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• cfDNA methylation profiling on longitudinally collected blood plasma of patients with esophageal adenocarcinoma

  Esophageal adenocarcinoma (EAC) is an aggressive cancer characterized by a high risk of relapse post-surgery. Analyzing cell-free DNA (cfDNA) from blood plasma emerges as a promising avenue for therapy response monitoring. This study aims to evaluate the cost-effective and genome-wide cell-free reduced representation bisulfite sequencing (cfRRBS) method combined with computational deconvolution for effective disease monitoring in EAC patients.

  Study EGAS50000000514

• Fastq files used for searching for variants associated with endometriosis at 9p21 region

  We performed target re-sequencing for 1.29 Mb interval of chromosome 9 (chr9:21299764–22590271, hg19). NimbleGen SeqCap EZ choice system was used as a target enrichment method (Roche Diagnostics). A DNA probe set complementary to the target region was designed by NimbleDesign. The libraries were sequenced on the Illumina MiSeq platform with 2×150-bp paired-end module (Illumina). Fastq files for 48 Japanese patients with endometriosis are deposited.

  Dataset EGAD00001001942

• Mutation_analysis_in_human_iPS_cells_

  PCR products were obtained from each target loci using genomic DNA from human iPS cells. Subsequently, PCR products are pooled and subjected to Illumina library preparation. The library will be sequenced by MiSeq. 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 EGAS00001000359

• CTCF-dependent enhancer hijacking by the EVI1 oncogene in leukemia

  Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements which are often therapy resistant. In a cohort of primary t(3;8)(q26;q24) AML samples we observed the translocation of a MYC super-enhancer to EVI1. We generated a patient-based t(3;8)(q26;q24) model in vitro using CRISPR-Cas9 technology and demonstrated hyper-activation of EVI1 by the hijacked MYC super-enhancer. One MYC super-enhancer element in particular, which recruits early hematopoietic regulators, is critical for EVI1 expression and enhancer-promoter interaction. This interaction is facilitated by a CTCF-bound motif upstream of the EVI1 promoter that acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of 3q26-rearranged AML samples point to a common mechanism by which EVI1 uses this CTCF-bound enhancer-docking site to hijack early hematopoietic enhancers.

  Study EGAS00001004808

• Cancer treatment re-shapes the somatic mutational landscape of normal esophagus - 2mm targeted

  Ageing epithelial tissues, including the esophagus, are progressively colonized by somatic mutant clones, some carrying mutations linked to cancer. However, whether normal epithelial mutational landscapes that evolve over decades can be altered by short term interventions such as cancer treatment is not known. Here we sequenced normal esophageal epithelium removed from patients after 5-8 weeks of therapy for esophageal cancer. Some patients had no prior treatment (NT), while others had 8 weeks of 5 Fluorouracil (5-FU) containing chemotherapy (FLOT) or 4 weeks of chemotherapy and radiation directed at the tumor (CROSS). Despite the brief duration of therapy, we observed treatment specific differences in the selection of mutant clones. The median size of mutant TP53 and PPM1D clones in the CROSS group was double that in the other groups. Mutants of the tumor suppressor SPOP were selected in CROSS but not FLOT or NT patients. In FLOT patients we found positive selection of activating MTOR mutations, consistent with the hypothesis that these mutants confer 5-FU resistance. Sequencing densely mutated normal epithelia after cancer reveals treatment specific selection of mutations with potential therapeutic impact.

  Dataset EGAD00001011184

• Cancer treatment re-shapes the somatic mutational landscape of normal esophagus - wgs

  Ageing epithelial tissues, including the esophagus, are progressively colonized by somatic mutant clones, some carrying mutations linked to cancer. However, whether normal epithelial mutational landscapes that evolve over decades can be altered by short term interventions such as cancer treatment is not known. Here we sequenced normal esophageal epithelium removed from patients after 5-8 weeks of therapy for esophageal cancer. Some patients had no prior treatment (NT), while others had 8 weeks of 5 Fluorouracil (5-FU) containing chemotherapy (FLOT) or 4 weeks of chemotherapy and radiation directed at the tumor (CROSS). Despite the brief duration of therapy, we observed treatment specific differences in the selection of mutant clones. The median size of mutant TP53 and PPM1D clones in the CROSS group was double that in the other groups. Mutants of the tumor suppressor SPOP were selected in CROSS but not FLOT or NT patients. In FLOT patients we found positive selection of activating MTOR mutations, consistent with the hypothesis that these mutants confer 5-FU resistance. Sequencing densely mutated normal epithelia after cancer reveals treatment specific selection of mutations with potential therapeutic impact.

