3967 results for "*geneti*"

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• Whole Exome Sequencing of monomorphic epitheliotropic intestinal T-cell lymphoma and enteropathy associated T-cell lymphoma

  Background : Enteropathy-associated T-cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) are aggressive malignancies with limited treatment options and poor prognosis. Our research on MEITL has uncovered its genetic portrait including hallmark SEDT2 mutations, expanded its pathological spectrum, and identified molecular biomarkers influencing patients’ outcome. In this study, we aimed to establish and clarify the similar and diverging features of EATL. Methods : A large combined cohort of patients with EATL (n=30) and MEITL (n=52) was assembled and tumor samples were used for whole-exome and RNA sequencing profiling.

  Study EGAS50000001126

• Single-cell multi-omics and mtDNA genotyping of human peripheral blood cells

  In this study, we characterize human peripheral blood cells using mitochondrial single-cell ATAC-seq (mtscATAC-seq), which simultaneously profiles mitochondrial genomes and chromatin accessibility at single-cell resolution. This submission includes PBMCs from one healthy pediatric donor and one 80-year-old patient diagnosed with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome.

  Study EGAS50000001020

• Dynamic human admixture histories over the past ~1,300 years at the northern Himalayan frontier

  Archaeological and paleogenomic evidence from the Tibetan Plateau and high-altitude Central Himalayas suggest biocultural connections with each other and with lowland East, Central, and South Asia. However, genetic histories at the northern frontier of the Indian Himalayas, which is geographically more proximal to Central and lowland South Asia, remain underexplored. We analyzed genome-wide data from 7 ancient (~2300 to 100 years old) and 10 present-day individuals from the northern Indian Himalayas and one ~3370-year-old individual from the Central Himalayas in Nepal. Ancient and present-day individuals from the northern Himalayas predominantly have Tibetan-related genetic ancestry, likely the source of high-altitude adaptive variants in these individuals, with substantial Steppe-related genetic ancestry that is observed in all individuals dating between ~1300 years and present day. In addition, some present-day individuals have lowland South Asian admixture. Our analyses reveal a dynamic interplay between genetic admixture and continuity in the northern Himalayas.

  Study EGAS50000001342

• Expression profiles and genetic makeup of metastases of a cancer of unknown primary.

  Study EGAS00001004059

• MorphoITH: A Framework for Deconvolving Intra-Tumor Heterogeneity Using Tissue Morphology

  This study introduces MorphoITH, a framework for deconvolving intra-tumor heterogeneity (ITH) in clear cell renal cell carcinoma (ccRCC) based on tissue morphology from histopathological slides. The study tested MorphoITH's ability to capture different aspects of morphology and to reflect genetic ITH. The data deposited here is derived from a morphology guided multi-regional sequencing dataset used to study the relationship between morphology and genetic evolution. This dataset consists of whole exome sequencing of tumor from multiple sites and adjacent normal samples which were collected from two patients treated in affiliated hospitals of the University of Texas Southwestern Medical Center (UTSW), including Parkland Hospital.

  Study EGAS50000001064

• Spatial Dynamics of the Developing Heart (single-cell)

  Heart development relies on a topologically defined interplay between diverse cardiac cells. We finely curated spatial and single-cell measurements with high-resolution imaging-based transcriptomics validation to explore spatial dynamics during early human cardiogenesis. Analyzing almost 80,000 individual cells and 70,000 spatially barcoded tissue regions between the 5.5th and 14th postconceptional weeks, we identified 31 coarse- and 72 fine-grained cell states and mapped them to highly resolved cardiac cellular niches. We provide novel insight into the development of the cardiac pacemaker-conduction system, heart valves, and atrial septum, and decipher heterogeneity of the hitherto elusive cardiac fibroblast population. Furthermore, we describe the formation of the cardiac autonomic innervation and present the first spatial account of chromaffin cells in the fetal human heart. Our study, supported by an open-access, spatially centric interactive viewer, delineates the cellular and molecular architecture of the developing heart, offering links to genetic causes of heart disease.

