Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA269625 | ENA |
REPOSITORIES: ENA
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Project description:Molecular profiling of breast cancer has achieved great depth in defining the mutational landscapes and molecular profiles of primary tumors, though little is still known regarding cancer evolution into a recurrence. Proteogenomic workflows are particularly useful in defining the multi-layered biology of complex diseases by combining genomic, transcriptomic, and proteomic technologies so to inform not only on mutational processes, but also on their repercussion at the effector level, proteins. We employed our recently developed proteogenomic workflow to analyze a cohort of 27 primary breast cancers and their matched loco-regional recurrences by whole genome sequencing, RNA sequencing, and mass spectrometry.
2023-02-03 | PXD032266 | Pride
Project description:Mutational profiling by targeted next-generation sequencing of a SCCHN cell line model and single-cell derived subclones displaying varying sensitivity to cisplatin was used to determine the extent of intratumoral heterogeneity and to dissect the molecular mechanisms involved in primary cisplatin resistance and treatment-induced clonal evolution.
2017-12-04 | E-MTAB-6021 | biostudies-arrayexpress
Project description:Human cancers arise through an evolutionary process whereby cells acquire somatic mutations that drive them to outgrow normal cells and create successive clonal populations. “Bottom-up” human cancer evolution models could help illuminate this process, but their creation has faced significant challenges. Here we combined human induced pluripotent stem cell (iPSC) and CRISPR/Cas9 technologies to develop a model of the clonal evolution of acute myeloid leukemia (AML). Through the sequential introduction of 3 disease-causing mutations (ASXL1 C-terminus truncation, SRSF2P95L and NRASG12D), we obtained single, double and triple mutant iPSC lines that, upon hematopoietic differentiation, exhibit progressive dysplasia with increasing number of mutations, capturing distinct premalignant stages, including clonal hematopoiesis, myelodysplastic syndrome, and culminating in a transplantable leukemia. iPSC-derived clonal hematopoietic stem/progenitor cells recapitulate transcriptional and chromatin accessibility signatures of normal and malignant hematopoiesis found in primary human cells. By mapping dynamic changes in transcriptomes and chromatin landscapes, we characterize transcriptional programs driving specific stage transitions and identify vulnerabilities for early therapeutic targeting. Such synthetic “de novo oncogenesis” models can empower the investigation of multiple facets of the malignant transformation of human cells.
2021-01-31 | GSE163034 | GEO
Project description:Human tumours show a high level of clonal heterogeneity that contributes to malignant progression and metastasis, but the processes that influence the timing of metastatic dissemination of subclones are unknown. Here, we have used whole exome sequencing of 98 matched benign, malignant, and metastatic skin tumours from genetically heterogeneous mice to demonstrate that most metastases disseminate synchronously from the primary tumour, but then evolve separately, acquiring an additional set of mutations during growth at distant sites. Shared mutations between primary carcinomas and their matched metastases have the distinct A>T signature of the initiating carcinogen Dimethylbanzanthracene (DMBA), but non-shared mutations are primarily G>T or C>T substitutions, associated with oxidative stress. We found recurrent point mutations in several hundred genes, including several in the Ras (Hras, Kras, and Pik3ca) pathway. We propose that carcinogen-driven mouse tumour models can aid our understanding of the forces that shape clonal and genetic evolution of human cancers.
