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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PROVIDER: PRJNA702070 | ENA |
REPOSITORIES: ENA
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Project description: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.
2021-03-01 | GSE166819 | GEO
Project description:Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are commonly used to model arrhythmogenic cardiomyopathy (ACM), a heritable cardiac disease characterized by severe ventricular arrhythmias, fibrofatty myocardial replacement and progressive ventricular dysfunction. Although ACM is inherited as an autosomal dominant disease, incomplete penetrance and variable expressivity are extremely common, resulting in different clinical manifestations. Here, we propose hiPSC-CMs as a powerful in vitro model to study incomplete penetrance in ACM. Six hiPSC lines were generated from blood samples of three ACM patients carrying a heterozygous deletion of exon 4 in the PKP2 gene, two asymptomatic (ASY) carriers of the same mutation and one healthy control (CTR), all belonging to the same family. Whole exome sequencing was performed in all family members and hiPSC-CMs were examined by ddPCR, western blot, Wes™ immunoassay system, patch clamp, immunofluorescence and RNASeq. Our results show molecular and functional differences between ACM and ASY hiPSC_x0002_CMs, including a higher amount of mutated PKP2 mRNA, a lower expression of the connexin-43 protein, a lower overall density of sodium current, a higher intracellular lipid accumulation and sarcomere disorganization in ACM compared to ASY hiPSC_x0002_CMs. Differentially expressed genes were also found, supporting a predisposition for a fatty phenotype in ACM hiPSC-CMs. These data indicate that hiPSC-CMs are a suitable model to study incomplete penetrance in ACM.
2023-07-14 | GSE222793 | GEO
Project description:The TP53-R337H founder mutation exists at a high frequency throughout southern Brazil and represents one of the most common germline TP53 mutations reported to date. It was identified in pediatric adrenocortical tumors in families with a low incidence of cancer. The R337H mutation has since been found in association with early-onset breast cancers and Li-Fraumeni syndrome (LFS). To study this variability in tumor susceptibility, we generated a knockin mutant p53 mouse model (R334H). Endogenous murine p53-R334H protein was naturally expressed at high levels in multiple tissues and was functionally compromised in a tissue- and stress-specific manner. Mutant p53-R334H mice developed tumors with long latency and incomplete penetrance, consistent with many human carriers being at a low but elevated risk for cancer. These findings suggest the involvement of additional cooperating genetic alterations when TP53-R337H occurs in the context of LFS, which has important implications for genetic counseling and long-term clinical follow-up. SIGNIFICANCE: A p53-R334H knockin mouse serves as an important model for studying the most common inherited germline TP53 mutation (R337H) that is associated with variable tumor susceptibility.
| S-EPMC8137600 | biostudies-literature
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
Project description:Modeling incomplete penetrance in arrhythmogenic cardiomyopathy by human induced pluripotent stem cell derived cardiomyocytes
| PRJNA923372 | ENA
Project description:Bcl11b hypomorphic mutant thymocytes
| PRJNA356604 | ENA
Project description:Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with a highly penetrant and diverse tumor spectrum characterized by germline mutations in the TP53 tumor suppressor gene. To better understand how TP53 mutations predispose individuals with LFS to cancer development, we characterized tp53 R217H and R242H zebrafish lines as the first zebrafish p53 hotspot mutants (human R248 and R273H). These mutants have lost several key wildtype p53 functions and recapitulate many LFS phenotypes. Specifically, we have shown that the R217H and R242H alleles result in partial-to-no activation of key p53 target genes, are resistant to apoptosis in a dominant negative manner and exhibit a defective G1 cell-cycle checkpoint in vivo. The loss of these wildtype p53 functions predisposed the fish to develop spontaneous tumors as early as 6 months of age. Tumor histology resembles human sarcomas, a predominant LFS tumor type. tp53 R242H mutants developed tumors earlier with a higher lifetime incidence than tp53 null or R217H mutants, suggesting it is a more aggressive mutation, while the R217H allele may be hypomorphic. Additionally, we observed mutation-specific differences both in the tumor type and sex bias across tp53 null, R217H, and R242H genotypes with associated diverse transcriptomic and DNA methylome profiles, impacting metabolism, cell signalling, and biological macromolecule synthesis and degradation. These tp53 zebrafish mutants demonstrate fidelity to their human counterparts and provide new insights into underlying tumorigenesis mechanisms and kinetics, which may inform more tailored tumor surveillance approaches and novel therapeutic targets in LFS.
