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The common germline TP53-R337H mutation is hypomorphic and confers incomplete tumor penetrance and late tumor onset in a mouse model

ABSTRACT: The TP53-R337H founder mutation exists at high frequency throughout southern Brazil and represents the most common germline TP53 mutation reported to date. It was originally identified in pediatric adrenocortical tumors in families with no reported history of cancer. The R337H mutation has since been found in association with early-onset breast cancers and Li-Fraumeni syndrome. To study this variability in tumor susceptibility we generated a knockin mutant p53 mouse model (R334H). Endogenous murine R334H is naturally expressed at abnormally high levels in multiple tissues and is functionally compromised in a cell type and stress-specific manner. The mutant p53 mice develop tumors with long latency and incomplete penetrance, consistent with many human carriers being at a low, but elevated risk for cancer We used microarrays to compare the global programme of gene expression in thymocytes obtained from WT or TP53R337H/R337H mutant mice that had either received 5 Gy whole body irradiation or no irradiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE166819 | GEO | 2021/03/01

REPOSITORIES: GEO

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TP53 c.1000G>C; p.G334R is an Ashkenazi Jewish predominant mutation associated with a low penetrance Li-Fraumeni Syndrome

Project description:Multiple family members with cancer or individuals with multiple primary cancers are indicative of potential genetic etiology1. Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li Fraumeni Syndrome (LFS)2. We identified a TP53 tetramerization domain (TD) missense mutation c.1000G>C;p.G334R, in a family with LFS-associated cancers. Twenty-one additional probands were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited haplotype. While classical p53 target gene activation was maintained in p.G334R mutant cell lines treated with Nutlin-3a, a subset of p53 target genes, including PCLO, PLTP, PLXNB3 and LCN15, showed defective transactivation. Structural analysis demonstrated thermal instability of the mutant TD, and the G334R mutant protein showed increased preponderance of mutant conformation protein. TP53 c.1000G>C;p.G334R is a rare AJ-predominant mutation associated with low penetrance Li-Fraumeni Syndrome

2020-07-24 | GSE143741 | GEO

A MUTATION IN THE POT1 GENE IS RESPONSIBLE FOR CARDIAC ANGIOSARCOMA IN TP53-NEGATIVE LI-FRAUMENI-LIKE FAMILIES

Project description:Whole Exome sequencing of two patients with Cardiac angiosarcoma in Li-Fraumeni-like families discovers that a mutation in the pot1 gene is responsible for cardiac angiosarcoma in tp53-negative li-fraumeni-like families

2015-09-14 | E-MTAB-3858 | biostudies-arrayexpress

The common germline TP53-R337H mutation is hypomorphic and confers incomplete tumor penetrance and late tumor onset in a mouse model

Project description:The common germline TP53-R337H mutation is hypomorphic and confers incomplete tumor penetrance and late tumor onset in a mouse model

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Genome sequencing of childhood medulloblastoma brain tumors links chromothripsis with TP53 mutations

Project description:Genomic rearrangements typically occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving chromosome shattering and reshuffling ('chromothripsis'), for which no genetic basis has yet been described. Whole-genome sequencing of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome) revealed massive, complex rearrangements resulting from chromothripsis. Integrating TP53 status with genomic rearrangement data in additional medulloblastomas revealed a striking association between TP53 mutation and chromothripsis in SHH-MBs. Unexpectedly, five seemingly sporadic SHH-MB patients with chromothripsis harbored TP53 germline mutations – findings relevant for clinical management. Analysis of additional tumor entities substantiated a link between TP53 mutation and chromothripsis, beyond general genomic instability. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings implicate p53 in the initiation of, or cellular reaction to, chromothripsis – a novel role for the 'guardian of the genome'. The DNA copy-number profiles of 11 primary medulloblastoma samples were analyzed on the Affymetrix Mapping250K Nsp array, together with data from 70 primary samples taken from GSE21140. Data from diploid reference samples were taken from GSE9222. Additionally, DNA copy-number profiles for 19 additional medulloblastoma samples were generated on the Affymetrix SNP6 platform with matched blood samples.