  Dataset EGAD00001011181

• Cancer treatment re-shapes the somatic mutational landscape of normal esophagus - 0.25mm punches targeted

  Ageing epithelial tissues, including the esophagus, are progressively colonized by somatic mutant clones, some carrying mutations linked to cancer. However, whether normal epithelial mutational landscapes that evolve over decades can be altered by short term interventions such as cancer treatment is not known. Here we sequenced normal esophageal epithelium removed from patients after 5-8 weeks of therapy for esophageal cancer. Some patients had no prior treatment (NT), while others had 8 weeks of 5 Fluorouracil (5-FU) containing chemotherapy (FLOT) or 4 weeks of chemotherapy and radiation directed at the tumor (CROSS). Despite the brief duration of therapy, we observed treatment specific differences in the selection of mutant clones. The median size of mutant TP53 and PPM1D clones in the CROSS group was double that in the other groups. Mutants of the tumor suppressor SPOP were selected in CROSS but not FLOT or NT patients. In FLOT patients we found positive selection of activating MTOR mutations, consistent with the hypothesis that these mutants confer 5-FU resistance. Sequencing densely mutated normal epithelia after cancer reveals treatment specific selection of mutations with potential therapeutic impact.

  Dataset EGAD00001011182

• Cancer treatment re-shapes the somatic mutational landscape of normal esophagus - nanoseq

  Ageing epithelial tissues, including the esophagus, are progressively colonized by somatic mutant clones, some carrying mutations linked to cancer. However, whether normal epithelial mutational landscapes that evolve over decades can be altered by short term interventions such as cancer treatment is not known. Here we sequenced normal esophageal epithelium removed from patients after 5-8 weeks of therapy for esophageal cancer. Some patients had no prior treatment (NT), while others had 8 weeks of 5 Fluorouracil (5-FU) containing chemotherapy (FLOT) or 4 weeks of chemotherapy and radiation directed at the tumor (CROSS). Despite the brief duration of therapy, we observed treatment specific differences in the selection of mutant clones. The median size of mutant TP53 and PPM1D clones in the CROSS group was double that in the other groups. Mutants of the tumor suppressor SPOP were selected in CROSS but not FLOT or NT patients. In FLOT patients we found positive selection of activating MTOR mutations, consistent with the hypothesis that these mutants confer 5-FU resistance. Sequencing densely mutated normal epithelia after cancer reveals treatment specific selection of mutations with potential therapeutic impact.

  Dataset EGAD00001011183

• ARDSnet and the iSPAAR Consortium: Genomic Basis of Susceptibility and Outcomes in Patients with the Acute Respiratory Distress Syndrome (ARDS)

  Acute Respiratory Distress Syndrome (ARDS)/ Acute Lung Injury (ALI) is a syndrome defined by the presence of acute hypoxemic respiratory failure, bilateral pulmonary infiltrates on chest radiograph, a known clinical risk factor (e.g. sepsis, pneumonia, trauma, gastric fluid aspiration, pancreatitis, massive transfusion), and the absence of physiologic or clinical evidence of congestive heart failure. The Identification of SNPs Predisposing to Altered ALI Risk (iSPAAR) study is a multi-institutional cooperative study, funded through the NHLBI Recovery Act, that assembled samples and phenotype information from existing cohorts. The consortium included samples from patients with ARDS from the NIH NHLBI ARDS Clinical Trials Network (ARDSNet). Samples were obtained from 3 interventional treatment trials in patients with ARDS, including the Fluid and Catheter Treatment Trial (FACTT), the Albuterol to Treat Acute Lung Injury (ALTA) trial, and the Omega-3 Fatty Acid/Antioxidant Supplementation for ALI trial (Omega). In addition to ARDSnet samples, samples from the other cohorts included cases of established ARDS but also controls: critically ill patients who were at-risk for ARDS but who did not develop ARDS during their hospital course. These cohorts included the Molecular Epidemiology of Acute Respiratory Distress (MEA) Study enrolled at the Harvard University/Massachusetts General Hospital, the Systemic Inflammatory Immune Response Syndrome (SIRS) Patient Database and ICU Traumatic Injury cohorts from Harborview Medical Center, and cohorts collected from the ALI research programs at the University of Pennsylvania and the University of California, San Francisco. The Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000631 ARDSnet iSPAAR Consortium. phs000334 ESP_LungGO_ALI phs000686 ALI_GeneticRisk