  Study EGAS50000001029

• Dynamics of Tumor Heterogeneity from Primary to Metastatic Dissemination in Prostate Cancer

  PRO-SPeCT: PROstate cancer heterogeneity deconvolution through Single cell Profiling of Chromatin accessibility and Transcriptomic output Identifying drivers of cancer progression to guide treatment selection is hindered by limited abilities to understand tumor heterogeneity’s impact on evolution. Here, we delineated the phenotypic variability across ~300,000 prostate tumor cells collected from multiple loci in primary and matched locoregional metastases. We found inter-patient heterogeneity to be confined to malignant populations. While malignant cell populations exhibit intra-locus heterogeneity, they maintain inter-loci phenotypic similarity within a patient’s prostate gland. In addition, the intra-locus heterogeneity between malignant cell populations is paired with a common clonal architecture. Lastly, we show that malignant cell populations disseminating to locoregional lymph nodes mirror the clonal architecture and phenotypic heterogeneity observed across primary tumor loci while showcasing cell state transition toward inflammatory phenotypes. These findings provide insights into distinct measures of tumor heterogeneity, revealing diverse evolutionary paths across patients converging to common phenotypic adaptations in early prostate cancer progression.

  Study EGAS50000000524

• Epigenetic reprogramming shapes monocytes and heterologous T cell derived cytokine responses in BCG vaccination

  Study EGAS00001007498

• Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH

  Initially IDH1 mutant gliomas are shown to have IDH1 is deletions or amplifications at recurrence yielding a higher-grade tumor with a reprogrammed epigenome. We also report systematic selection for cells with IDH1 CNA in vitro and in vivo.

  Study EGAS00001002618

• Khoe-San Genome Project

  The dataset contains BAM files of whole genome sequencing data of African Khoe-San population (n=169, 30X coverage) recruited from South Africa and Namibia. The population captured the true extent of human genetic diversity as represent the earliest diverged human population. The project described a detailed divergence of human population and identified positive selections associated forager lifestyles in Khoe-San population. These findings emphasise an inclusive catalogue with better representation of the earliest human genomic diversity to better advance biomedical research.

  Study EGAS50000001408

• Global RNA sequencing data of human iPSC-derived microglia from frontotemporal dementia (FTD) patients

  Global RNA sequencing was performed in RNA samples extracted from human iPSC-derived microglia from healthy controls and sporadic (non-genetic) and genetic C9orf72 hexanucleotide repeat expansion-carrying patients with FTD.

  Study EGAS50000001688

• Whole genome sequencing data of paediatric hyperdiploid acute lymphoblastic leukemia

  The hyperdiploid (HeH) subtype with 51–67 chromosomes is the most common subtype in childhood, presented in 25–30% of the cases, and is associated with excellent prognosis . The HeH subtype harbors relatively few additional genetic alterations, suggesting that extra chromosomes are the driving event for leukemia onset. Secondary hits usually affect the RAS signaling pathway and histone modifiers.

  Study EGAS50000001690

• Multi-omic analyses from a randomized phase II study of epigenetic priming followed by nivolumab in previously treated metastatic non-small cell lung cancer

  Emergence of resistance to immune checkpoint blockade (ICB) mandates the development of strategies for ICB sensitization. We aimed to understand the effects of epigenetic priming in re-shaping the tumor microenvironment, together with molecular drivers of therapeutic response of epigenetic therapy followed by ICB in non-small cell lung cancer (NSCLC; NCT01928576). This was done through a multi-omic approach encompassing both genomic and transcriptomic analyses. Findings suggest that epigenetic therapy may reshape the tumor microenvironment towards a more inflamed phenotype and prime responses to immunotherapy.

  Study EGAS50000000913

• DNA methylation and transposable element landscapes define human regulatory T cells in tissues and identify their blood recirculating counterpart

  Regulatory T cells (Treg cells) in tissues can perform immunoregulatory and tissue-regenerative functions. Despite these important tasks, human-tissue Treg cells lack understanding, specifically, the epigenetic basis of their differentiation as well as re-circulating tissue-Treg cells are incompletely understood. Here, we performed genome-wide DNA methylation analysis of human Treg cells from skin and blood and embedded this in a multi-omic epigenetic framework including chromatin accessibility and gene-expression. We thereby revealed novel epigenetic programs defining human skin Treg cell differentiation and delineated how these are present on the different epigenetic levels. We discovered that transposable elements are an integral constituent of the demethylation landscape in skin Treg cells. Based on TCR-sequencing and DNA demethylation homologies, our data unveil that blood CCR8+ Treg cells are recirculatory human tissue-Treg cells. Our data provide novel insights in human tissue-Treg biology, required to harness these cells for therapeutic avenues.

