9931 results for "cancer rna-seq"

in 44.23 milliseconds.

• Intratumoural Heterogeneity Underlies Distinct Therapy Responses and Treatment Resistance in Glioblastoma

  Glioblastomas are the most common and lethal neoplasms of the central nervous system. Neighbouring glioma cells maintain extreme degrees of genetic and phenotypic variation that forms intratumoural heterogeneity. This genetic diversity allows the most adaptive tumour clones to show treatment resistance and conserve the tumour bulk. We aimed to model this phenomenon and test the effectiveness of several targeted therapeutic interventions to overcome therapy resistance. Heterogenic tumour masses were first deconstructed into single tumour cells, which were expanded independently as single-cell clones. SNP arrays, whole-genome and RNA sequencing, and CpG methylation analysis validated the unique molecular profile of each tumour clone, which displayed distinct pathologic features, including cell morphology, growth rate, and resistance to temozolomide and ionizing radiation. We also identified variable sensitivities to AURK, CDK, and EGFR inhibitors, consistent with the heterogenic molecular alterations that each clone harboured. These targeted therapies effectively eliminated the temozolomide- and/or irradiation-resistant clones and also parental polyclonal cells. Our findings indicate that polyclonal tumours create a dynamic environment that consists of diverse tumour elements and treatment responses. Designing targeted therapies based on a range of molecular profiles can be a more effective strategy to eradicate treatment resistance, recurrence, and metastasis.

  Study EGAS00001003438

• Multi-omics integration reveals only minor long-term molecular and functional sequelae in immune cells of individuals recovered from COVID-19

  The majority of COVID-19 patients experience mild to moderate disease course and recover within a few weeks. An increasing number of studies characterized the long-term changes in the specific anti-SARS-CoV-2 immune responses, but how COVID-19 shapes the innate and heterologous adaptive immune system after recovery is less well known. To comprehensively investigate the post-SARS-CoV-2 infection sequelae on the immune system, we performed a multi-omics study by integrating single-cell RNA-sequencing, single-cell ATAC-sequencing, genome-wide DNA methylation profiling, and functional validation experiments in convalescent COVID-19 and healthy individuals. We showed that immune responses generally recover without major sequelae after COVID-19. However, subtle differences persist at the transcriptomic level in monocytes, with downregulation of the interferon pathway, while DNA methylation also displays moderate changes in convalescent COVID-19 individuals. However, these differences did not affect the cytokine production capacity of PBMCs upon different bacterial, viral, and fungal stimuli, although baseline release of IL-1RA and IFN?? was higher in convalescent individuals. In conclusion, despite minor differences in epigenetic and transcriptional programs, the immune system of convalescent COVID-19 patients largely recovers to the homeostatic level of healthy individuals.

  Study EGAS00001005529

• Transcriptomics identifies blunted immunomodulatory effects of vitamin D in people with multiple sclerosis

  Vitamin D deficiency is a risk factor for developing multiple sclerosis (MS). However, the immune effects of vitamin D in people with MS are not well understood. We analyzed transcriptomic datasets generated by RNA sequencing of immune cell subsets (CD4+, CD8+ T cells, B cells, monocytes) from 33 healthy controls and 33 untreated MS cases. We utilized a traditional bioinformatic pipeline and weighted gene co-expression network analysis (WGCNA) to determine genes and pathways correlated with endogenous vitamin D. In controls, CD4+ and CD8+ T cells had 1079 and 1188 genes, respectively, whose expressions were correlated with plasma 25-hydroxyvitamin D level (P<0.05). Functional enrichment analysis identified association with TNF-alpha and MAPK signaling. In CD4+ T cells of controls, vitamin D level was associated with expression levels of several genes proximal to multiple sclerosis risk loci (P=0.01). Genes differentially associated with endogenous vitamin D by case-control status were enriched in TNF-alpha signaling via NF-κB. WGCNA suggested a blunted response to vitamin D in cases relative to controls. Collectively, our findings provide further evidence for the immune effects of vitamin D, and demonstrate a differential immune response to vitamin D in cases relative to controls, highlighting a possible mechanism contributing to MS pathophysiology.