  Study phs000631

• Single-cell RNA-Seq of human lymphoma reveals malignant B cell diversity and patterns of T cell immune checkpoint co-expression

  Follicular lymphoma (FL) is a generally incurable B-cell malignancy which has the potential to transform into highly aggressive lymphomas. Genomic studies indicate it is often a small subpopulation rather than the dominant population in the FL that gives rise to the more aggressive subtype. To resolve the underlying transcriptional networks of follicular B-cell lymphomas at single molecule and cell resolution, we leveraged droplet-based barcoding technology for highly parallel single cell RNA-Seq. We analyzed the transcriptomes from tens of thousands of cells derived from five primary FL tumors. Simultaneously, we conducted multi-dimensional flow cell sorting to validate our characterizing of cellular lineages and critical expressed proteins. For each tumor, we identified multiple cellular subpopulations, matching known hematopoietic lineages. Comparison of gene expression by matched malignant and normal B cells from the same patient revealed tumor-specific features. Malignant B cells exhibited restricted immunoglobulin light chain expression (either Ig Kappa or Ig Lambda), as well the expected upregulation of the BCL2 gene, but also down-regulation of the FCER2, CD52 and MHC class II genes. By leveraging the single-cell resolution on large numbers of cells per patient, we were able to examine tumor-resident T cells. We identified pairs of immune checkpoint molecules that were co-expressed, providing a potentially useful strategy for selection of patient-tailored combination immunotherapies. In summary, massively parallel measurement of single-cell expression in thousands of tumor cells and tumor-resident lymphocytes can be used to obtain a systems-level view of the tumor microenvironment and identify new avenues for therapeutic development.

  Study phs001378

• Nuclease deficiencies alter plasma cell-free DNA methylationprofiles (mouse)

  The effects of DNASE1L3 or DNASE1 deficiency on cfDNA methylation was explored in plasma of mice deficient in these nucleases and in DNASE1L3-deficient humans. Compared to wildtype cfDNA, cfDNA in Dnase1l3-deficient mice was significantly hypomethylated, while cfDNA in Dnase1-deficient mice was hypermethylated. The cfDNA hypomethylation in Dnase1l3-deficient mice was due to increased fragmentation and representation from open chromatin regions (OCRs) and CpG islands (CGIs). These findings were absent in Dnase1-deficient mice.

  Study EGAS00001004696

• Nuclease deficiencies alter plasma cell-free DNA methylationprofiles (Human)

  The effects of DNASE1L3 or DNASE1 deficiency on cfDNA methylation was explored in plasma of mice deficient in these nucleases and in DNASE1L3-deficient humans. Compared to wildtype cfDNA, cfDNA in Dnase1l3-deficient mice was significantly hypomethylated, while cfDNA in Dnase1-deficient mice was hypermethylated. The cfDNA hypomethylation in Dnase1l3-deficient mice was due to increased fragmentation and representation from open chromatin regions (OCRs) and CpG islands (CGIs). These findings were absent in Dnase1-deficient mice.

  Study EGAS00001004897

• HERBY trial RNASeq

  RNA sequencing of non-brainstem paediatric high grade glioma from the HERBY phase II randomised trial. RNA from fresh frozen surgical tissue in 20 cases was subjected to Illumina whole transcriptome paired end sequencing. Data is provided as paired-end FASTQ files

  Dataset EGAD00001004070

• RNA sequencing data of pediatric B-other acute lymphoblastic leukemia

  For a long time, approximately 70% of childhood B-ALL cases could be classified routinely, and the remaining 30% were classified into the “B-other” group lacking the known genetic features. However, more recently, new genomic tools have uncovered new subtypes among the B-other groups. Approximately 10% of B-ALL cases lack the recurrent genetic abnormalities, and are referred as "B-other". They are typically more heterogeneous than other subtypes of B-ALL, and their prognoses are more variable. In a more recent update of the B-ALL classification, 27 subtypes were identified (Arber et al., 2022). The identification of some of these subtypes is dependent on NGS methods, such as RNA sequencing, which are not routinely used in all clinical laboratories. For example, ETV6::RUNX1-like and DUX4-rearranged subtypes have been identified using RNA sequencing. For this study, subtype predictions for some of the cases were acquired by using the ALLIUM (Krali et al., NPJ Precis Oncol., 2023) and ALLCatchR (Beder et al., Blood, 2022) tools for the RNA sequencing data.

