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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

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

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

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

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

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