Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1280189 | ENA |
REPOSITORIES: ENA
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Project description:Colorectal cancer is the third most common and the second deadliest tumour type in both sexes world-wide. To understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary colorectal cancers in a population-based cohort with long-term follow-up. High quality transcriptome sequences from 1,063 tumours and 120 tissue normals enabled integration analyses of gene mutations and gene expression levels.
2024-05-15 | E-MTAB-12862 | biostudies-arrayexpress
Project description:Polymerase epsilon mutant (POLE-mut) endometrial cancers (EC) are characterized by a near 100% disease-specific survival rate, even when treated by surgery alone. This spectacular survival, combined with the ultramutated genome and high level of neoantigens in these tumors, indicates a substantial degree of immune control in preventing disease spread and recurrence. Although these features are intriguing, the immune infiltration of POLE-mut EC has predominantly been confined to immunohistochemistry studies. Here, we used state of the art single-cell RNA and TCR sequencing to characterize the immune landscape of POLE-mutant ECs. Moreover, we uniquely analyzed patient blood samples taken two to eight years after curative treatment to assess formation of long-term immune memory in circulation. We identified specialized tumor-infiltrating myeloid subsets at different stages of maturation, an array of lymphocytes ranging from immature to cytotoxic and adaptive natural killer (NK) as well as tumor-reactive exhausted and effector T cells, contributing to a highly inflammatory anti-tumor response. Remarkably, our analysis of blood samples taken years after curative treatment uncovered the presence of tumor-reactive T cell clones that matched the primary tumor. This indicates the formation of systemic long-term memory immune responses in POLE-mut EC survivors. Our study highlights the distinctive immunogenicity of POLE-mut EC and identifies key features associated with persistent anti-tumor immunity that may contribute to prolonged, relapse-free survival.
2025-07-16 | GSE298320 | GEO
Project description:Studies of the RNA polymerase-binding molecule ppGpp in bacteria and plants have shown that changes to the kinetics of the RNA polymerase can have dramatic biological effects in the short-term as a stress response. Here we describe the reprogramming of the kinetic parameters of the RNAP through mutations arising during laboratory adaptive evolution of Escherichia coli in minimal media. The mutations cause a 10- to 30-fold decrease in open complex stability at a ribosomal promoter and approximately a 10-fold decrease in transcriptional pausing in the his operon. The kinetic changes coincide with large scale transcriptional changes, including strong downregulation of motility, acid-resistance, fimbria, and curlin genes which are observed in site-directed mutants containing the RNA polymerase mutations as well as the evolved strains harboring the mutations. Site-directed mutants also grow 60% faster than the parent strain and convert the carbon-source 15% to 35% more efficiently to biomass. The results show that long-term adjustment of the kinetic parameters of RNA polymerase through mutation can be important for adaptation to a condition. Mutations in the RNA polymerase beta prime subunit (rpoC) were discovered in E. coli following adaptation to continual logarithmic growth (OD <= 0.3) in glycerol M9 minimal media at 30 C. We used site-directed mutagenesis to make strains of E. coli isogenic to wild-type except for single adaptive rpoC mutations. We found they increase growth rate in this condition by 60%. In order to understand how the mutations affect gene expression in this condition, we extracted total mRNA from the strains, which had been growing in the adaptive evolution condition, at OD=0.3. There were three RNAP mutants and the wild-type (E. coli K-12 MG1655). Each strain had three flasks from which RNA was extracted (three biological replicates). There were no technical replicates. The mRNA was synthesized into cDNA, labeled, and hybridized to an Affymetrix E. coli 2.0 GeneChip.
2010-04-12 | E-GEOD-15500 | biostudies-arrayexpress
Project description:Somatic mutations in the proofreading domain of the replicative DNA polymerase epsilon (POLE-exonuclease domain mutations, POLE-EDMs) are frequently found in colorectal and endometrial cancers and, occasionally, in other tumours. POLE-associated cancers typically display hypermutation, microsatellite stability and a unique mutational signature, with predominance of C > A transversions in the context TCT. To understand better the contribution of hypermutagenesis to tumour development, we have modelled the most recurrent POLE-EDM (POLE-P286R) in Schizosaccharomyces pombe. Whole-genome sequencing analysis revealed that the corresponding pol2-P287R also has a strong mutator effect in vivo, with high frequency of base substitutions and relatively few frameshift mutations. The mutations are equally distributed across different genomic regions, but they occur within an AT-rich context. The most abundant mutations are TCT > TAT transversions and, in contrast to human, TCG > TTG transitions are not elevated, likely due to the absence of cytosine methylation in fission yeast. The high mutation burden of pol2-P287R leads to increased sensitivity to elevated dNTP levels and DNA damaging agents and a phenotype that is exacerbated by depletion of the Pfh1 helicase. In addition, S phase is aberrant and RPA foci are elevated, suggestive of persistent ssDNA or DNA damage, and pol2-P287R shows synthetic lethality with rad3 deletion, indicative of checkpoint activation. Significantly, deletion of translesion polymerases kappa and eta partially suppresses pol2-P287R hypermutation, indicating that both enzymes contribute to this phenotype.