  Study EGAS50000001803

• Thymic epithelial transplantation for complete DiGeorge syndrome: RNA (2025-07-22)

  Single cell transcriptomics study of thymic transplant biopsies Allogeneic thymus transplantation is the only curative therapy for complete DiGeorge Syndrome (cDGS), a rare severe primary immunodeficiency characterised by athymia. GOSH is one of only two centres worldwide to offer this treatment. Despite a lack of major histocompatibility complex (MHC)-matching between donor and host, transplanted thymus becomes repopulated by recipient bone marrow derived precursor cells and supports development of functional T-cells. The mechanisms underlying thymopoiesis in this context are poorly understood, but over time we observe reconstitution of T-cell immunity, with the ability to produce host naïve T-cells showing a broad T-cell receptor (TCR) repertoire and to generate MHC-restricted T-cell proliferative responses. Although lifesaving, the achieved immunological reconstitution is typically not complete with circulating T-cell numbers usually remaining below the age related normal ranges. Additionally, we observe persistence of donor-derived T-cells of unknown clinical significance. To gain more insight into the mechanisms by which MHC-mismatched transplanted thymus supports T-cell development with self-tolerance, as well as into the basis of suboptimal T-cell immunity, we now aim to investigate immune reconstitution after thymus transplantation in further detail by using single-cell transcriptomics, applied to thymic transplant biopsies and peripheral blood samples collected during standard post-transplant patient care. By identifying which lineages of host- derived cells repopulate the thymic tissue after transplantation, we will be able to address the role of MHC in positive and negative T-cell selection during T-cell differentiation. We will also be able to clarify the exact ontogeny of the persistent donor T-cells, as well as their possible role. Understanding the mechanisms of action of HLA-mismatched transplanted thymus will contribute to treatment optimisation. Additionally, our research provides a unique opportunity to further investigate key immunological concepts, such as tolerance and autoimmunity, challenging existing paradigms in thymus immunology. 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/ . This dataset contains all the data available for this study on 2025-07-22.

  Dataset EGAD00001015648

• Interruption of BTK Inhibitor Improves Response to SARS-CoV-2 Booster Vaccination in Patients with Chronic Lymphocytic Leukemia

  This study investigates the effect of booster SARS-CoV-2 vaccination and Bruton tyrosine kinase inhibitor (BTKi) interruption on antibody response to vaccination. Patients with chronic lymphocytic leukemia (CLL) are immunocompromised, at increased risk of infection, and have historically poor response to immunization. BTKi therapy is a standard treatment for CLL in frontline and salvage settings and further suppresses antibody vaccine responses.

  Study phs003319

• Transcriptomic and Clonal Characterization of T Cells in the Human Central Nervous System

  The cerebrospinal fluid (CSF) is thought to be a main route for immune surveillance in the central nervous system (CNS). Understanding the composition and state of CSF in healthy individuals may provide insight into perturbations present during neuroinflammation. Here, we have used single-cell RNA and TCR sequencing to profile CSF and peripheral blood mononuclear cells (PBMCs) from healthy individuals and patients with relapsing-remitting multiple sclerosis (MS), a chronic autoimmmune disease. In addition, with the goal of understanding how transcriptional artefacts are introduced in transcriptomics experiments, we have performed single-cell and TCR sequencing to profile PBMCs from a healthy individual that were processed with the same enzymatic digestion used for tissues (such as the brain) in the presence or absence of transcription inhibitors. 

  Study phs002222

• Healthy control cfMeDIP-seq

  This dataset comprises 46 raw fastq files derived from 23 plasma cfDNA samples from 23 healthy (CTL) cancer-free donors. For each sample, 10ng of cfDNA was used for library preparation utilizing the cfMeDIP-seq technology based on the 5mC antibody-immunoprecipitation strategy. Libraries were validated via Bioanalyzer trace analysis and sequenced on the Illumina NovaSeq 6000 platform with paired-end 150-bp model for ~100 million reads per sample.

