14977 results for "cancer studies using rna-seq"

in 89.55 milliseconds.

• Genomic Basis of Phenotypic Variability of Complex Disorders

  The 520-kbp deletion on chromosome 16p12.1 is associated with multiple neurodevelopmental outcomes, including intellectual disability/developmental delay (ID/DD), schizophrenia, autism, and epilepsy. This variant is inherited in >95% of cases from carrier parents manifesting neuropsychiatric features, while affected children with the deletion were more likely to carry another large Copy Number Variation (CNV) or rare deleterious mutation elsewhere in the genome, or "second-hits", compared to carrier parents. Thus, while the 16p12.1 deletion confers significant risk for a range of disorders, the ultimate phenotypic trajectory is determined by "second-hit" variants in the genetic background. However, outstanding questions remain about the genetic background in these disorders, including the functional effects of "second-hit" variants towards gene expression or developmental phenotypes, the full spectrum of "second-hit" variants, and the mechanisms driving accumulation of these variants.In version 1, we performed deep clinical phenotyping, whole-genome sequencing (WGS), SNP microarray analysis, and RNA-sequencing of lymphoblastoid cell lines of 32 individuals in five large families with the 16p12.1 deletion. We found that specific classes of rare single-nucleotide and structural variants in coding and non-coding regions contributed towards expression changes in affected children based on their inheritance patterns, including a subset of variants that acted synergistically with the deletion to alter expression. We further found that rare variant-mediated expression changes contribute to specific developmental phenotypes in the carrier children, suggesting a potential genetic mechanism for variable expressivity of the deletion.In version 2, we additionally analyzed genetic and phenotypic data from individuals with 16p12.1 deletion and their spouses to assess the role of assortative mating modulating phenotypic outcomes of the 16p12.1 deletion. We identified significant within- and cross- disorder phenotypic correlations between spouses, but observed no significant genetic correlations between spouses, in line with expectations.

  Study phs002450

• Genomic profiling of paediatric high grade gliomas from the HERBY clinical trial

  The HERBY trial was a phase-II open-label, randomised, multicentre trial evaluating bevacizumab in patients with newly-diagnosed non-brainstem high grade glioma (HGG) between the ages of 3-18yrs. 121 patients were randomised with 1yr event-free survival as the primary end-point. Confirmation of HGG diagnosis by reference pathology was mandatory before randomisation, followed by review with five independent expert neuropathologists. We collected specimens from 89 patients consenting to translational research, and performed Sanger sequencing for H3F3A, Illumina 450K BeadArray methylation profiling, and whole exome sequencing and RNA sequencing where possible. 7/89 patients (8%) harboured H3F3A G34R/V mutations, whilst 24/89 (27%) harboured H3F3A K27M, the latter reflecting a high proportion of the novel entity recognised in the 2016 WHO classification of diffuse midline glioma with H3K27M mutation. Both histone mutations conferred a significantly shorter progression-free (p=0.0104) and overall survival (p=0.00159). 450K methylation subtyping additionally identified a number of subgroups in histone wild-type cases. These included infrequent (4/86, 4.6%) cases with IDH1 mutation in older children, further categorised into astrocytic ATRX-mutant (n=3) or 1p19q co-deleted with TERT promoter mutation (n=1). 9/74, (12%) of cases were classified as biologically resembling pleomorphic xanthoastrocytoma (PXA) by methylation profiling, with 5/9 harbouring BRAF V600E mutations and epithelioid histology, and 3/9 NF1 mutation and giant cell features. Three cases had methylation profiles more closely resembling low grade gliomas, though were morphologically high grade, and harboured MAPK dysregulation in two cases, with the third part of an additional infant (<3yrs) cohort. Finally, four cases had a mutational burden several orders of magnitude higher than the rest, with (2197-5332) somatic coding variants/sample reflecting a hypermutator phenotype. These data provide an important insight into the wide biological diversity of ‘HGG’ found in the paediatric age group and allow for a profound refinement of clinical trial interpretation.

