Beagle Frameshift mutation-BE020
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REPOSITORIES: ENA
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Project description:DNA mismatch repair deficiency (MMRD) drives microsatellite instability (MSI). Cells with MSI accumulate numerous frameshift mutations. Frameshift mutations affecting cancer-related genes may promote tumorigenesis and, therefore, are shared among independently arising MSI tumors. Consequently, such recurrent frameshift mutations can give rise to shared immunogenic frameshift peptides (FSPs) that represent ideal candidates for a vaccine against MSI cancer. Pathogenic germline variants of mismatch repair genes cause Lynch syndrome (LS), a hereditary cancer syndrome affecting approximately 20-25 million individuals worldwide. LS individuals are at high risk of developing MSI cancer. Previously, we demonstrated safety and immunogenicity of an FSP-based vaccine in a Phase I/IIa clinical trial. However, the cancer-preventive effect of FSP vaccination in the scenario of LS has not been demonstrated so far.
2021-08-30 | GSE175744 | GEO
Project description:Lynch syndrome (LS) patients develop DNA mismatch repair deficient tumors which generate high loads of neoantigens (neoAgs), thus constituting a well-defined population that can benefit from cancer immune-interception strategies, including neoantigen-based vaccines. Using paired whole-exome sequencing and mRNAseq of colorectal cancers (CRC) (n=13) and pre-cancers (n=61) from our LS patient cohort (N=46), we performed in-silico prediction and immunogenicity ranking of highly recurrent frameshift-neoags, followed by their in-vitro validation. We described the somatic mutation landscape in all cancers and pre-cancers, and showed that mutation burden is positively correlated with neoAgs load. Furthermore, our in-vitro validation showed a 65% validation rate of our top 100 predicted neoags. Consistent with neoAgs burden, our transcriptomic results revealed increased infiltration of CD8+ and CD4+ T-cells in microsatellite unstable samples. Overall, our neoAgs catalog and all other findings, improve our understanding of cancer development in LS and guide us towards the advancement of immunoprevention vaccine strategies.
2024-03-25 | GSE224707 | GEO
Project description:programmed ribosomal frameshift Raw sequence reads
| PRJNA310019 | ENA
Project description:Twelve human THAP proteins share the THAP domain, an evolutionary conserved zinc-finger DNA-binding domain. Studies of different THAP proteins have indicated roles in gene transcription, cell proliferation and development. We have analyzed this protein family, focusing on THAP7 and THAP11. We show that human THAP proteins possess differing homo- and heterodimer formation properties and interaction abilities with the transcriptional co-regulator HCF-1. HEK-293 cells lacking THAP7 were viable but proliferated more slowly. In contrast, HEK-293 cells were very sensitive to THAP11 alteration. Nevertheless, HEK-293 cells bearing a human THAP11 mutation identified in a patient suffering from cobalamin disorder (THAP11F80L) were viable although proliferated more slowly. Cobalamin disorder is an inborn vitamin deficiency characterized by neurodevelopmental abnormalities, most often due to biallelic mutations in the MMACHC gene, whose gene product MMACHC is a key enzyme in the cobalamin metabolic pathway. We show that THAP11F80L selectively affected promoter binding by THAP11, having more deleterious effects on a subset of THAP11 targets, and resulting in altered patterns of gene expression. In particular, THAP11F80L exhibited a strong effect on association with the MMACHC promoter and led to a decrease in MMACHC gene transcription, suggesting that the THAP11F80L mutation is directly responsible for the observed cobalamin disorder.
2019-12-20 | GSE138207 | GEO
Project description:Twelve human THAP proteins share the THAP domain, an evolutionary conserved zinc-finger DNA-binding domain. Studies of different THAP proteins have indicated roles in gene transcription, cell proliferation and development. We have analyzed this protein family, focusing on THAP7 and THAP11. We show that human THAP proteins possess differing homo- and heterodimer formation properties and interaction abilities with the transcriptional co-regulator HCF-1. HEK-293 cells lacking THAP7 were viable but proliferated more slowly. In contrast, HEK-293 cells were very sensitive to THAP11 alteration. Nevertheless, HEK-293 cells bearing a human THAP11 mutation identified in a patient suffering from cobalamin disorder (THAP11F80L) were viable although proliferated more slowly. Cobalamin disorder is an inborn vitamin deficiency characterized by neurodevelopmental abnormalities, most often due to biallelic mutations in the MMACHC gene, whose gene product MMACHC is a key enzyme in the cobalamin metabolic pathway. We show that THAP11F80L selectively affected promoter binding by THAP11, having more deleterious effects on a subset of THAP11 targets, and resulting in altered patterns of gene expression. In particular, THAP11F80L exhibited a strong effect on association with the MMACHC promoter and led to a decrease in MMACHC gene transcription, suggesting that the THAP11F80L mutation is directly responsible for the observed cobalamin disorder.
