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

Varley, Jennifer; Chapman, Peter; McGown, Gail; Thorncroft, Mary; White, Gavin R M; Greaves, Martin J; Scott, David; Spreadborough, Anne R; Tricker, Karen; Birch, Jillian M; Evans, D. Gareth; Reddel, Roger R.; Camplejohn, R. S.; Burn, John; Boyle, J M

doi:10.1038/sj.onc.1201878

Cited by 48 publications

(39 citation statements)

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“…Two other distantly related families showed a silent mutation in codon 125 (ACG?ACA) at the exon 4-intron 4 junction, generating three aberrant-spliced products (Warneford et al, 1992;Varley et al, 1998a). This substituted coding G nucleotide is highly conserved, as described in family 3 of our study.…”

Section: Discussionsupporting

confidence: 69%

“…Intron 5 AG?CG Exon 6 skipping (Jolly et al, 1994) splice acceptor site 7* Codon 125 at intron ACG?ACA Intron 4 inclusion, use of cryptic donor (Warneford et al, 1992; 4 splice donor site sites in exon 4 and intron 4 Varley et al, 1998a) 8 Intron 5 deletion 11 bp Exon 6 skipping (Felix et al, 1993) branch point and polypyrimidine tract…”

Section: Ascertainmentmentioning

confidence: 99%

“…Outside this core region, deleterious p53 changes tend to be nonsense or frameshift mutations that cause premature protein translation termination (Ishioka et al, 1995;Hainaut et al, 1997;Beroud and Soussi, 1998;Sedlacek et al, 1998). In addition, mutations that cause alternate splicing of precursor mRNA have been described in six LFS kindreds (Warneford et al, 1992;Felix et al, 1993;Jolly et al, 1994;Frebourg et al, 1995;Varley et al, 1997bVarley et al, , 1998a. In this study we describe three additional LFS families with inherited p53 splice site mutations.…”

Section: Introductionmentioning

confidence: 99%

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Novel p53 splice site mutations in three families with Li-Fraumeni syndrome

et al. 2000

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Germline mutations in the p53 tumor suppressor gene predispose to a variety of cancers in families with LiFraumeni syndrome. Most germline p53 mutations observed to date cause amino acid substitutions in the protein's central sequence-speci®c DNA binding domain. Outside this conserved core region, however, we found novel alterations in sequences that regulate precursor mRNA splicing in three Li-Fraumeni syndrome families. Two splice site mutations a ected the consensus sequence at the splice donor sites of introns 1 and 9, and produced unstable variant transcripts in normal cells. A third mutation at the splice acceptor site of intron 9 generated splicing at a cryptic acceptor site in intron 9. These splice site alterations emphasize the need to examine both noncoding and untranslated regions of the p53 gene for germline mutations in Li-Fraumeni syndrome families. Oncogene (2000) 19, 4230 ± 4235.

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Section: Discussionsupporting

confidence: 69%

Section: Ascertainmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel p53 splice site mutations in three families with Li-Fraumeni syndrome

et al. 2000

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“…Most fibroblast strains used here and their culture conditions have been described in detail Varley et al, 1998). The origins of additional strains are given in Table 1.…”

Section: Fibroblast Strains and Clonogenic Survivalmentioning

confidence: 99%

Radiation-induced G1 arrest is not defective in fibroblasts from Li-Fraumeni families without TP53 mutations