  Study EGAS00001007254

• TNF-induced dynamic regulation of mRNA stabilome in rheumatoid arthritis fibroblast-like synoviocytes

  During rheumatoid arthritis (RA), TNF activates fibroblast-like synoviocytes (FLS) inducing in a temporal order a constellation of genes, which perpetuate synovial inflammation. Although the molecular mechanisms regulating TNF-induced transcription are well characterized, little is known about the impact of mRNA stability on gene expression and the impact of TNF on decay rates of mRNA transcripts in FLS. To address these issues we performed RNA sequencing and genome-wide analysis of the mRNA stabilome in RA FLS. We found that TNF induces a biphasic gene expression program: initially, the inducible transcriptome consists primarily of unstable transcripts but progressively switches and becomes dominated by very stable transcripts. This temporal switch is due to: a) TNF-induced prolonged stabilization of previously unstable transcripts that enables progressive transcript accumulation over days and b) sustained expression and late induction of very stable transcripts. TNF- induced mRNA stabilization in RA FLS occurs during the late phase of TNF response, is MAPK-dependent, and involves several genes with pathogenic potential such as IL6, CXCL1, CXCL3, CXCL8/IL8, CCL2, and PTGS2. These results provide the first insights into genome-wide regulation of mRNA stability in RA FLS and highlight the potential contribution of dynamic regulation of the mRNA stabilome by TNF to chronic synovitis.

  Study phs001371

• Identification and Targeting of Inflammatory Macrophage-Fibroblast Crosstalk in Rheumatoid Arthritis

  Macrophages tailor their function according to the signals found in tissue microenvironments, assuming a wide spectrum of phenotypes. A detailed understanding of macrophage phenotypes in human tissues is limited. Using single-cell RNA sequencing, we defined distinct macrophage subsets in the joints of patients with the autoimmune disease rheumatoid arthritis (RA), which affects ~1% of the population. The subset we refer to as HBEGF+ inflammatory macrophages is enriched in RA tissues and is shaped by resident fibroblasts and the cytokine tumor necrosis factor (TNF). These macrophages promoted fibroblast invasiveness in an epidermal growth factor receptor-dependent manner, indicating that intercellular cross-talk in this inflamed setting reshapes both cell types and contributes to fibroblast-mediated joint destruction. In an ex vivo synovial tissue assay, most medications used to treat RA patients targeted HBEGF+ inflammatory macrophages; however, in some cases, redirecting them into a state is not expected to resolve inflammation. These data highlight how advances in our understanding of chronically inflamed human tissues and the effects of medications therein can be achieved by studies on local macrophage phenotypes and intercellular interactions. Reprinted from Kuo, Ding et al., Science Translational Medicine 2019, PMID: 31068444, with permission from American Association for the Advancement of Science.

  Study phs001340

• InTEAM Consortium - Alcoholic Hepatitis

  Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we describe the transcriptional programs involved in disease progression. We uncovered that development of AH is characterized by the defective activity of liver-enriched transcription factors (LETFs). The PPARG predicted activation state was found increased in early forms of ALD, while AH was associated by a marked decrease in HNF4A-dependent gene expression along with a marked expression of the fetal HNF4A isoform (P2). TGFB1, a key upstream transcriptome regulator in AH, induced the use of HNF4a P2 promoter in hepatocytes, which resulted in abnormal bile acid synthesis and defective metabolic and synthetic functions. PPARG agonists partially prevented this effect. We conclude that targeting TGFB1 and epigenetic drivers that modulate HNF4A-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH. The study was conducted thanks to a multicenter collaboration under the National Institute of Alcohol Abuse and Alcoholism (NIAAA)-funded consortium: Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis (InTEAM).

  Study phs001807

• Generation of a Cellular Atlas of Human Adipose Tissue

  White adipose tissue (WAT), once regarded as morphologically and functionally bland, is now recognized to be dynamic, plastic, heterogenous, and involved in a wide array of biological processes including energy homeostasis, glucose and lipid handling, blood pressure control, and host defense.  High fat feeding and other metabolic stressors cause dramatic changes in adipose morphology, physiology, and cellular composition, and alterations in adiposity are associated with insulin resistance, dyslipidemia, and Type 2 diabetes (T2D). Here we provide detailed cellular atlases of human and murine subcutaneous and visceral white fat at single-cell resolution across a range of body weight. We identify subpopulations of adipocytes, adipose stem and progenitor cells (ASPCs), vascular, and immune cells and demonstrate commonalities and differences across species and dietary conditions. We link specific cell types to increased risk of metabolic disease, and we provide an initial blueprint for a comprehensive set of interactions between individual cell types in the adipose niche in leanness and obesity. We also utilize bulk RNA sequencing data of enzymatically digested human adipocytes to scale these findings to a larger cohort. These data comprise an extensive resource for the exploration of genes, traits, and cell types in the function of WAT across species, depots, and nutritional conditions. 