  Study EGAS50000000738

• Translational analyses from a phase II study of pembrolizumab and epigenetic modification with azacitidine in platinum-resistant epithelial ovarian cancer

  Epigenetic modulators may sensitize platinum-resistant ovarian cancer (PROC) to immune checkpoint inhibition by reprogramming the tumor microenvironment. We report clinical and translational findings from a phase II non-randomized study of pembrolizumab and oral azacytidine in 34 women with PROC (NCT02900560). The effect of combined epigenetic and immunotherapy was evaluated by transcriptomic analyses of serially biopsied tumors. Differential gene expression analyses revealed an upregulation of inflammatory and cytolytic genes and co-inhibitory checkpoints 6 weeks on-therapy. Upregulation of interferon signaling, antigen presentation and immune cell adhesion and migration gene sets was prominent on-therapy, together with an increased density of CD8+ T -cells. Patients with a CA-125 and/or clinical response showed an enrichment of adaptive and conserved immune response gene sets on-therapy.

  Study EGAS50000001165

• RNA-seq data in hMPC, MSC_Pat and EWIma

  Ewing sarcoma is characterized by pathognomonic translocations fusing most frequently EWSR1 with FLI1 (EF1). In addition, Ewing sarcoma can also display alterations in STAG2, TP53 and CDKN2A (SPC). Starting from Ewing sarcoma derived human mesenchymal stem cells (MSCpat), we recapitulated this translocation and SPC alterations using a CRISPR/cas9 approach and generated a bona fide Ewing sarcoma model (EWIma1) displaying transcriptomic and epigenetic hallmarks of EwS.

  Study EGAS50000001173

• IDH-wildtype untreated human glioblastoma samples (GB-UK cohort), published in Noorani & Haughey et al 2025.

  Extrachromosomal DNA (ecDNA) oncogene amplification is associated with treatment resistance and shorter survival in cancer. Currently, the spatial dynamics of ecDNA, and their evolutionary impact, are poorly understood. Here, we investigate the spatiotemporal evolution of ecDNA by integrating computational modeling with samples from 94 treatment-naive human IDH wild-type glioblastoma patients. Random ecDNA segregation combined with ecDNA-conferred fitness advantages induce distinct spatial ecDNA copy number patterns which depend on ecDNA oncogenic makeup. EGFR-ecDNAs often reach high copy numbers and confer strong fitness advantages. In contrast, PDGFRA-ecDNAs reach lower copy numbers and confer weaker fitness advantages. EGFR structural variants occur exclusively on ecDNA, arise from and are intermixed with wild-type EGFR-ecDNAs. Computational modeling suggests wild-type and variant EGFR-ecDNAs often accumulate before clonal expansion. Using a genetically engineered mouse model, we confirm that the accumulation of oncogenic ecDNA prior to clonal expansion under strong positive selection is observable both in vivo and in vitro in mouse neural stem cells. Intermixed wild-type and variant ecDNAs remain prevalent at diagnosis, as less fit wild-type ecDNAs hitchhike on strongly selected variant EGFR-ecDNAs. A dN/dS analysis in the Genomics England cohort further suggests positive selection of variants on EGFR-ecDNAs but not PDGFRA-ecDNAs in glioblastoma. Overall, our results suggest ecDNA oncogenic makeup determines unique evolutionary trajectories in glioblastoma. New concepts like ecDNA tumor clonality, ecDNA heteroplasmy and multi-species ecDNAs require a refined evolutionary interpretation of genomic data in a large subset of glioblastoma patients and likely other solid cancers.

  Study EGAS00001008126

• Germline variants in UHRF1 are associated with multi-locus imprinting disturbance in humans and mice

  Genomic imprinting provides is an epigenetic process crucial for normal development and is disrupted in congenital imprinting disorders(CIDs). There is great interest in the clinical consequences and aetiology of multilocus imprinting disturbance(MLID) which occurs in some individuals with CID, though the cause of MLID is unknown in most cases. We investigated a kindred with a CID and MLID and identified a rare genetic variant in the UHRF1 gene which has a critical role in the establishment and maintenance of DNA methylation. We generated a mouse model and found that the equivalent Uhrf1 variant was associated with prenatal lethality and disruption of normal imprinting mechanisms. These findings support UHRF1 as a novel candidate gene for CIDs with MLID.

  Study EGAS50000001179

• BE_screens_of_WRN_gene_in_MSI_models

  We will take advantage of a base-editing screening strategy to engineer mutations in the WRN gene by deep mutagenesis. Two MSI-H cell lines sensitive to WRNi will be genetically modified to express doxycycline-inducible ABE and CBE base editors through a knock-in strategy. Moreover, we will design a pooled library of ~4000 gRNAs targeting the WRN gene plus appropriate controls gRNAs. Library-transduced cells will be selected with WRNi to identify WRN mutations able to interfere with the activity of WRNi.