  Dataset EGAD50000000652

• Dynamics of tumor ecosystems and microbiome in response to neoadjuvant atezolizumab, bevacizumab, and FOLFOX treatment in patients with unresectable colorectal cancer with liver metastasis

  This study aims to explore the effects of neoadjuvant atezolizumab, bevacizumab, leucovorin, 5-fluorouracil, and oxaliplatin (ABFOLFOX) in patients with unresectable colorectal liver metastases (CRLM), focusing on the molecular dynamics of tumor ecosystems (TE) of CRLM and their impact on treatment outcomes. The study comprises two cohorts with CRLM tissue samples analyzed with RNA sequencing and immunohistochemical staining: cross-sectional cohort A (n = 60, CRLM treated with or without neoadjuvant chemotherapy) and prospective cohort B (n = 20 with serial sampling and treated with ABFOLFOX). Shotgun metagenomic sequencing was done for stool samples from cohort B.

  Study EGAS50000000677

• RNAseq of MCL cell lines

  This study provides bulk RNA sequencing data from Mino and Jeko-1 mantle cell lymphoma (MCL) cell lines treated with CDK9 inhibitors, including the novel compound YX0798. CDK9 is a key regulator of RNA polymerase II–mediated transcription, and its inhibition disrupts transcriptional programs critical for tumor survival. The dataset captures transcriptomic changes associated with CDK9 inhibition, including downregulation of oncogenic drivers such as MYC and MCL-1. These data support mechanistic studies of transcriptional reprogramming and therapeutic vulnerability in aggressive MCL.

  Study EGAS50000001089

• Genomic Signatures Reveal DNA Damage Response Deficiency in Brain Metastases of Colorectal Cancer

  Brain metastasis (BM) of colorectal cancer (CRC) is rare but lethal, and lacks effective therapies or a good understanding of its genomic landscapes. We conduct an analysis of whole-exome sequencing (WES) and whole-genome sequencing (WGS) data on 19 trios of patient-matched BMs, primary CRC tumors, and adjacent normal tissue to (1) document genomic signatures during the evolution of CRC BM; (2) identify clinically actionable targets for the BM treatment; and (3) identify potential drivers in CRC BM.

  Study EGAS00001003659

• Genomic Analysis of Head and Neck Cancers

  These aggregate studies focus on specimens from head and neck squamous cell carcinoma (HNSCC) patients who were treated with standard of care or window of opportunity clinical trial approaches. Specimens were interrogated with exome and RNA-Seq analysis. Patient derived xenografts (PDXs) represent a robust platform for performing co-clinical trial approaches. In the first study we generated a large panel of PDXs and compared genomic profiles between the primary tumor and matched PDX with the patients blood serving as a source of somatic variants. In the second study, we performed a window of opportunity clinical trial in oral cavity squamous cell carcinoma patients using the MEK inhibitor trametinib. In addition, PDX models were generated from these specimens also and analyzed as in the first study. Finally, the third approach used pembrolizumab, an anti-PD1 blocking antibody, in a window of opportunity setting in HNSCC patients. For the latter two studies genomic matched sample analysis was performed to define response and resistance mechanisms. Together, these genomic data will inform several therapeutic approaches for HNSCC patients.

  Study phs001623

• Tumor-resident T-cell regulate responses to checkpoint blockade immunotherapies

  In cancer models, CD103+CD8 TRM cells are implicated in the response to anti-PD-1 immunotherapy, and a subset of CD4 TRM cells expressing the integrin CD49a is required for response to anti-CTLA-4 immunotherapy. We performed single-cell RNA sequencing on tumour-infiltrating T lymphocytes (TILs) isolated from colon carcinoma et unsupervised analyses reveal several TRM populations.

  Study EGAS50000000826

• NOTCH-mutations drive immune-escape mechanisms in B cell malignancies

  Here we provide access to MCL expression data that were used for interrogating the molecular functions of NOTCH1 and NOTCH2, which are two of the most commonly mutated genes in CLL and MCL and associated with a poor clinical outcome. The mechanisms underlying how NOTCH1 contributes to disease progression, resistance to treatment and Richter’s transformation remain largely unknown. The main goal of this study is to compare the gene expression profile of primary MCL cells transduced with the intracellular part of NOTCH1 or NOTCH2 lacking of the PEST domain vs cells transduced with an empty vector.