  Study phs002766

• NHLBI TOPMed - NHGRI CCDG: Atherosclerosis Risk in Communities (ARIC)

  Participants from the Atherosclerosis Risk in Communities (ARIC) Study, a large population-based longitudinal cohort study, have been included in this Project and whole genome sequencing will be performed to contribute to analyses of early-onset atrial fibrillation and venous thromboembolism. Additional phenotype and genotype data are available for these individuals on dbGaP and can be accessed through the parent ARIC Cohort accession (phs000280). The National Heart, Lung and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program is designed to generate scientific resources to enhance understanding of fundamental biological processes that underlie heart, lung, blood and sleep disorders (HLBS). It is part of a broader Precision Medicine Initiative, which aims to provide disease treatments that are tailored to an individual's unique genes and environment. TOPMed will contribute to this initiative through the integration of whole genome sequencing (WGS) and other -omics (e.g., metabolic profiles, protein and RNA expression patterns) data with molecular, behavioral, imaging, environmental, and clinical data. In doing so, this program seeks to uncover factors that increase or decrease the risk of disease, identify subtypes of disease, and develop more targeted and personalized treatments. The Whole Genome Sequencing (WGS) Project is part of NHLBI's TOPMed program and serves as an initial step for the larger initiative.

  Study phs001211

• Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell RCC-- CA209-025

  Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials of treatment with PD-1 blockade (or mTOR inhibition as control arm) by whole-exome and RNA-sequencing, integrated with immunofluorescence analysis, to define the somatic alteration landscape of late-stage ccRCC and to uncover the immunogenomic determinants of therapeutic response. While conventional genomic markers (tumor mutation burden, neoantigen load) and degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations in advanced ccRCC associated with response or resistance to PD-1 blockade. These advanced tumors were highly CD8+ T cell infiltrated, with only 22% and 5% with an immune desert and immune excluded phenotype, respectively. Our analysis revealed that CD8+ infiltrated tumors are depleted of favorable PBRM1 mutations and are enriched for unfavorable chromosomal losses of 9p21.3 when compared to non-infiltrated tumors. These data demonstrate how the interplay of somatic alterations and immunophenotypes impacts therapeutic efficacy.

  Study EGAS00001004292

• Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell RCC -- CA209-010

  Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials of treatment with PD-1 blockade (or mTOR inhibition as control arm) by whole-exome and RNA-sequencing, integrated with immunofluorescence analysis, to define the somatic alteration landscape of late-stage ccRCC and to uncover the immunogenomic determinants of therapeutic response. While conventional genomic markers (tumor mutation burden, neoantigen load) and degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations in advanced ccRCC associated with response or resistance to PD-1 blockade. These advanced tumors were highly CD8+ T cell infiltrated, with only 22% and 5% with an immune desert and immune excluded phenotype, respectively. Our analysis revealed that CD8+ infiltrated tumors are depleted of favorable PBRM1 mutations and are enriched for unfavorable chromosomal losses of 9p21.3 when compared to non-infiltrated tumors. These data demonstrate how the interplay of somatic alterations and immunophenotypes impacts therapeutic efficacy.

  Study EGAS00001004291

• Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell RCC -- CA209-009

  Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials of treatment with PD-1 blockade (or mTOR inhibition as control arm) by whole-exome and RNA-sequencing, integrated with immunofluorescence analysis, to define the somatic alteration landscape of late-stage ccRCC and to uncover the immunogenomic determinants of therapeutic response. While conventional genomic markers (tumor mutation burden, neoantigen load) and degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations in advanced ccRCC associated with response or resistance to PD-1 blockade. These advanced tumors were highly CD8+ T cell infiltrated, with only 22% and 5% with an immune desert and immune excluded phenotype, respectively. Our analysis revealed that CD8+ infiltrated tumors are depleted of favorable PBRM1 mutations and are enriched for unfavorable chromosomal losses of 9p21.3 when compared to non-infiltrated tumors. These data demonstrate how the interplay of somatic alterations and immunophenotypes impacts therapeutic efficacy.