  Study EGAS00001006872

• Feasibility study of enzymatic methylation sequencing of cell-free DNA from cerebrospinal fluid of pediatric brain tumors for classification

  Array-based DNA methylation profiling is the gold standard for molecular classification of brain tumors. However, it relies on significant amount of input DNA extracted from surgical tissue, thus limiting its use for tumors where biopsy is challenging or limited in quantity. Cell-free tumor DNA (cfDNA) in cerebrospinal fluid (CSF) presents alternative opportunities for brain tumor diagnosis and disease monitoring following treatment. Novel enzymatic DNA methylation sequencing (EM-seq) methods may allow us to overcome input DNA limitations and accurately quantify methylation from cfDNA for tumor classification.

  Study EGAS50000000871

• Epigenetic and transcriptional profile of memory B cells in Multiple sclerosis

  Methylome and transcriptome data of non-proliferating and autoproliferating memory B cells (CD27+) from Multiple sclerosis patients under natalizumab treatment, that have been generated and analyzed for the study "T-bet+ CXCR3+ B cells drive hyperreactive B-T cell interactions in multiple sclerosis". Aim is to understand epigentic and transcriptional differences in activated memory B cells in MS and how epigentic differences translated in transcriptional changes in the same patient.

  Study EGAS50000000872

• A Comprehensive Genetic Study of Classical Hodgkin Lymphoma Using Circulating Tumour DNA

  This study on classical Hodgkin lymphoma (cHL) used advanced methods to analyse circulating tumour DNA (ctDNA) in 297 cases, offering insights into its genetic landscape and linking it to disease pathophysiology and clinical progression. Key findings include the identification of whole genome duplication as a predictor of poor chemotherapy response. Additionally, a highly recurrent somatic expression quantitative trait locus of the BCL6 gene was discovered, implicating regulatory mutations in cHL pathophysiology and highlighting BCL6 as both a vulnerability and therapeutic target. Consensus clustering identified two cHL subtypes distinguished by the underlying mechanisms of genetic instability, rather than by specific genetic mutations or EBV infection. The study also linked the number and clonality of neoantigens with tumour microenvironment and response to checkpoint blockade. Finally, our results suggested ctDNA analysis as a tool to distinguish ambiguous PET/CT-positive lesions persisting after treatment, aiming to reduce unnecessary medical interventions.

  Study EGAS50000000873

• Genetic and Microenvironmental Analysis of Peripheral T-cell Lymphoma

  This study enrolled 129 patients diagnosed with PTCL, comprising 94 cases of nTFHL and 35 cases of PTCL-NOS. Whole exome sequencing (WES) and RNA sequencing (RNA-seq) were performed using DNA and RNA of sufficient quality extracted from their tumor specimens. WES was conducted for all 129 cases, while RNA-seq was performed on 57 tumor samples.

  Study EGAS50000001258

• Young Boost Trial for Breast Cancer patients

  The Young Boost Trial (YBT, YOUNG BOOST / BOOG 2004-01 (Borstkanker) | Kanker.nl investigated the optimal radiation dose for breast cancer patients aged 50 years or younger, treated with breast-conserving therapy (BCT). In this randomized study, participants were assigned to receive either a 26 Gy or a 16 Gy radiation boost, with the primary endpoint being local recurrence. To explore potential predictive biomarkers of treatment response in this patient group, whole exome sequencing (WES) was performed on tumor samples to identify genetic factors that could guide personalized treatment strategies and improve clinical outcomes for these young breast cancer patients.

  Study EGAS50000000797

• Impact of Glycolysis Inhibition on the Epigenome of Synovial Fluid T Cells in Juvenile Idiopathic Arthritis