  Study EGAS00001005793

• DAC Admixture histories of São Tomé e Príncipe

  Contacts: Paul Verdu +33144057317 paul.verdu@mnhn.fr CNRS-MNHN-Université de Paris UMR7206 Eco-anthropology Jorge M. Rocha jrocha@cibio.up.pt CIBIO Short description The Data Access Committee for acess to genotype and sample information used in the article "Nested admixture during and after the Trans-Atlantic Slave Trade in the island of Sao Tome" by Ciccarella M et al.2025 ensures that data-access requests comply with the Informed Consent provided by donors, and with ethical and deontological guidelines with respect to privacy. Research sampling protocols followed the Declaration of Helsinki guidelines and written informed consent was obtained from all volunteer participants involved in the sampling in São Tomé e Príncipe. The study of the São Tomé e Príncipe sample was undertaken with the support and permission of the Provincial Government of the Ministry of Health of the Democratic Republic of São Tomé e Príncipe, and the Provincial Government of Príncipe. Research sampling protocols also followed the French laws of scientific research deontology (Loi n° 2016-483 du 20 avril 2016) and were approved by the French ethics committees and CNIL (Declaration n°1972648).

  Dac EGAC50000000437

• Whole Exome Characterization of Squamous Cell Lung Cancers (Lung SQCC) from Appalachian Kentucky (APPKY)

  This is a pilot study of squamous cell lung cancer and matched normal tissue pairs collected (convenience sample) from patients from Central Appalachia, in Southeastern Kentucky. This study performed whole exome sequencing on tumor and matched normal DNA samples from 51 lung squamous cell carcinoma (SQCC) subjects from Appalachian Kentucky (AppKY). Somatic genomic alteration profiles were compared between the AppKY and TCGA SQCC cohorts. We found that IDH1 and PCMTD1 had higher mutation rates in AppKY versus TCGA. These findings suggest population differences in the genetics of lung SQCC between AppKY and US populations that have implications for personalized treatment for this disease.

  Study phs001651

• Covid19 Transcriptomic Data analysis in Irish Population

  The Samples were collected from Saint James's Hospital, Dublin and after informed consent. RNA-Sequencing library preparation was performed using the Illumina TruSeq Stranded Total RNA Library Prep Globin kit (20020612) with an input amount of 100 – 1000 ng. Library preparation was automated and processed using a Hamilton NGS Star. Library quality was assessed using the Roche KAPA Library Quantification Kit (7960298001) and GX Caliper HS Assay (CLS760672, 760517), run on Roche Lightcycler 480 II and Perkin Elmer LabChip GX Touch analyser respectively. Libraries were pooled and sequenced (75bp PE) on an Illumina NovaSeq 6000 instrument using NovaSeq 6000 S2 Reagent Kit v1.5 (20028314) targeting 50M paired reads. Raw data (BCL format) were demultiplexed and converted to FASTQ format using BCL2FastQ (Illumina). Adapters were trimmed using Skewer (PMID: 24925680) and QC assessed using FASTQC. STAR (PMID: 23104886) was used to align reads to the reference genome (GRCh38/hg38) as well as to the transcriptome (GENCODE v. 25). Quality of the RNA alignment was assessed using Picard QC. Gene and isoform quantification was performed using RSEM (PMID: 21816040). The study shares expression data (gene.results) and chimeric.junction.out.

  Study EGAS00001007116

• Somatic mutations predict an aggressive phenotype in meningioma but do not drive grade progression

  A subset of meningiomas progress in histopathological grade and drivers of progression are poorly understood. We aimed to identify somatic mutations and copy number alterations (CNAs) associated with grade progression in a unique matched tumour dataset. Utilising a prospective database, we identified 10 patients with meningiomas that had undergone grade progression and for whom matched pre- and post-progression tissue (n=50 samples) was available for targeted next-generation sequencing. Mutations in NF2 were identified in 4/10 patients, 94% were non-skull base tumours. In one patient, three different NF2 mutations were identified in four tumours. NF2 mutated tumours showed large scale CNAs, with highly recurrent losses in 1p, 10, 22q, and frequent CNAs on chromosomes 2, 3 and 4. There was a correlation between grade and CNAs in a subset of patients. In two patients with sphenoid wing Grade III tumours without detected NF2 mutations, a STAT6-NAB2 inversion was identified. Two patients with tumours without detected NF2 mutations showed a combination of loss and high gain on chromosome 17q. Mutations in SETD2, TP53, TERT promoter and NF2 were not uniform across recurrent tumours and did not correspond with grade progression. Meningiomas that progress in grade generally have a mutational profile already detectable in the pre-progressed tumour, suggesting an aggressive phenotype . CNA profiling shows frequent alterations in NF2 mutated tumours compared to non NF2 mutated tumours and the pattern of CNAs may be associated with grade progression in a subset of cases.

