Chromosome instability is a predominant trait of fibroblasts from Li-Fraumeni families

Previous work has indicated a role for p53 in cell cycle control, genomic stability and cellular responses to DNA-damaging agents. However, few data are available for human fibroblasts heterozygous for defined germline mutations in TP53. We report studies on 25 strains derived from 12 families with...

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Bibliographic Details
Published in:British journal of cancer 1998-06, Vol.77 (12), p.2181-2192
Main Authors: BOYLE, J. M, MITCHELL, E. L. D, GREAVES, M. J, ROBERTS, S. A, TRICKER, K, BURT, E, VARLEY, J. M, BIRCH, J. M, SCOTT, D
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Biological and medical sciences
Child
Chromosome Aberrations
Female
Fibroblasts - radiation effects
Fibroblasts - ultrastructure
Genes, p53
Germ-Line Mutation
Heterozygote
Humans
Li-Fraumeni Syndrome - genetics
Li-Fraumeni Syndrome - pathology
Male
Medical sciences
Middle Aged
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Phenotype
Tumors
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Summary:Previous work has indicated a role for p53 in cell cycle control, genomic stability and cellular responses to DNA-damaging agents. However, few data are available for human fibroblasts heterozygous for defined germline mutations in TP53. We report studies on 25 strains derived from 12 families with Li-Fraumeni syndrome (LFS) and 18 strains from normal volunteers. The families include three that are classical LFS families, but in whom no TP53 mutation has been found. In the families with mutations, increased longevity and resistance to low-dose-rate ionizing radiation showed a statistically significant association with the presence of TP53 mutations. However, not all heterozygotes had increased longevity or were radioresistant, and fibroblasts from cancer-affected members of LFS families without TP53 mutations showed no significant increase in either of these end points. In contrast, all mutation-carrying strains showed evidence of genomic instability, expressed as aneuploidy, and accumulated structural chromosome aberrations in up to 100% of cells, usually accompanied by loss of the wild-type TP53 allele, immediately before senescence. Levels of aneuploidy higher than in normal cells were also observed in fibroblasts from families without TP53 mutations, suggesting that chromosome instability is a major factor in determining the cancer proneness of these families.
ISSN:0007-0920
1532-1827
DOI:10.1038/bjc.1998.364