  Juvenile Idiopathic Arthritis (JIA) encompasses a group of childhood-onset autoimmune conditions characterized by joint inflammation and mononuclear cell infiltration, especially of activated CD4+ memory/effector T (Tmem/Teff) cells in synovial fluid (SF). JIA CD4+ T cells exhibit a distinct inflammation-associated epigenomic profile, though the underlying molecular mechanisms remain unclear. This study investigates the role of glycolysis in shaping the epigenomic landscape of JIA SF CD4+ T cells, with a focus on H3K27ac histone modifications. Using an ex vivo model of antigen stimulation, CD4+ T cells were isolated from peripheral blood (PB) of healthy controls (HC) and synovial fluid from JIA patients. Cells were activated in vitro with anti-CD3/CD28 for 24 hours, and changes in H3K27ac were assessed by chromatin immunoprecipitation followed by sequencing (ChIP-seq). To explore the specific role of glycolysis, cells were also treated with 2-deoxyglucose (2DG), an inhibitor of glucose-6-phosphate production. This inhibition impacted both H3K27ac acetylation patterns and gene expression associated with the activated epigenomic regions. Additionally, HC CD4+ T cells were activated in vitro in the presence of 30% SF or 30% plasma from JIA patients. RNA sequencing (RNA-seq) was performed to examine SF-induced transcriptional changes, providing insight into the metabolic dysregulation and epigenomic alterations observed in JIA SF CD4+ T cells. This dataset includes ChIP-seq and RNA-seq data that collectively advance our understanding of how glycolysis and the SF environment contribute to the epigenetic and transcriptional regulation in JIA CD4+ T cells.

  Study EGAS50000000808

• MethylBERT enables read-level DNA methylation pattern identification and tumour deconvolution using a Transformer-based model

  DNA methylation (DNAm) is a key epigenetic mark that shows profound alterations in cancer. Read-level methylomes enable more in-depth DNAm analysis due to the broad coverage and preservation of rare cell-type signals, compared to array-based data such as 450K/EPIC array. Here, we propose MethylBERT, a novel Transformer-based model for read-level methylation pattern classification. MethylBERT identifies tumour-derived sequence reads based on their methylation patterns and genomic sequence and the method estimates tumour cell fractions within bulk samples. In our evaluation, MethylBERT outperforms existing deconvolution methods and demonstrates high accuracy regardless of methylation pattern complexity, read length and read coverage. Moreover, we show its applicability to cell-type deconvolution as well as non-invasive early cancer diagnostics using liquid biopsy samples. MethylBERT represents a significant advancement in read-level methylome analysis and enables accurate tumour purity estimation. The broad applicability of MethylBERT will enhance studies on both tumour and non-cancerous bulk methylomes.

  Study EGAS50000000806

• ATAC-Seq and CTCF ChIP-Seq on the OCIAML-2 cell line

  Study EGAS00001004741

• Discordant_Monozygotic_Twins_ALS(Genetics)

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Regarding genetic factors, pathogenetic mutations in more than 35 genes have been identified as playing a role in disease pathogenesis. However, a substantial portion of ALS heritability remains unaccounted for, pointing to the potential involvement of additional genetic and epigenetic factors. For this reason, we conducted a multi-omics study on a monozygotic twin pair discordant for amyotrophic lateral sclerosis, performing whole exome sequencing, transcriptomic and epigenetic analyses to gain crucial insights into underlying pathogenetic disease mechanisms. Here, we share genetic data.

  Study EGAS50000000908

• WES samples of patients with anti-PD-1 resistant HNSCC from a non-randomized, open-label phase 1b clinical trial

  Immune checkpoint blockade (ICB) is an effective treatment for a subset of patients with head and neck squamous cell carcinoma (HNSCC); however, the majority remain refractory. In a nonrandomized, open-label Phase 1b clinical trial, participants with recurrent and/or metastatic (R/M) HNSCC who had progressed on ICB were treated with low-dose 5-azacytidine (5-aza) daily for either 5 or 10 days, in combination with durvalumab and tremelimumab. The primary objective was to determine the biologically effective dose of 5-aza. In this study, whole exome sequencing (WES) was performed on baseline samples from 12 participants, and genomic alterations were analyzed to access the genetic background of these participants.

  Study EGAS50000000729

• Transcriptional and epigenetic profiling of bone marrow blood progenitors across age

  Bone marrow from donors without known malignancy was isolated and CD34-enriched, FACS-purified to further enrich for CD34+CD38- primitive cells, and then profiled by single-cell 10X genomics chromium Multiome (RNA+ATAC).

  Study EGAS50000001623

• A benchmark of DNA methylation deconvolution methods for tumoral fraction estimation using DecoNFlow

  In cancer patients, circulating cell-free DNA (cfDNA) originates from both healthy and cancer cells, and the proportion of tumor-derived cfDNA serves as a surrogate marker of tumor burden. Tumoral cfDNA can be identified using patient-specific mutations or more general tumor-specific DNA methylation patterns that are preserved in cfDNA, enabling non-invasive cancer detection and monitoring. Accurately estimating tumor fractions remains challenging due to the heterogeneous mixture of cfDNA sources in body fluids. Computational DNA methylation deconvolution methods can address this by estimating tumoral fraction with or without reference methylomes. Here, we benchmarked 10 reference-based and 2 reference-free DNAm deconvolution tools and provide the data generated for this benchmarking, consisting of 10 neuroblastoma cell lines and one healthy cfDNA sample (pooled from 15 healthy cfDNA samples), profiled using cfRRBS.