  Study EGAS00001006585

• Exome data: Histone mutations in human Pre-Leukemic HSC and AML

  Exome sequencing was performed on samples from patients 064, 105, and 8760, including the remission sample for 105. Exomes were captured using the Agilent SureSelect All Exon kit v5 kit and libraries sequenced on HiSeq 2000 or 2500 or 4000.

  Dataset EGAD00001004436

• In vitro modeling of renal injury-induced cardiac effects using human iPSC-derived organoids

  The bidirectional communication between the heart and kidney essential for physiological homeostasis, with injury in one organ often impairing in the other. Although cardiorenal crosstalk is clinically relevant in conditions such as cardiorenal syndrome (CRS), the underlying molecular and cellular mechanisms remain poorly understood, and in vitro models are lacking. Here, we developed a co-culture system using human induced pluripotent stem cell (hiPSC)-derived kidney organoids (kOs) and cardiac microtissues (cMTs) to model the cardiorenal axis. kOs exposed to nephrotoxic compounds for 72 hours displayed glomerular and tubular damage, reduced cell viability, and altered gene expression. When subsequently co-cultured with cMTs for 72 hours, injured kOs induced secondary cardiac dysfunction characterized by reduced cell viability, impaired contractility, and endothelial cell loss. These findings demonstrate that kidney injury can elicit detrimental effects on cardiac tissues in vitro. This organoid-based platform offers a valuable tool for studying cardiorenal interactions and underlines the potential of multi-organ models for investigating mechanisms of interdependent organ dysfunction.

  Study EGAS50000001300

• WGS_of_healhy_mesothelial_cells_and_primary_mesothelima_cell_lines

  Mesothelioma is a rare and aggressive cancer associated with previous exposure to asbestos. Currently there are no effective treatments for mesothelioma and majority of patients will die within a year after diagnosis. Although a large number of preclinical and clinical trials assessed the efficacy of various therapuetic modes, none of the tested molecules entered the clinic. Thus, to better understand what drives mesothelioma carcinogenesis and to identify novel targets for therapy, here we aim at performing WGS of heathy mesothelial cells and a panel of mesothelioma cells lines. Primary mesothelial cell lines were established in prof. Marciniak lab from human pleural specimens, while primary mesothelioma cell lines were obtained from MesobanK. Both models constitute low passage cell lines and therefore should closely represent genetics of the original tissue.

  Study EGAS00001005559

• RNA sequencing of untreated head and neck cancer patient-derived xenografts (PDXs) and matched patient tumor tissue.

  RNA sequencing was performed on untreated patient tumor tissue and matched patient-derived xenograft (PDX) models of primary head and neck squamous cell carcinoma (HNSCC). The aim of this analysis was to characterize the transcriptional landscape of the tumors in the in vivo setting.

  Study EGAS50000001595

• WGS patient 130

  Whole genome sequencing on DNA from snap frozen tumour sample and matched whole blood of patient #130. Analysis used the QIAamp DNA Mini Kit. Libraries were prepared using the Illumina TruSeq Nano library method using 200ng of DNA. Extracted DNA was sheared using the Covaris M220 Focused-ultrasonicator with a target fragment length of 550bp through bead size selection. The libraries were sequenced at depth of 40x for germline DNA and 80-100x for tumour DNA using paired 150bp reads.

  Dataset EGAD00001011271

• Quantitative analysis of a novel DNA hypermethylation panel using bronchial specimen for lung cancer diagnosis

  The dataset includes IDAT raw files for 10 samples and the analyzed DMP file which describes the differential methylation positions based on Illumina Infinium MethylationEPIC BeadChip. All samples (5 lung cancer cases vs. 5 benign lung disease controls) were obtained from bronchial washings at the site of the lesion under bronchoscopy manipulation. The histological type of the five lung cancer cases is adenocarcinoma and squamous cell carcinoma.

  Dataset EGAD00010002465

• Phylogenetic reconstruction of adult blood cancer reveals early origins and lifelong evolution - WGS