2019-12-20 | GSE138205 | GEO
Project description:The transcription factor GATA3 is a favorable prognostic indicator in estrogen receptor-M-NM-1 (ERM-NM-1)-positive breast tumors in which it participates with ERa and FOXA1 in a complex transcriptional regulatory program driving tumor growth. Paradoxically, GATA3 mutations are frequent in breast cancer and have been classified as drivers. To elucidate the contribution(s) of GATA3 alterations to oncogenesis, we studied two breast cancer cell lines, MCF7, which carries a heterozygous frameshift mutation in the second zinc finger of GATA3, and T47D, wild-type at this locus. Heterozygosity for the truncating mutation conferred protection from regulated turnover of GATA3, ERa and FOXA1 following estrogen stimulation. Thus, mutant GATA3 uncouples protein-level regulation of master regulatory transcription factors from hormone action. Consistent with increased protein stability, ChIP-seq profiling identified stronger accumulation of GATA3 in cells bearing the mutation, albeit with a similar distribution across the genome. We propose that this specific, cancer-derived mutation in GATA3 deregulates physiologic protein turnover, stabilizes GATA3 binding across the genome and modulates the response of mammary epithelial cells to hormone signaling, thus conferring a selective growth advantage. Genome-wide mapping of GATA3 in two cell lines. There were two biological replicates and unchipped (input) DNA was used as reference.
2014-04-01 | E-GEOD-51274 | biostudies-arrayexpress
Project description:The transcription factor GATA3 is a favorable prognostic indicator in estrogen receptor-α (ERα)-positive breast tumors in which it participates with ERa and FOXA1 in a complex transcriptional regulatory program driving tumor growth. Paradoxically, GATA3 mutations are frequent in breast cancer and have been classified as drivers. To elucidate the contribution(s) of GATA3 alterations to oncogenesis, we studied two breast cancer cell lines, MCF7, which carries a heterozygous frameshift mutation in the second zinc finger of GATA3, and T47D, wild-type at this locus. Heterozygosity for the truncating mutation conferred protection from regulated turnover of GATA3, ERa and FOXA1 following estrogen stimulation. Thus, mutant GATA3 uncouples protein-level regulation of master regulatory transcription factors from hormone action. Consistent with increased protein stability, ChIP-seq profiling identified stronger accumulation of GATA3 in cells bearing the mutation, albeit with a similar distribution across the genome. We propose that this specific, cancer-derived mutation in GATA3 deregulates physiologic protein turnover, stabilizes GATA3 binding across the genome and modulates the response of mammary epithelial cells to hormone signaling, thus conferring a selective growth advantage.
2014-04-01 | GSE51274 | GEO
Project description:We are interested in using both spontaneous and stimulated Raman microscopy to visualize these metabolomic changes as spectral alterations. We have two isogneic cell lines of normal human astrocytes differing only by a point mutation in the IDH-1 gene. We will work with the metabolomics core to elucidate the changes in central metabolism and lipid synthesys in an effort to determine the precise biochemical alterations underlying observed spectral differences. We wil then use a selective inhibitor of the IDH1 R132H to demonstrate to attempt to return TCA metabolome and lipidome to WT phenotype. Lastly, we will use a cell-permeablized variant of 2HG (2R-octyl-alpha-hydroxyglutarate) to recaptitulate the R132H mutant phenotype in wild-type cells, providing strong evidence that 2HG accumulation uderlies the metabolomic (and thus, spectral) changes observed.
2017-07-14 | ST000821 | MetabolomicsWorkbench
Project description:POC1A encodes a WD repeat protein localizing to centrioles and spindle poles and associated with Short stature, onychodysplasia, facial dysmorphism and hypotrichosis (SOFT) syndrome (OMIM #614813). In our study, we reported on two patients with primordial dwarfism (PD) from the same family. We utilized Whole Exome Sequencing (WES) in the patients to screen all PD related genes and to define putative novel candidate genes. A novel homozygous p.T120A missense mutation was detected in POC1A, a known causative gene of SOFT syndrome, and confirmed using Sanger sequencing. To confirm the pathogenicity of the detected mutation, primary fibroblast cultures obtained from the patients and a control individual were used. Gene expression profiles of the fibroblast cultures were taken. We performed gene expression arrays on fibroblasts cultured from patients with SOFT syndrome and POC1A mutation and compared their expression profiles to that of control fibroblast cells.
2015-07-15 | E-GEOD-66314 | biostudies-arrayexpress
Project description:We are interested in using both spontaneous and stimulated Raman microscopy to visualize these metabolomic changes as spectral alterations. We have two isogneic cell lines of normal human astrocytes differing only by a point mutation in the IDH-1 gene. We will work with the metabolomics core to elucidate the changes in central metabolism and lipid synthesys in an effort to determine the precise biochemical alterations underlying observed spectral differences. We wil then use a selective inhibitor of the IDH1 R132H to demonstrate to attempt to return TCA metabolome and lipidome to WT phenotype. Lastly, we will use a cell-permeablized variant of 2HG (2R-octyl-alpha-hydroxyglutarate) to recaptitulate the R132H mutant phenotype in wild-type cells, providing strong evidence that 2HG accumulation uderlies the metabolomic (and thus, spectral) changes observed.
2017-07-14 | ST000822 | MetabolomicsWorkbench