  Study EGAS00001004290

• Cell type mapping of inflammatory muscle diseases highlights selective myofiber vulnerability in inclusion body myositis

  Inclusion body myositis (IBM) is the most prevalent inflammatory muscle disease in older adults with no effective therapy available. In contrast to other inflammatory myopathies like subacute immune-mediated necrotizing myopathy (IMNM), IBM follows a chronic disease course with both inflammatory and degenerative features of pathology. Moreover, causal factors and molecular drivers of IBM progression are largely unknown. Therefore, we paired single-nucleus RNA sequencing with spatial transcriptomics from patient muscle biopsies to map cell type-specific drivers underlying IBM pathogenesis compared to IMNM muscles and non-inflammatory skeletal muscle samples. In IBM muscles, we observed a selective loss of type 2 myonuclei paralleled by increased levels of cytotoxic T and cDC1 cells. IBM myofibers were either characterized by upregulation of cell stress markers featuring GADD45A and NORAD, or protein degradation markers including RNF7 associated with p62 aggregates. GADD45A upregulation was preferentially seen in type 2A myofibers associated with severe tissue inflammation. We also noted IBM-specific upregulation of ACHE encoding acetylcholinesterase, which can be regulated by NORAD activity and result in functional denervation of myofibers. Our results provide promising insights into possible mechanisms of myofiber degeneration in IBM and suggest a selective type 2 fiber vulnerability linked to genomic stress and denervation pathways.

  Study EGAS50000000310

• Pediatric Non-Down Syndrome Acute Megakaryoblastic Leukemia is Characterized by Distinct Genomic Subsets with Varying Outcomes

  Acute Megakaryoblastic Leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts.  While extremely rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML1-3.  A significant proportion of pediatric AMKL cases occur in children with Down syndrome (DS).  These patients have excellent outcomes and are characterized at the genomic level by a founding GATA1 mutation4-6.  In contrast, AMKL in patients without DS (non-DS-AMKL) is frequently associated with poor outcomes.  Previous efforts have identified chimeric oncogenes in a significant number of cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements and NUP98-KDM5A7-9.  The etiology of 30-40% of cases, however, remains unknown.  To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult).  We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes.  These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes.  Overall, these data shed light on the etiology of AMKL and provide useful information for treatment tailoring. 

  Study EGAS00001002183

• Jackson Heart Study (JHS) Cohort

  The Jackson Heart Study (JHS) is a large, community-based, observational study whose participants were recruited from urban and rural areas of the three counties (Hinds, Madison and Rankin) that make up the Jackson, MS metropolitan statistical area (MSA). Participants were enrolled from each of 4 recruitment pools: (1) random, 17%, (2) volunteer, 30%, (3) currently enrolled in the Atherosclerosis Risk in Communities (ARIC) Study, 31%, and (4) secondary family members, 22%. The final cohort of 5,306 participants included 6.59% of all African American Jackson MSA residents, aged 35-84, during the baseline exam (N-76,426, US Census 2000). Among these, approximately 3,600 gave consent that allows genetic research and deposition of data into dbGaP. Major components of three clinic examinations (see study history) include medical history, physical examination, blood/urine analytes, and interview questions on areas such as physical activity, stress, coping and spirituality, racism and discrimination, socioeconomic position, and access to health care. Extensive clinical phenotyping includes anthropometrics, electrocardiography, carotid ultrasound, ankle-brachial blood pressure index, echocardiography, CT chest and abdomen for coronary and aortic calcification, liver fat, and subcutaneous and visceral fat measurements, and cardiac MRI. At 12-month intervals after the baseline clinic visit (Exam 1), participants have been contacted by telephone to update information, confirm vital statistics, document interim medical events, hospitalizations and functional status, and obtain additional sociocultural information. Questions about medical events, symptoms of cardiovascular disease and functional status are repeated annually. Ongoing cohort surveillance includes abstraction of medical records and death certificates for relevant International Classification of Diseases (ICD) codes and adjudication of nonfatal events and deaths. CMS data are currently being incorporated into the dataset. Note: Regarding date variables warehoused in the Jackson Heart Study (JHS) Cohort on dbGaP, the coordinating center has developed an algorithm that will systematically review and de-identify any of the (nearly 100) date-related variable types stored in the data package. To simultaneously minimize (i) de-identifiability of the data and (ii) impact on analyses utilizing sensitive data elements, a participant-level random number was generated to avoid the necessity of sharing any potentially sensitive data. The coordinating center maintains an archived linkage of these data in their raw form and regularly reviews ad hoc requests to utilize the raw data on a project-by-project basis. The JHS Cohort is utilized in the following dbGaP substudies. To view genotypes, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000286 JHS Cohort. phs000402 ESP Heart GO JHS phs000498 JHS Allelic Spectrum Seq phs000499 JHS CARephs001069 MI Gen JHS phs001098 T2D GENES Exome Seq phs001356 Exome Chip phs002256 Cardiometabolic Renal Proteomics phs002369 Metabolomics Insulin Resistance