  Study EGAS00001002328

• A circulating biomarker for severity of facioscapulohumeral muscular dystrophy

  Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable skeletal myopathy. Clinical trials for FSHD are hindered by heterogeneous biomarkers poorly associated with clinical severity, requiring invasive muscle biopsy. Macroscopically FSHD presents with slow fatty replacement of muscle, rapidly accelerated by inflammation. Mis-expression of the transcription factor DUX4 is currently accepted to underlie FSHD pathogenesis and mechanisms including PAX7 target gene repression have been proposed. Here we perform RNA-sequencing on MRI guided inflamed (n=24) and isogenic non-inflamed (n=24) muscle biopsies from the same clinically characterised FSHD patients, alongside isogenic peripheral blood mononucleated cells from a subset of patients (n=13), and unaffected controls. We employ multivariate models to evaluate the clinical associations of 5 published FSHD transcriptomic biomarkers. We demonstrate that PAX7 target gene repression can discriminate control, inflamed and non-inflamed FSHD muscle independently of age and sex (p<0.013), while the discriminatory power of DUX4 target genes is limited to distinguishing FSHD muscle from control. Importantly, the level of PAX7 target gene repression in non-inflamed muscle associates with clinical assessments of FSHD severity (p=0.04). DUX4 target gene biomarkers in FSHD muscle show associations with lower limb fat fraction and D4Z4 array length, but not clinical assessment. Lastly, PAX7 target gene repression in FSHD muscle correlates with the level in isogenic peripheral blood mononucleated cells (p=0.002). A refined PAX7 target gene biomarker comprising 143/601 PAX7 target genes computed in peripheral blood (the FSHD muscle-blood biomarker) associates with clinical severity in FSHD patients (p<0.036). Our new circulating biomarker validates as a classifier of clinical severity in an independent data set of 54 FSHD patient blood samples, with improved power in older patients (p=0.03). In summary, we present the minimally invasive FSHD muscle-blood biomarker of FSHD clinical severity valid in patient muscle and blood, with potential utility in routine disease monitoring and clinical trials.

  Study EGAS00001007350

• IFN-γ and TNF-α drive a CXCL10+ CCL2+ Macrophage Phenotype Expanded in Severe COVID-19 Lungs and Inflammatory Diseases with Tissue Inflammation

  We explored how the human macrophages response to different inflammatory factors, focusing particularly on the effects of antiviral interferons (IFN-β and IFN-γ), pro-inflammatory cytokines such as TNF-α, and other mediators like IL-4. Co-cultured fibroblasts were a component in some conditions to generate factors produced by resident stroma. We used a single-cell antibody-based hashing strategy to multiplex samples from different stimulatory conditions in one sequencing run. This macrophage transcriptomic data reveals distinct macrophage activation states and polarizations shaped by different tissue-related inflammatory conditions at single-cell resolution. We further performed an unbiased integration between tissue-level macrophages and this stimulated human blood-derived macrophages, which pinpoint an IFN-γ and TNF-α synergistically driven inflammatory macrophage phenotype expanded in severe COVID-19 lungs and other inflamed disease tissues.

  Study phs002780

• A Multimodal Atlas of Human Brain Cell Types

  "A multimodal atlas of human brain cell types" includes sample data targeting two cell types that show species differences between mouse and human. First, it includes a detailed transcriptomic, morphological, and electrophysiological characterization of cell types in layer 1 of human middle temporal gyrus, focusing primarily on different inhibitory cell types. This project also includes gene expression data collected from nuclei in layer 5 of human fronto-insula, with a goal of identifying transcriptomic signatures of Von Economo neurons. Control samples collected as part of the same experiment are also included in the data set. This study was conducted as part of a collaboration between the Allen Institute for Brain Science, the University of Szeged, and the J. Craig Venter Institute. Collaborators request that publications resulting from these data cite their original publication: Transcriptomic and morphophysiological evidence for a specialized human cortical GABAergic cell type (PMID: 30150662).

  Study phs001791

• Anaplastic oligodendroglioma exome and RNA sequencing data

  Anaplastic oligodendrogliomas (AOs) are rare primary brain tumors which are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosome 1p/19q co-deletion and IDH mutation. We analyzed 51 AOs by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. 80% of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frame shift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumor type. Our analysis provides further insights into the unique and shared pathways driving AO.

  Study EGAS00001001209

• RNA sequencing CYLD cutaneous syndrome

  Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. We comprehensively profiled the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families. Novel recurrent mutations were found in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumours suggest that isoform specific DNMT3A2 mutations are associated with dysregulated Wnt/ß-catenin pathway signaling. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumours. These findings add novel dimensions to existing paradigms of cutaneous tumorigenesis and metastasis.

  Study EGAS00001003841

• Molecular characterization of NASH-HCC

  We collected 80 NASH-HCCs formalin fixed paraffin-embedded (FFPE) samples from 5 different institutions. NASH was diagnosed in FFPE samples by at least two expert pathologists following a described histological algorithm (Bedossa et al., Hepatology, 2012). All NASH patients included in the study were HBV- and HCV-negative. Patients reporting alcohol consumption ≥ 20 g/day for women and 30 g/day for men, as well as patients with a known liver disease superimposed to NASH were excluded. Tumour and paired non-tumour gDNA of NASH-HCC FFPE samples was submitted to Whole Exome Sequencing (WES). Exome capture and sequencing library preparation were performed using the SureSelect Human All Exon V5, no UTR hybridization capture kit from Agilent (Target Size 50 Mb). Libraries were sequenced on an Illumina HiSeq 4000 instrument with 100-bp paired-end reads.