2024-05-29 | GSE268283 | GEO
Project description:Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with a highly penetrant and diverse tumor spectrum characterized by germline mutations in the TP53 tumor suppressor gene. To better understand how TP53 mutations predispose individuals with LFS to cancer development, we characterized tp53 R217H and R242H zebrafish lines as the first zebrafish p53 hotspot mutants (human R248 and R273H). These mutants have lost several key wildtype p53 functions and recapitulate many LFS phenotypes. Specifically, we have shown that the R217H and R242H alleles result in partial-to-no activation of key p53 target genes, are resistant to apoptosis in a dominant negative manner and exhibit a defective G1 cell-cycle checkpoint in vivo. The loss of these wildtype p53 functions predisposed the fish to develop spontaneous tumors as early as 6 months of age. Tumor histology resembles human sarcomas, a predominant LFS tumor type. tp53 R242H mutants developed tumors earlier with a higher lifetime incidence than tp53 null or R217H mutants, suggesting it is a more aggressive mutation, while the R217H allele may be hypomorphic. Additionally, we observed mutation-specific differences both in the tumor type and sex bias across tp53 null, R217H, and R242H genotypes with associated diverse transcriptomic and DNA methylome profiles, impacting metabolism, cell signalling, and biological macromolecule synthesis and degradation. These tp53 zebrafish mutants demonstrate fidelity to their human counterparts and provide new insights into underlying tumorigenesis mechanisms and kinetics, which may inform more tailored tumor surveillance approaches and novel therapeutic targets in LFS.
2024-05-22 | GSE267760 | GEO
Project description:Mutational inactivation of TP53 is a common event in cancer. Germline mutations in TP53 that inactivate this protein also occur in Li Fraumeni syndrome, which predisposes to early-onset cancer. In addition, there are dozens of other germline variants in TP53 that do not completely inactivate the function of this protein. In many cases studies have shown strong support for an impact of these lesser-functioning hypomorphs with increased cancer risk in humans and mouse models; however, the majority of these hypomorphs have yet to be categorized as pathogenic in clinical genetics databases. There is thus need for a functional assay to distinguish lesser-functioning hypomorphic p53 variants from wild type p53, or benign, fully-functional, variants. We report the surprising finding that two different African-centric genetic hypomorphs of p53, which occur in distinct functional domains of the protein, share common activities. We show that the Pro47Ser variant in the transactivation domain and the Tyr107His variant in the DNA binding domain both share increased propensity to misfold into a conformation specific for mutant p53. Moreover, cells and tissues with these variants show increased NF-B activity. We have identified a common gene signature from unstressed lymphocyte cell lines that is shared between these two, and other, genetic missense hypomorphs of TP53. We show that this gene signature successfully distinguishes wild type p53 and a benign p53 variant from lesser-functioning hypomorphic variants. These findings should allow us to better understand how hypomorphic variants contribute to cancer risk, and to better inform cancer risk in hypomorph carriers.
2023-03-01 | GSE209837 | GEO
Project description:Background: The tumor suppressor gene TP53 is frequently mutated or inactivated in bladder cancer (BLCA), which is implicated in the pathogenesis of tumor. However, the cellular mechanisms of TP53 mutations are complicated, yet well-defined, but their clinical prognostic value in the management of BLCA remains controversial. This study aimed to explore the role of TP53 mutation in regulating the tumor microenvironment (TME), elucidate the effects of TP53 activity on BLCA prognosis and immunotherapy response. Methods: A TP53-related signature based on TP53-induced and TP53-repressed genes was used to construct a TP53 activity-related score and classifier. The abundance of different immune cell types was determined using CIBERSORT to estimate immune cell infiltration. Moreover, the heterogeneity of the tumor immune microenvironment between the high and low TP53 score groups was further evaluated using single-cell mass cytometry (CyTOF) and imaging mass cytometry (IMC). Moreover, pathway enrichment analysis was performed to explore the differential biological functions between tumor epithelial cells with high and low TP53 activity scores. Finally, the receptor–ligand interactions between immune cells and tumor epithelial cells harboring distinct TP53 activity were analyzed by single-cell RNA-sequencing. Results: The TP53 activity-related gene signature differentiated well between TP53 functional retention and inactivation in BLCA. BLCA patients with low TP53 scores had worse survival prognosis, more TP53 mutations, higher grade, and stronger lymph node metastasis than those with high TP53 scores. Additionally, CyTOF and IMC analyses revealed that BLCA patients with low TP53 scores exhibited a potent immunosuppressive TME. Consistently, single-cell sequencing results showed that tumor epithelial cells with low TP53 scores were significantly associated with high cell proliferation and stemness abilities and strongly interacted with immunosuppressive receptor–ligand pairs. Conclusions: Patients with BLCA with low TP53 scores have a worse prognosis and a more immunosuppressive TME. This TP53 activity-related signature can serve as a potential prognostic signature for predicting the immune response, which may facilitate the development of new strategies for immunotherapy in BLCA. Keywords: bladder cancer, TP53, immunosuppression, tumor microenvironment
2022-10-24 | GSE216037 | GEO