  Study phs000286

• Preclinical_evolution_of_haematological_malignancies_

  This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002128

• CELM

  This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002261

• Dedifferentiated_Melanoma_RNAseq

  De- and transdifferentiation of melanoma is a rare histopathological phenomenon that has not be characterised genetically. In this project we plan to sequence the genomes of de and transdifferentiated cases so as to define their genetic make-up.

  Study EGAS00001003601

• H021-Master Umbrella study2 (not to be released)

  Study EGAS00001005145

• Single Cell RNAseq of blood and tumor from renal cancer patients

  Single-cell RNASeq (scRNAseq) showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and high IL8 expression was associated with the downregulation of the antigen presentation machinery in myeloid cells.

  Study EGAS00001004230

• Highly differentiated, fusion-negative rhabdomyosarcoma.

  Sequencing was performed using OncoPanel v.2 (OPv2), an Agilent SureSelect custom designed bait set consisting of the coding regions of 504 genes, previously linked to human cancer. Sequencing wa sperformed on an Illumina HiSeq 2500. 14 highly differentiated, fusion-negative rhabdomyosarcoma tumor samples, and 8 non-matched normal skeletal muscle samples weer sequenced. BAM files are available for download.

  Dataset EGAD00001003746

• Exome sequencing and RNAseq data

  Whole Exome Sequencing of 9 Colorectal Cancer (CRC) samples performed on Illumina HiSeq4000 consisting of aligned paired reads. RNAseq data sequenced on Illumina NextSeq500 consisting of FASTQ single reads from 3 CRC colon samples. A total of 12 samples from five patients (we matched normal tissue or pbmc and tumors) were sequenced on Illumina NextSeq500.

  Dataset EGAD00001003788

• Single-cell transcriptome sequencing of regulatory and conventional T cells in breast cancer patients and healthy individuals.

  Identification of tumor-specific effects on gene expression profile of regulatory T cells and conventional T cells in humans, investigation of the clonal origin of regulatory T cells and impact analysis of tumor-specific conversion of conventional T cells into induced regulatory T cells on the peripheral regulatory T cell repertoire in humans.

  Dataset EGAD00001004069

• T Cell Receptor Sequencing

  The T cell Receptor Sequencing dataset contains 84 files related to T cell receptor sequences obtained using ImmunoSeq by Adaptive Biotechnologies and phenotype metadata from 23 patients enrolled on a phase II clinical trial of neoadjuvant immune checkpoint blockade in high-risk resectable melanoma at MD Anderson Cancer Center (NCT02519322). Included are data on baseline and on-treatment samples from tumor and blood.

  Dataset EGAD00010001608

• Circulating tumour DNA abundance and potential utility in de novo metastatic prostate cancer

  We set out to determine ctDNA abundance at de novo mCSPC diagnosis and whether ctDNA provides complementary clinically relevant information to a prostate biopsy. We collected and sequenced 77 plasma cell-free DNA samples from 53 newly diagnosed patients with mCSPC. Targeted sequencing was also performed on DNA from 48 diagnostic prostate tissue samples.

  Dataset EGAD00001004526

• Anaplastic Thyroid Cancer aligned whole exome sequence data

  Whole exome sequence data in fastq format was aligned to the GRCH38 reference genome. Aligned sequence was preprocessed with GATK for Indel Realignment and Base Quality Score Recalibration. Duplicates were marked with Picard Mark Duplicates. Aligned sequence is in bam format. Details of the alignment can be found in he bam header. Tumour samples were classified as Anaplastic Thyroid, Poorly-differentiated or well-differentiated cancers.

  Dataset EGAD00001005791