrome +/mut and six normal fibroblast strains to induced numerical and unstable structural aberrations at six population doublings after exposure to 3 or 6 Gy gamma rays. Four of the irradiated Li-Fraumeni syndrome strains showed small increases in both aberration types, similar to those seen in the normal strains. In two irradiated Li-Fraumeni syndrome strains, there were high levels of induced structural changes, and one of these showed a modest increase in hyperploidy. We suggest that enhanced sensitivity to delayed radiation-induced chromosome changes in Li-Fraumeni syndrome cells requires other genetic alterations in addition to TP53 heterozygosity, apparently in contrast to the situation in Trp53 heterozygous null mice. If such additional alterations occur in vivo in Li-Fraumeni syndrome patients, they may predispose them to radiogenic cancers, mainly through enhanced structural rather than numerical chromosome changes. Our findings raise questions about the validity of quantitative extrapolation of cytogenetic data from Trp53-defective mice to radiogenic cancer risk in humans.


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