2015-10-11 | GSE63967 | GEO
Project description:Gene-corrected patient-specific induced pluripotent stem (iPS) cells offer a novel approach to gene therapy. Yet it is unknown whether selective pressures during prolonged culture and multiple clonal events would introduce a mutational load incompatible with therapeutic use. Here we begin to assess whether the mutational load of gene-corrected iPS cells is compatible with use in the treatment of genetic causes of retinal degenerative disease. We isolated iPS cells free of transgene sequences from a patient with gyrate atrophy caused by a point mutation in the gene encoding ornithine-δ-aminotransferase (OAT) and used homologous recombination to correct the genetic defect. Cytogenetic analysis, array comparative genomic hybridization (aCGH), and exome sequencing were performed to assess the genomic integrity of an iPS cell line after three sequential clonal events: initial reprogramming, gene targeting, and subsequent removal of a selection cassette. No abnormalities were detected following standard G-band metaphase analysis. However, aCGH and exome sequencing identified two deletions, one amplification, and nine point mutations in protein-coding regions in the initial iPS cell clone. Except for the targeted correction of the single nucleotide in the OAT locus and a single synonymous base pair change, no additional mutations or copy number variation were identified in iPS cells following the two subsequent clonal events. These findings confirm that iPS cells themselves may carry a significant mutational load at initial isolation, but that the clonal events and prolonged cultured required for correction of a genetic defect can be accomplished without a substantial increase in mutational burden. Array comparative genomic hybridization (aCGH) were performed to assess the genomic integrity of an iPS cell line after three sequential clonal events: initial reprogramming, gene targeting, and subsequent removal of a selection cassette. Human CGH 2.1M Whole-Genome Tiling v2.0D Array plus 4633 custom-designed probes which cover the gene targeting construct and the reprogramming plasmid vectors. Comparison of patient iPS cell with full skin fibroblast cells was performed on this design.
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Project description:Predicting and constraining RNA virus evolution require understanding the molecular factors that define the mutational landscape accessible to these pathogens. RNA viruses typically have high mutation rates, resulting in frequent production of protein variants with compromised biophysical properties. Their evolution is necessarily constrained by the consequent challenge to protein folding and function. We hypothesize that host proteostasis mechanisms, may be significant determinants of the fitness of viral protein variants, serving as a critical force shaping viral evolution. Here, we test this hypothesis by propagating influenza in host cells displaying chemically-controlled, divergent proteostasis environments. We find that both the nature of selection on the influenza genome and the accessibility of specific mutational trajectories are significantly impacted by host proteostasis. These findings provide new insights into features of host–pathogen interactions that shape viral evolution, and into the potential design of host proteostasis-targeted antiviral therapeutics that are refractory to resistance.
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Project description:Natural mitochondrial DNA (mtDNA) sequence variation plays a fundamental role in human disease and enables the clonal tracing of native human cells. While various genotyping approaches revealed mutational heterogeneity in human tissues and single cells, current methodologies are limited by scale. Here, we introduce a high-throughput, droplet-based mitochondrial single-cell Assay for Transposase Accessible Chromatin with sequencing (mtscATAC-seq) protocol and computational framework that facilitate high-confidence mtDNA mutation calling in thousands of single cells. Further, the concomitant high-quality accessible chromatin readout enables the paired inference of individual cell mtDNA heteroplasmy, clonal lineage, cell state, and accessible chromatin regulatory features. Our multi-omic analyses reveals single-cell variation in heteroplasmy of a pathologic mtDNA variant (m.8344A>G), which we tie to intra-individual chromatin variability and clonal evolution. Further, using somatic mtDNA mutations, we clonally trace thousands of hematopoietic cells in vitro and in patients with chronic lymphocytic leukemia, linking epigenomic variability to subclonal evolution in vivo.
2020-07-13 | GSE148509 | GEO
Project description:Natural mitochondrial DNA (mtDNA) sequence variation plays a fundamental role in human disease and enables the clonal tracing of native human cells. While various genotyping approaches revealed mutational heterogeneity in human tissues and single cells, current methodologies are limited by scale. Here, we introduce a high-throughput, droplet-based mitochondrial single-cell Assay for Transposase Accessible Chromatin with sequencing (mtscATAC-seq) protocol and computational framework that facilitate high-confidence mtDNA mutation calling in thousands of single cells. Further, the concomitant high-quality accessible chromatin readout enables the paired inference of individual cell mtDNA heteroplasmy, clonal lineage, cell state, and accessible chromatin regulatory features. Our multi-omic analyses reveals single-cell variation in heteroplasmy of a pathologic mtDNA variant (m.8344A>G), which we tie to intra-individual chromatin variability and clonal evolution. Further, using somatic mtDNA mutations, we clonally trace thousands of hematopoietic cells in vitro and in patients with chronic lymphocytic leukemia, linking epigenomic variability to subclonal evolution in vivo.
2020-07-13 | GSE148508 | GEO