  Study EGAS50000001529

• ATAC-seq, H3K27ac CUT&Tag, and UMI-4C in LCLs derived from constitutional MLH1 epimutation carriers and non-carrier relatives

  ATAC-seq, H3K27ac CUT&Tag, and UMI-4C in lymphoblastoid cell lines derived from constitutional MLH1 epimutation carriers and non-carrier relatives

  Study EGAS50000000499

• Transcriptomic and epigenetic characterization of ex vivo expanded T cells

  In this study, we investigated the transcriptomic and epigenetic landscape of primary human T cells stimulated ex vivo under various conditions. Naïve CD8+ T cells isolated from healthy donor PBMCs were subjected to ex vivo stimulation and used for bulk RNA-seq and ATAC-seq library preparation. These datasets were generated to characterize global changes in gene expression and chromatin accessibility associated with ex vivo T-cell stimulation. The data may support comparative analyses of molecular states arising under distinct culture conditions.

  Study EGAS50000001718

• Knoll et al.: The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation

  Following the demonstration of its life-saving effect in clinical trials, dexamethasone quickly became standard-of-care in the treatment of severe COVID-19. Beneficial effects were reported for patients requiring supplemental oxygen or invasive mechanical ventilation. Yet, a substantial proportion of patients still progressed to a critical condition or succumbed to the disease, despite timely initiation of glucocorticoid treatment. No molecular or cellular correlate of this beneficial treatment response has been defined. Here, we identify distinct cellular and molecular changes in circulating immune cells in patients with COVID-19 elicited in response to dexamethasone treatment. The most profound transcriptional changes in response to dexamethasone treatment were noted in monocytes and in B cells. In monocytes, we observed a reversal of hallmark signatures previously associated with COVID-19 severity, and the induction of a specific monocyte substate enriched in glucocorticoid response gene expression which we here refer to as dexamethasone response cluster. Molecular responses to dexamethasone treatment were directly linked to clinical outcome, since the reversal of pathogenic signatures and induction of glucocorticoid response genes were enriched in patients who survived the disease in response to dexamethasone treatment. Cellular responsiveness of circulating monocytes was thus identified as a correlate of clinical response to dexamethasone treatment. Changes in monocyte transcriptomes could also be linked to epigenetic alterations highlighting early differences in monocytes of dexamethasone responders and non-responders. Further, monocyte single-cell transcriptome-derived signatures were enriched in whole blood transcriptomes from patients with fatal outcome in two independent cohorts, highlighting the potential clinical value for early identification of non-responders who are refractory to dexamethasone treatment. Overall, our findings indicate that the life-saving effects of dexamethasone in COVID-19 patients are linked to a specific immunomodulatory effect based on the reversion of monocyte dysregulation. Our study elucidates the potential mechanism of action of one of the most efficient and cost-effective drugs for the treatment of COVID-19. It further highlights the potential of single-cell omics for monitoring target engagement of immunomodulatory drugs and for the stratification of patients for precision medicine approaches.

  Study EGAS00001007461

• Monosomy 7 delineates a primitive acute myeloid leukemia with adverse prognosis and responsiveness to epigenetic therapy

  The mechanistic basis for adverse risk associated with monosomy 7 remains undetermined in AML. In contrast to del(7q), monosomy 7 conferred adverse prognosis independent of TP53 and complex karyotype. Single-cell RNA and ATAC-seq revealed an epigenetically remodeled landscape and expansion of multipotent progenitor (MPP)-like cells. Monosomy 7 derived progenitors were distinguished by reduced chromatin accessibility and expression of STK17A and NT5C3A, which conferred resistance to cytotoxic and venetoclax-based therapy. To circumvent resistance mediated by monosomy 7 and deficient TP53, histone deacetylase inhibitors (HDACi) effectively restored apoptotic potential and augmented the activity of venetoclax. In a randomized clinical trial including older unfit patients with AML and monosomy 7, responses were observed in the majority that received low-dose cytarabine, venetoclax and the HDACi pracinostat, some with durable remissions exceeding 3 years. Longitudinal studies highlighted diminution of MPP-like cells, linking epigenetic remodeling to clinical response and therapeutic vulnerability of monosomy 7 AML.

