The mRNA expression in the sarcomas of Li-Fraumeni syndrome mouse harboring a deleterious p53 mutation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE234883 | GEO | 2023/12/06
REPOSITORIES: GEO
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Project description:The mRNA expression in the sarcomas of Li-Fraumeni syndrome mouse harboring a deleterious p53 mutation
| PRJNA983498 | ENA
Project description:p53 is one of the most extensively studied proteins in cancer research. Mutations in p53 generally abolish normal p53 function, and some mutants can gain new oncogenic functions. However, the mechanisms underlying p53 mutation-driven cancer remains to be elucidated. Our study investigated the function of a heterozygous p53 mutation (p.Asn268Glufs*4) in a Li-Fraumeni syndrome (LFS) patient. We used episomal technology to perform somatic reprogramming, and used molecular and cell biology methods to determine the p53 mutation levels in patient-originated induced pluripotent stem (iPS) cells at the RNA and protein levels. We found that p53 protein expression was not increased in this patient's somatic cells compared with those of a healthy control. p53 mutation facilitates the proliferation of tumor cells by inhibiting apoptosis and promoting cell division. It can inhibit the efficiency of somatic reprogramming by inhibiting OCT4 expression during reprogramming stage. Moreover, not all p53 mutant iPS cell lines have mutant p53 RNA sequences. A small percentage of mutant p53 mRNA is present in the somatic cells from the patient and his mother. In summary, this p53 mutation can promote tumor cell proliferation, inhibit somatic reprogramming, and exhibit random p53 allelic expression of heterozygous mutations in the patient and iPS cells which may be one of the reasons why the people with p53 mutations develop cancer at random. This finding suggested that mutant p53 allelic expression should be added to the risk forecasting of cancer.
| S-EPMC7282642 | biostudies-literature
Project description:Li-Fraumeni Syndrome (LFS), which is a rare dominantly inherited cancer predisposition syndrome, is associated with germline P53 mutations. Mutations of the tumor suppressor protein P53 are associated with more than 50% of human cancers; however, almost 30% of P53 mutations occur rarely and this has raised questions about their significance. It therefore appeared of particular interest that we identified a novel mutation in a patient suffering from breast cancer and fulfilling the diagnostic criteria of LFS. In this study, a patient with remarkable family history developed breast cancer and was diagnosed with LFS. By performing next-generation sequencing on the patient and subsequent verification by Sanger sequencing among other family members, a new germ-line P53 replication error, a trinucleotide repeat mutation in the coding region, was identified in two generations of this Li-Fraumeni family.
| S-EPMC5794730 | biostudies-literature
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
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
2008-07-16 | GSE8798 | GEO
Project description:Li-Fraumeni syndrome (LFS) is a classic cancer predisposition disorder that is commonly associated with germline mutations of the p53 tumor suppressor gene. Examination of the wide spectrum of adult-onset and childhood cancers and the distribution of p53 mutations has led to a greater understanding of cancer genotype-phenotype correlations. However, the complex LFS phenotype is not readily explained by the simple identification of germline p53 mutations in affected individuals. Recent work has identified genetic events that modify the LFS phenotype. These include intragenic polymorphisms, mutations/polymorphisms of genes in the p53 regulatory pathway, as well as more global events such as aberrant copy number variation and telomere attrition. These genetic events may, in part, explain the breadth of tumor histiotypes within and across LFS families, the apparent accelerated age of onset within families, and the range of clinical outcomes among affected family members. This review will examine the clinical and genetic definitions of LFS and offer insight into how lessons learned from the study of this rare disorder may inform similar questions in other familial cancer syndromes.
| S-EPMC3135649 | biostudies-literature
Project description:Thousands of diverse p53 mutations have been identified in cancer. The leukemia-treating drug arsenic trioxide (ATO) rescues a part of p53 mutations with high potency. To repurpose ATO in personalized p53-targeted therapy, here we quantitatively determined the frequent 800 p53 mutations, covering 95.8% p53 missense-mutation cases in cancer, for their rescue potencies of cell growth inhibitory activity and mouse tumor suppressive activity by ATO. Furthermore, we determined the temperature sensitivity of 800 mutations in mammalian U937 cells and founded that ATO preferentially rescued temperature-sensitive subtype of structural p53 mutants.
2024-08-01 | GSE182927 | GEO
Project description:Germline Hemizygous Deletion of CDKN2A-CDKN2B Locus in a Patient Presenting with Li-Fraumeni Syndrome
| PRJEB13761 | ENA
Project description:Li-Fraumeni syndrome (LFS) is a rare hereditary cancer disorder with highly variable clinical outcomes that results from germline mutations in the TP53 gene. Here we report that the quaternary structure of p53 is an important factor affecting cellular functions and the clinical outcomes of LFS patients (n = 87). Specifically, carriers of monomeric p53 mutants (n = 56) exhibited complete penetrance, with a 2.11-fold greater risk of cancer-related death (95% confidence interval [CI] = 1.07 to 4.30) and a statistically significantly lower median survival age as compared with carriers of multimeric (dimeric or tetrameric, n = 31) p53 mutants (33 years, 95% CI = 30 to 50, vs 51 years, 95% CI = 40 to NA, respectively, two-sided P = .03), who presented incomplete penetrance. Cellular functional assays using p53-null H1299 cells expressing clinically relevant p53 mutants confirmed that the cellular effects observed upon loss of p53 oligomerization are associated with clinical outcomes of LFS patients. The association between p53 oligomeric state and clinical phenotype suggests that TP53 mutations are not all equivalent and supports the implementation of new genotype-adapted guidelines for the management of LFS patients with TP53 mutations in the oligomerization domain.
| S-EPMC6292786 | biostudies-literature
Project description:Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li-Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. Further, p53(A347D) induces striking mitochondrial network aberration and associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Thus, dimer-forming p53 demonstrates both loss-of-function (LOF) and gain-of-function (GOF) properties compared with the wild-type form of the protein.SignificanceA mutant p53 (A347D), which can only form dimers, is associated with increased cancer susceptibility in LFS individuals. We found that this mutant wields a double-edged sword, driving tumorigenesis through LOF while gaining enhanced apoptogenic activity as a new GOF, thereby yielding a potential vulnerability to select therapeutic approaches. See related commentary by Stieg et al., p. 1046. See related article by Gencel-Augusto et al., p. 1230. This article is highlighted in the In This Issue feature, p. 1027.
| S-EPMC10287063 | biostudies-literature