et al. 1999

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Classical Li-Fraumeni syndrome (LFS) families have a proband with sarcoma under the age of 45 years, a first-degree relative with any cancer under age 45, and a first-or second-degree relative with either a sarcoma at any age or any other cancer under age 45 years (Li and Fraumeni, 1969;Li et al, 1988). Li-Fraumeni-like (LFL) families conform to a broader definition (Birch et al, 1994) with a proband having any childhood cancer or sarcoma, brain tumour or adrenal cortical tumour diagnosed before age 45 years with one first-or second-degree relative with a typical syndromal cancer at any age, plus a first-or second-degree relative with any cancer under age 60 years. In both syndromes the predominant cancers are bone and soft tissue sarcomas and breast cancer, plus an excess of brain tumours, leukaemia and adrenocortical carcinomas diagnosed under age 45 years. We have reported germline mutations in the tumour suppressor gene, TP53, in 14 of 21 LFS families and four of 18 LFL families (Birch et al, 1994;Varley et al, 1997). An understanding of the consequences of the p53 mutations, particularly in the mesenchymal cells, could have implications for the management and counselling of these families.Pioneering work by Little (1968Little ( , 1970 demonstrated that human cells arrest in the G 1 phase of the cell cycle following exposure to ionizing radiation. Subsequently, it was shown that radiationsensitive fibroblasts from patients with the cancer predisposition syndrome, ataxia-telangiectasia (AT), did not show this response Nagasawa et al, 1985). These observations can be explained by the fact that radiation-induced stabilization of p53 expression in AT cells is both delayed and is reduced compared to normal cells, resulting in lower levels of transactivation of the cyclin-dependent protein kinase inhibitor, p21 WAF1/CIP1 , which has been strongly implicated in the permanent arrest of cells in G 1 (Di Leonardo et al, 1994;Dulic et al, 1994).Recently, we reported that radiation-resistant fibroblasts from Li-Fraumeni (LF) individuals also show reduced G 1 arrest (Williams et al, 1997). We now report an enlarged study of G 1 arrest in which we have compared the variability in responses of 12 fibroblast strains from normal volunteers with that of 30 strains from 20 classic LFS or LFL families. We have used this material to answer the following questions:1. Permanent G 1 arrest has been reported following irradiation of cells synchronized in G 1 (Little, 1968(Little, , 1970 Summary Radiation-induced G 1 arrest was studied in four classes of early passage skin fibroblasts comprising 12 normals, 12 heterozygous (mut/wt) TP53 mutation-carriers, two homozygous (mut/-) TP53 mutation-carriers and 16 strains from nine Li-Fraumeni syndrome or LiFraumeni-like families in which no TP53 mutation has been found, despite sequencing of all exons, exon-intron boundaries, 3′ and 5′ untranslated regions and promoter regions. In an assay of p53 allelic expression in yeast, cDNAs from these non-mutation strains behaved as wild-type p53. ...

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“…It is part of the Li-Fraumeni tumor syndrome and thus specifically linked to germline mutations in TP53 (30,31). Accordingly, TP53 polymorphisms and their impact on p53 function may be particularly relevant in ACC.…”

Section: Introductionmentioning

confidence: 99%

Less common genotype variants of TP53 polymorphisms are associated with poor outcome in adult patients with adrenocortical carcinoma

Heinze

Herrmann

Fassnacht

et al. 2014

European Journal of Endocrinology

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Context: The Li-Fraumeni tumor syndrome is strongly associated with adrenocortical carcinoma (ACC) and is caused by germline mutations in TP53 in 70% of cases. Also, TP53 polymorphisms have been shown to influence both cancer risk and clinical outcome in several tumor entities. We, therefore, investigated TP53 polymorphisms in a cohort of adult patients with ACC. Objective: Evaluation of the role of TP53 polymorphisms in adult patients with ACC. Subjects and methods: Peripheral blood for DNA extraction was collected from 72 ACC patients. Polymorphism analysis was carried out by amplification and sequencing of exons and adjacent intron sections of TP53. Results were correlated with clinical data and the distribution of the polymorphisms was compared with published Caucasian control groups. Results: Compared with control groups, genotype frequencies of analyzed TP53 polymorphisms among ACC patients were significantly different in three out of four polymorphisms: IVS2C38GOC (G/G, PZ0.0248), IVS3ins16 (NoIns/NoIns, P!0.0001; NoIns/Ins, P!0.0001), and IVS6C62AOG (G/G, P!0.0001; G/A, P!0.0001). Overall, the survival of ACC patients, which harbored at least one of the less frequent genotype variants of four analyzed polymorphisms (nZ23), was significantly inferior (median survival: 81.0 months in patients with the common homozygous genotypes vs 20.0 months in patients with the less frequent genotypes, HR 2.56, 95% CI 1.66-7.07; PZ0.001). These results were confirmed by multivariable regression analysis (HR 2.84, 95% CI 1.52-7.17; PZ0.037). Conclusion: Some TP53 polymorphisms seem to influence overall survival in ACC patients. This effect was observed for a combination of polymorphic changes rather than for single polymorphisms.

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

Cited by 48 publications

References 17 publications

Novel p53 splice site mutations in three families with Li-Fraumeni syndrome

Novel p53 splice site mutations in three families with Li-Fraumeni syndrome

Radiation-induced G1 arrest is not defective in fibroblasts from Li-Fraumeni families without TP53 mutations

Less common genotype variants of TP53 polymorphisms are associated with poor outcome in adult patients with adrenocortical carcinoma

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