  Study EGAS50000001641

• AGECAN - Interespecies conservation of brain specific DNA methylation in aging and cancer

  Study EGAS00001004851

• Single-nucleus ATAC sequencing of the human motor cortex

  Single-nucleus ATAC-sequencing of the human motor cortex in patients with ALS, C9ORF72-ALS-FTD, ALS-FTD and unaffected controls.

  Study EGAS50000001563

• Single-nucleus chromatin accessibility profiling of human fetal liver hematopoiesis (10x Multiome)

  The fetal liver is the primary haematopoietic organ during early human development, yet the timing and regulatory mechanisms governing blood formation remain incompletely understood. To define the cellular, transcriptional, and epigenetic changes underlying human fetal liver hematopoiesis over development, we generated a high-resolution, time-resolved single-nucleus multiome atlas of human fetal liver spanning 5–18 post-conception weeks (PCW) for CD45+CD235- cells. In total, 308,021 high-quality nuclei from 53 donors were profiled using paired chromatin accessibility and transcriptomic modalities. This study is for the chromatin accessibility.

  Study EGAS50000001632

• TULIPs decorate the three-dimensional genome of PFA ependymoma

  Study EGAS00001005476

• Repression of CADM1 transcription by HPV type 18 is mediated by three-dimensional rearrangement of promoter-enhancer interactions

  Repression of CADM1 transcription by HPV type 18 is mediated by three-dimensional rearrangement of promoter-enhancer interactions

  Study EGAS50000000773

• Genetics of gene expression in primary human immune cells

  The purpose of this study was to identify cell specific expression quantitative trait loci in freshly isolated highly purified primary B-cells and monocytes from healthy subjects of European ancestry. Cells were purified from Ficoll gradient prepared peripheral blood mononuclear cell fractions using positive selection via magnetic bead labelling of the B-cell marker CD19 and monocyte marker CD14. RNA was extracted from 287 B-cell samples and 288 monocyte samples. RNA was then hybridised to HumanHT-12 v4 BeadChips whole genome expression arrays (Illumina). Individuals were genotyped on HumanOmniExpress-12v1.0 BeadChips (Illumina) at 733202 genetic markers. Data presented include the raw expression values and Robust Spline Normalised values (RSN) for expression for each cell type per individual. Additional genotype data per individual is available on request.

  Study EGAS00000000109

• Association studies using the Metabochip array - Samples analysed by the WTCCC (1958 British Birth Cohort (58BC), Hypertension cohort (HT), Type 2 Diabetes Cohort (T2D) and Coronary Artery Disease (CAD) cohort)

  Genomewide association studies (GWAS) have proven a powerful hypothesis-free method to identify common disease-associated variants. Even quite large GWAS, however, have only at best identified moderate proportions of the genetic variants contributing to disease heritability. To provide cost-effective genotyping of common and rare variants to map the remaining heritability and to fine-map established loci, the Metabochip Consortium has developed a 200,000 SNP chip that has been produced in very large numbers for a fraction of the cost of GWAS chips. This chip provides a powerful tool for genetic studies of metabolic, cardiovascular and anthropometric traits (Voight et al., in press PLoS Genetics).

  Study EGAS00000000115

• Circulating cell-free DNA methylation profiling for detection, distinction, and estrogen receptor status classification of advanced breast cancer

  We developed cell-free DNA (cfDNA) methylation signatures for minimally invasive breast cancer detection, distinction, and estrogen receptor (ER) status classification with cell-free Methylated DNA Immunoprecipitation and Sequencing (cfMeDIP-seq). We profiled peripheral blood plasma from 87 patients with mBC spanning ER-positive/HER2-negative (ER+/HER2-), HER2-positive, and triple-negative breast cancer (TNBC).

  Study EGAS50000001675

• Processing of tissue and cfDNA samples of CRC patients using Active-seq

  In this study, we have developed a novel technology called Active-Seq (Azide Click Tagging for In Vitro Epigenomic sequencing), a base conversion-free technology used to profile the DNA methylation status of a sample, based on the isolation of DNA containing unmodified CpG sites using a mutated bacterial methyltransferase enzyme and a synthetically prepared cofactor analogue. We procured samples from colorectal cancer (CRC) patients including tumour tissue as well as normal adjacent tissues. The data enabled us to identify CRC-specific markers that could then be used to track and monitor the presence of tumour DNA in cell-free DNA plasma (cfDNA) samples procured in the same patients. The FASTQ files of all the colorectal cancer tissues, normal adjacent tissues as wells as the cfDNA samples are available in this submission. The data made available in this study have been used to outline an approach for tumour-informed disease profiling in colorectal cancer cfDNA samples using Active-Seq.