2012-01-20 | E-GEOD-34258 | biostudies-arrayexpress

Genome sequencing of childhood medulloblastoma brain tumors links chromothripsis with TP53 mutations

2012-01-20 | GSE34258 | GEO

A molecular signature of normal breast epithelial and stromal cells from Li-Fraumeni syndrome mutation carriers

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2010-10-21 | E-GEOD-23994 | biostudies-arrayexpress

Incomplete X-inactivation initiated by a hypomorphic Xist allele in the mouse

Project description:Mammals have evolved a mechanism to compensate for the difference in the number of X chromosome genes between XX females and XY males by inactivating one of the two X chromosomes in females. This X chromosome inactivation phenomenon is triggered by Xist gene, which is essential for X-inactivation to occur in cis. We demonstrate that an Xist mutant, XistIVS, is unique in that it retains a partial function to silence the X chromosome, which would provide an opportunity to dissect the molecular mechanism of Xist RNA-mediated chromosome silencing. To study the effect of XistIVS mutation on silencing of X-linked genes, global expression levels of X-linked genes were measured in mutant and control cells. We used female trophoblast stem (TS) cells carrying XistIVS mutation and gene expression was assayed using microarray containing 572 probes corresponding most of the X-linked genes. Then the result was compared with that obtained from wild-type control cells.

2011-03-30 | E-GEOD-27373 | biostudies-arrayexpress

Genomic profiling of TP53 and non-TP53 Li-Fraumeni syndrome tumors reveals hits in the p53 and overlapping pathways

Project description:Li-Fraumeni syndrome (LFS) is a rare, clinically and genetically heterogeneous inherited cancer syndrome. Most cases are due to mutations in TP53. CHK2 is a minor predisposing locus; we recently mapped a third locus to 1q23. In both TP53 and non-TP53 LFS, there is evidence for risk heterogeneity within and between kindreds, suggesting additional risk modifiers. Using BAC- and SNP-based microarrays, we performed genomic profiling of primary soft tissue sarcomas, osteosarcomas and matching constitutive samples of 10 LFS patients (6 with and 4 without TP53 mutations), to identify genome-wide patterns of copy number changes and loss-of-heterozygosity (LOH). Our complementing global approaches revealed several interesting patterns for TP53 and non-TP53 LFS tumors, including positive (1q/7, 3p/15, 4q/9q, 8q/19p, 9p/10q, 13/14 and 15q/18q) and negative (2q/9q, 3q/14q and 4q/6q) associations between chromosomal regions. The region containing the oncogene TWIST1 (7p21.1) was the most common gain independent of TP53 status and tumor type, while LOH of 8q11.2 with the tumor suppressor ST18 was the only region exclusively associated with non-TP53 soft tissue sarcomas. We resequenced known mutations in BRAF, KRAS and NRAS and identified somatic NRAS mutations in 2 of 10 tumors. TP53 and non-TP53 LFS tumors shared multiple hits in genes of the p53 and overlapping pathways. Although common dogma in cancer genetics holds that multiple hits in the same pathway are redundant and thus unlikely, we show that different combinations of genetic alterations in both TP53 and non-TP53 LFS tumors appear to act together in the p53 network in LFS tumorigenesis Keywords: Comparative genomic hybridization Using the Spectral Genomics dye-swap BAC arrays we studied 10 Li Fraumeni syndrome tumor cases

2008-07-16 | E-GEOD-8798 | biostudies-arrayexpress

The Common Germline <i>TP53-R337H</i> Mutation Is Hypomorphic and Confers Incomplete Penetrance and Late Tumor Onset in a Mouse Model.

Project description: Not available

| S-EPMC8137600 | biostudies-literature

5-Fluorouridine restores functional full-length p53 in TP53 nonsense mutant human tumor cells (Ribo-Seq)

Project description:The tumor suppressor gene TP53 is mutated in approximately half of all human tumors. Of those, around 10% are nonsense mutations that produce truncated and inactive p53 protein. Induction of translational readthrough is a promising approach for rescuing full-length p53 and thereby eliminate tumor cells with nonsense mutant TP53. To find novel nonsense mutant TP53 readthrough-inducing compounds with a tolerable toxicity profile, we performed an in silico screening of data at the National Cancer Institute database and identified 5-Fluorouracil (5-FU). We show here that 5-FU induces full-length p53 in human tumor cells carrying R213X nonsense mutant TP53 and that this activity is mediated by its metabolite 5-Fluorouridine (FUr). Ribo-seq analysis validated induction of translational readthrough by FUr. We also show that FUr is incorporated into RNA where it potentially allows base pairing of Arg tRNA at the R213X UGA premature termination codon. Full-length p53 rescued by FUr is transcriptionally active and triggers p53-dependent cell death. Moreover, treatment with 5-FU or FUr restores full-length p53 expression in TP53 R213X mutant human tumor xenografts in vivo. Our results suggest that induction of readthrough by 5-FU/FUr could contribute to therapeutic efficacy in patients with TP53 nonsense mutant tumors.

2022-12-01 | GSE196709 | GEO

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