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

Boyle, John M; Mitchell, Erika L D; Greaves, Martin J; Roberts, Stephen A; Tricker, Karen; Burt, Emma; Varley, Jennifer; Birch, Jillian M; Scott, David

doi:10.1038/bjc.1998.364

Cited by 46 publications

(46 citation statements)

References 28 publications

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“…From three independent experiments the surviving fractions (mean+standard deviation) following 3 and 6 Gy respectively were 28.6+7.2% and 9.1+2.0% for 178MA and 23.6+11.9% and 6.2+2.8% for 190MA. These values fell within two standard deviations of the corresponding mean values of 12 strains from normal healthy volunteers that we have used to establish the normal response range (Boyle et al, 1998).…”

Section: Functional Assayssupporting

confidence: 72%

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

et al. 1998

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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 aected family members available for testing. The mutation abolishes correct splicing of intron 4 and techniques of RT ± PCR have identi®ed three dierent 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 unaected 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 ®broblast survival following low dose rate ionising radiation exposure. However germline mutation carriers show increased sensitivity to radiation-induced chromosome damage in the G 2 phase of the cell cycle, and decreased transient and permanent G 1 arrest. These studies demonstrate the importance of fully characterising the eects of TP53 germline mutations, and may explain some of the phenotypic features of this family.

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Section: Functional Assayssupporting

confidence: 72%

“…Fibroblast cell strains were established from thirteen family members using techniques as described in Boyle et al (1998). All studies on ®broblasts were carried out at early passage (520 population doublings).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 1998

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“…The extent and detail of this analysis is unprecedented. Furthermore, in each family in whom a mutation was detected, the biological signi®cance of the mutation has been assessed and segregation of the mutation with cancers in the families demonstrated (Varley et al, 1997b;Boyle et al, 1998; R Camplejohn personal communication). These features have enabled us to undertake a study to determine whether there are phenotypic variations in terms of cancer incidence in Li ± Fraumeni families according to their constitutional TP53 genotype.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1998

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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 signi®cantly 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 signi®cantly 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.

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“…Primary ®broblasts were cultured from skin biopsies obtained with informed consent from LFS patients and normal control individuals, as previously described (Boyle et al, 1998).…”

Section: Li-fraumeni Cellsmentioning

confidence: 99%

RNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome

et al. 2002

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RNA polymerase (pol) III synthesizes essential small RNAs, including tRNA and 5S rRNA. Wild-type p53 can repress pol III transcription both in vitro and in vivo. Many tumours carry substitutions in p53 which have selective e ects on its functions. We identify tumourderived mutations that compromise the ability of p53 to regulate pol III transcription. Furthermore, substitution R175H, the most common mutation in cancers, converts p53 from a repressor to an activator of pol III. Oncoproteins neutralize p53 in some tumours; we show that human papillomavirus E6 and cellular hdm2 can both release pol III from repression by p53. These data suggest that the restraining in¯uence of p53 on pol III will be lost in many tumours. In addition to these features of sporadic cancers, some individuals inherit mutant forms of p53 and consequently su er from LiFraumeni syndrome, showing genetic predisposition to certain malignancies. We ®nd that pol III transcriptional activity is often highly elevated in primary ®broblasts from Li-Fraumeni patients, especially if the germline p53 mutation is followed by loss of the remaining allele. Our data suggest that p53 status can have a profound e ect upon pol III transcription and hence on the biosynthetic capacity of cells.

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

Cited by 46 publications

References 28 publications

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

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

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

RNA polymerase III transcription can be derepressed by oncogenes or mutations that compromise p53 function in tumours and Li-Fraumeni syndrome

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