  Study EGAS50000001226

• Axes of Biological Variation in Diffuse Large B-Cell Lymphoma

  To explore the DLBCL molecular and genetic environment, we conducted genome-wide NGS sequencing on 103 DLBCL biopsy samples (named as Cornell-NCI cohort) with NGS platforms, including bulk WES, etc. The raw fastq files of the bulk WES were deposited on the EGA for user access. For additional information regarding the genomic data associated with the study, please also see the paper companion website at https://llmpp.ccr.cancer.gov/local/DLBCL_singlecell/

  Study EGAS50000001227

• Bone morphogenetic protein-9 controls pulmonary vascular growth and remodeling

  Human PMECs from 10 donor lungs were isolated, cultured (passages 3 to 4), synchronized by serum starvation (0.3% FCS), and stimulated with 10 ng/mL BMP-9 for 4 h. Single-cell profiling was performed using the 10X Genomics Chromium RNA 3' V3.1 kit. Five experimental groups were analyzed using cell hashing and sequenced on an Illumina NextSeq500. Data were processed with Cell Ranger and Seurat for differential gene expression and functional enrichment analysis.

  Study EGAS50000001026

• Dataset of DNA methylation profiles of 189 pediatric central nervous system, soft tissue, and bone tumors

  The research of CNS tumors brought knowledge about the role of epigenetics in these tumors. Certain subgroups of tumors are defined solely by their epigenetic profiles. In this study we carried on epigenetic profiling using targeted methylation sequencing of aproximately 180 pediatric CNS and Sarcoma tumor samples.

  Study EGAS50000000051

• Procardis study on novel susceptibility genes for coronary artery disease (CAD)

  An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood. METHODS: We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects. RESULTS: Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished. CONCLUSIONS: We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.

  Study EGAS00000000055

• The patterns and dynamics of genomic instability in metastatic pancreatic cancer

  Pancreatic cancer is an aggressive malignancy with a five-year mortality of 97–98%, usually due to widespread metastatic disease. Previous studies indicate that this disease has a complex genomic landscape, with frequent copy number changes and point mutations, but genomic rearrangements have not been characterized in detail. Despite the clinical importance of metastasis, there remain fundamental questions about the clonal structures of metastatic tumours, including phylogenetic relationships among metastases, the scale of ongoing parallel evolution in metastatic and primary sites, and how the tumour disseminates. Here we harness advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. We find that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, namely dysregulated G1-to-S-phase transition with intact G2–M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing, parallel and even convergent evolution among different metastases. We find evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumours, and that phylogenetic trees across metastases show organ-specific branches. These data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.

  Study EGAS00000000064

• Recurrent somatic DICER1 mutations in non-epithelial ovarian tumors

  Background: Germline truncating mutations in DICER1, an RNase III-type endoribonuclease essential for processing of microRNAs, are seen in families with the pleuropulmonary blastoma-family tumor and dysplasia syndrome; these individuals have a propensity to develop non-epithelial ovarian tumors (i.e. sex-cord stromal and germ cell tumors). Methods: We sequenced the whole transcriptomes or exomes of 14 non-epithelial ovarian tumors and noted closely clustered mutations in the RNase IIIb domain of DICER1 in four cases. Using Sanger sequencing, we then analyzed additional ovarian tumors for mutations in this region. The impact of the mutations on the enzymatic activity of Dicer1 was determined using in vitro RNA cleavage assays. Results: RNase IIIb domain DICER1 mutations were found in 30/102 non-epithelial ovarian tumors (29%), predominantly Sertoli-Leydig cell tumors (26/43, 60%), including 4/4 from individuals with germline DICER1 mutations. The mutations were restricted to metal binding sites within the RNase IIIb catalytic centres critical for miRNA interaction and cleavage, and were somatic in all 14 cases where germline DNA was available for testing. Of 266 epithelial ovarian and endometrial cancers tested, one case, an ovarian carcinosarcoma, had a hotspot mutation. In vitro, the mutant DICER proteins showed reduced RNase IIIb activity but retained RNase IIIa activity. Conclusions: Somatic missense mutations of the RNase IIIb domain of DICER1 are common in non-epithelial ovarian tumors. Genetic, pathologic, and functional evidence suggest that these mutations do not obliterate DICER1 function, rather, they alter it in specific cell types, a novel mechanism through which perturbed microRNA expression is oncogenic.

  Study EGAS00001000135