  Dataset EGAD00001007524

• Multi-region sequencing of RCC with VTT and metastasis using WES and RNAseq

  This dataset contains multi-region sequencing of 16 RCC patients with venous tumor thrombus (VTT), 11 of which were either metastatic on diagnosis or recurred with metastasis. Whole exome sequencing is available for 94 samples across all 16 patients, including 1 matched normal sample per patient, 2-3 primary tumor samples per patient, 1-2 VTT samples per patient, and 0-3 metastasis samples per patient (metastatic lesions were only sampled for 8 of the 11 metastatic patients). RNAseq, generated by exome capture, is available for 67 samples across 12 patients, including 0-1 matched normal samples per patient, 3 primary tumor samples per patient, 0-1 VTT samples per patient, and 0-3 metastasis samples per patient (RNAseq was only available for 4 of the 8 patients from whom metastatic lesions were sampled).

  Dataset EGAD00001008441

• Systolic Blood Pressure Intervention Trial (SPRINT-BioLINCC)

  Available DataThe available data include all elements of the previously released SPRINT Primary Outcome Paper (SPRINT-POP) data, the full SPRINT clinical data including the MRI and MIND data, and select ancillary study data (Ambulatory Blood Pressure Monitoring, APOL1, Acute Kidney Injury, ASK, Heart, FAST, PWV, Renal Resistance, Biomarkers, Plasma AD).ObjectiveThe Systolic Blood Pressure Trial (SPRINT) was conducted to test the hypothesis that treating systolic blood pressure to a target of less than 120 mm Hg, as compared to a target of less than 140 mm Hg, would reduce the incidence of cardiovascular disease.BackgroundHypertension is a highly prevalent condition among adults and is a leading risk factor for myocardial infarction and stroke. Further, isolated systolic hypertension is the most common form of hypertension in adults over 50 years of age. Observational studies have shown a monotonic increase in cardiovascular risk with systolic blood pressures above 115 mm Hg; however, general population clinical trials have only documented the benefits of lowering systolic blood pressure to a target of 150 mm Hg. A 2007 expert panel sponsored by the National Heart, Lung, and Blood Institute designated the hypothesis that lowering the systolic blood pressure goal to a level SubjectsA total of 9361 participants were enrolled, with 4,678 randomized to the intensive-treatment group and 4,683 randomized to the standard-treatment group.DesignSPRINT was a randomized, single blinded (outcome adjudicators were blinded to treatment assignment) treatment trial with participants randomized to a systolic blood-pressure target of either less than 140 mm Hg (the standard-treatment group) or less than 120 mm Hg (the intensive-treatment group). Following randomization, baseline hypertensive regimens were adjusted in accordance with study treatment algorithms established for each group. The study formulary included all major classes of antihypertensive agents. Investigators could prescribe other antihypertensive medications, but the use of drug classes with the strongest evidence for reduction in cardiovascular outcomes was encouraged. This included thiazide-type diuretics as the first-line agent, loop diuretics for participants with advanced chronic kidney disease, and beta-adrenergic blockers for participants with coronary artery disease. Medications for participants in the intensive-treatment group were adjusted on a monthly basis to target a systolic blood pressure of less than 120 mm Hg. Medications for participants in the standard-treatment group were adjusted to target a systolic blood pressure of 135 to 139 mm Hg, and the dose was reduced if systolic blood pressure was less than 130 mm Hg on a single visit or less than 135 mm Hg on two consecutive visits. Lifestyle modification was encouraged as part of the management strategy.Participants were seen monthly for the first 3 months and every 3 months thereafter. Demographic data were collected at baseline. Clinical and laboratory data were obtained at baseline and every 3 months thereafter. A structured interview was used in both groups every 3 months to obtain self-reported cardiovascular disease outcomes. Medical records and electrocardiograms were obtained for documentation of events. Incidences of hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia that were evaluated in an emergency department were included in adverse event reporting. Occurrences of acute kidney injury or acute renal failure requiring hospitalization were also monitored. The primary outcome was a composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.ConclusionsThe blood pressure intervention was stopped in August of 2015 (median follow-up of 3.26 years) after the cardiovascular outcome results exceeded the boundary for efficacy at two consecutive time points. Compared with a systolic blood pressure target of less than 140 mm Hg, an intensive systolic blood pressure target of 120 mm Hg resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause. Significantly higher rates of some adverse events were observed in the intensive-treatment group.

  Study phs003483