Delayed chromosome changes in gamma-irradiated normal and Li-Fraumeni fibroblasts.

2.50
Hdl Handle:
http://hdl.handle.net/10541/84038
Title:
Delayed chromosome changes in gamma-irradiated normal and Li-Fraumeni fibroblasts.
Authors:
Boyle, John M; Spreadborough, Anne R; Greaves, Martin J; Birch, Jillian M; Varley, Jennifer; Scott, David
Abstract:
Knockout 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.
Affiliation:
CRC Cancer Genetics Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 9BX, United Kingdom.
Citation:
Delayed chromosome changes in gamma-irradiated normal and Li-Fraumeni fibroblasts. 2002, 157 (2):158-65 Radiat. Res.
Journal:
Radiation Research
Issue Date:
Feb-2002
URI:
http://hdl.handle.net/10541/84038
PubMed ID:
11835679
Type:
Article
Language:
en
ISSN:
0033-7587
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorBoyle, John Men
dc.contributor.authorSpreadborough, Anne Ren
dc.contributor.authorGreaves, Martin Jen
dc.contributor.authorBirch, Jillian Men
dc.contributor.authorVarley, Jenniferen
dc.contributor.authorScott, Daviden
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.en
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

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