2021-06-11 | GSE169231 | GEO
Project description:Studies of the RNA polymerase-binding molecule ppGpp in bacteria and plants have shown that changes to the kinetics of the RNA polymerase can have dramatic biological effects in the short-term as a stress response. Here we describe the reprogramming of the kinetic parameters of the RNAP through mutations arising during laboratory adaptive evolution of Escherichia coli in minimal media. The mutations cause a 10- to 30-fold decrease in open complex stability at a ribosomal promoter and approximately a 10-fold decrease in transcriptional pausing in the his operon. The kinetic changes coincide with large scale transcriptional changes, including strong downregulation of motility, acid-resistance, fimbria, and curlin genes which are observed in site-directed mutants containing the RNA polymerase mutations as well as the evolved strains harboring the mutations. Site-directed mutants also grow 60% faster than the parent strain and convert the carbon-source 15% to 35% more efficiently to biomass. The results show that long-term adjustment of the kinetic parameters of RNA polymerase through mutation can be important for adaptation to a condition.
2010-04-01 | GSE15500 | GEO
Project description:Escherichia coli can survive for long periods in batch culture in the laboratory, where they experience a stressful and heterogenous environment. During this incubation, E. coli acquires mutations that are selected for in response to this environment, ultimately leading to evolved populations that are better adapted to these complex conditions, which can lead to a better understanding of evolutionary mechanisms. Mutations in regulatory genes often play a role in adapting to heterogenous environments. To identify such mutations, we examined transcriptional differences during log phase growth in unaged cells compared to those that had been aged for 10-days and regrown. We identified expression changes in genes involved in motility and chemotaxis after adaptation to long-term cultures. We hypothesized that aged populations would also have phenotypic changes in motility and that motility may play a role in survival and adaptation to long-term cultures. While aged populations did show an increase in motility, this increase was not essential for survival in long-term cultures. We identified putative mutations in the regulatory gene sspA, as well as other genes, that may contribute to the observed differences in motility. Taken together, these data provide an overall picture of the role of mutations in regulatory genes for adaptation, while underscoring that all changes that occur during evolution in stressful environments are not necessarily adaptive.
2022-05-27 | GSE188790 | GEO
Project description:Evolve and resequence experiments have provided us a tool to understand bacterial adaptation to antibiotics by the gain of genomic mutations. In our previous work, we used short term evolution to isolate mutants resistant to the ribosome targeting antibiotic kanamycin. We had reported the gain of resistance to kanamycin via multiple different point mutations in the translation elongation factor G (EF-G). Furthermore, we had shown that the resistance of EF-G mutants could be increased by second site mutations in the genes rpoD / cpxA / topA / cyaA. In this work we expand on our understanding of these second site mutations. Using genetic tools we asked how mutations in the cell envelope stress sensor kinase (CpxAF218Y) and adenylate cyclase (CyaAN600Y) could alter their activities to result in resistance. We found that the mutation in cpxA most likely results in an active Cpx stress response. Further evolution of an EF-G mutant in a higher concentration of kanamycin than what was used in our previous experiments identified the cpxA locus as a primary target for a significant increase in resistance. The mutation in cyaA results in a loss of catalytic activity and probably results in resistance via altered CRP function. Despite a reduction in cAMP levels, the CyaAN600Y mutant has a transcriptome indicative of increased CRP activity, pointing to an unknown non-catalytic role for CyaA in gene expression. From the transcriptomes of double and single mutants we describe the epistasis between EF-G mutant and these second site mutations. We show that the large scale transcriptomic changes in the topoisomerase I (FusAA608E-TopAS180L) mutant likely result in supercoiling changes in the cell. Finally, genes with known roles in aminoglycoside resistance were present among the mis-regulated genes in the mutants.
2016-07-14 | GSE82343 | GEO
Project description:BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis are poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of BrafV600E in the intestinal tissue of an inducible mouse model. We show that BrafV600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, BrafV600E leads to a persistent transcriptional reprogramming with enrichment of numerous gene signatures indicative of proliferation and tumorigenesis, and signatures suggestive of metabolic rewiring. We focused on the top-ranking cholesterol biosynthesis signature and confirmed its increased expression in human serrated lesions. Functionally, the cholesterol lowering drug atorvastatin prevents the establishment of intestinal crypt hyperplasia in BrafV600E-mutant mice. Overall, our work unveils the long-term impact of BrafV600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins.
2023-09-27 | GSE236515 | GEO
Project description:BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis are poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of BrafV600E in the intestinal tissue of an inducible mouse model. We show that BrafV600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, BrafV600E leads to a persistent transcriptional reprogramming with enrichment of numerous gene signatures indicative of proliferation and tumorigenesis, and signatures suggestive of metabolic rewiring. We focused on the top-ranking cholesterol biosynthesis signature and confirmed its increased expression in human serrated lesions. Functionally, the cholesterol lowering drug atorvastatin prevents the establishment of intestinal crypt hyperplasia in BrafV600E-mutant mice. Overall, our work unveils the long-term impact of BrafV600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins.
2023-09-07 | GSE234372 | GEO