  Mutations in cancer-associated genes drive tumour outgrowth. However, the timing of driver mutations and dynamics of clonal expansion that lead to human cancers are largely unknown. We used 580,133 somatic mutations from whole-genome sequencing of 1013 clonal haematopoietic colonies to reconstruct the phylogeny of haematopoiesis, from embryogenesis to clinical disease, in 12 patients with myeloproliferative neoplasms which are blood cancers more common in older age. JAK2V617F, the pathognomonic mutation driving the majority of these cancers, was acquired in utero or childhood, with upper estimates of age of acquisition from 33 weeks gestation to 10.8 years, in all 5 patients in whom JAK2V617F was either the only or the first driver event.  Driver mutations associated with age-related clonal haematopoiesis occurred prior to or following JAK2V617F,  as independent clonal expansions in JAK2V617F-mutated patients, and as large clonal expansions in JAK2V617F-unmutated patients . These mutations were also acquired in utero or childhood, with DNMT3A mutations occurring by 8 weeks of gestation to 7.6 years across 4 patients, and PPM1D mutation occurring by age 5.8yrs in a patient with MPN lacking phenotypic driver mutations. Sequential driver mutation acquisition was common, separated by decades across life, and often outcompeted ancestral clones. The mean latency between JAK2V617F acquisition and clinical presentation was 30 years (range 11-54 years). Rates of clonal expansion were inferred from phylogenetic trees and varied substantially (3% to 190% expansion/year), were affected by additional driver mutations, and were predictive of latency to clinical presentation. Driver mutations and rates of expansion would have been detectable in blood one to four decades before clinical presentation. This study reveals how driver mutation acquisition early in life with life-long growth and evolution underlie adult myeloproliferative neoplasms, providing opportunities for early detection and intervention and a new paradigm for cancer development.

  Dataset EGAD00001007714

• Malnutrition and Enteric Disease Network (Mal-ED) Case-Control Study in Brazil

  The Malnutrition and Enteric Disease Network (Mal-ED) Case-Control Study enrolled children in the age range 6-24 months between 2010 and 2014 in Fortaleza, Ceará, Brazil.The aim of the study was to understand the etiology and pathogenesis of malnutrition. Children were prospectively enrolled cases defined as weight for age Z Score (WAZ) <-2 and age and neighborhood matched controls defined as WAZ>-1.This submission includes genetic and associated phenotypic data on a subset of 336 participants. More information on this project and its related projects can be found here: Studies of diarrheal susceptibility, growth, and development, in pediatric populations in Northeastern Brazil

  Study phs003173

• A molecular signature for IL-10-producing Th1 cells in protozoan parasitic diseases

  Control of the intracellular parasites that cause malaria and visceral leishmaniasis (VL) is dependent on the generation of pro-inflammatory, IFNγ+ Tbet+ CD4+ T (Th1) cells by infected hosts. Immunoregulatory IL-10 produced by Th1 cells serves to mitigate subsequent inflammation and related disease pathology. However, these IL-10-producing Th1 (Tr1) cells can also not only promote parasite persistence, but may impair immunity to re-infection and potential vaccine efficacy. Here, we identify molecular and phenotypic signatures that distinguish Th1 cells from Tr1 cells in both experimental VL, caused by infection of C57BL/6 mice with the human parasite Leishmania donovani, and in Plasmodium falciparum-infected humans participating in controlled human malaria infection (CHMI) studies. Such characterisations allow for the better understanding of Tr1 cell development and function in the context of these parasitic diseases, and for the identification of targets for immune modulation to improve anti-parasitic immunity.

  Study EGAS00001004454

• Using de novo assembly to identify structural variation of complex immune system gene regions

  Driven by the necessity to survive environmental pathogens, the human immune system has evolved exceptional diversity and plasticity. Several factors contribute to this including inheritable structural polymorphism of the underlying genes. To investigate this we generated data for a single healthy European individual (identified as HV31) using multiple long-read (PacBio Sequel II and Oxford Nanopore), short-read (Illumina HiSeq and MGI G400) and linked-read (10X Chromium and stLFR) sequencing platforms, and optical mapping using the Bionano Saphyr platform. DNA was extracted from monocytes or from peripheral blood mononuclear cells. We used these data to assemble a set of regions encoding components of the immune system and to investigate structural variation. The raw data and analysis results are deposited here for generate research use. A complete description of these data and results can be found in the accompanying article at https://doi.org/10.1101/2021.02.03.429586.

  Study EGAS00001005046

• Cell-Free DNA Genomic Profiling and its Clinical Implementation in Advanced Prostate Cancer

  Sixty-eight patients with advanced prostate cancer in castration-resistant or castration-sensitive settings undergoing treatment at the University Hospital Basel or the St. Claraspital Basel (Switzerland) were selected for targeted parallel sequencing analysis on liquid biopsy (plasma cfDNA) and matched formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples. The liquid biopsy sequencing (plasma cfDNA) was performed using a custom-designed targeted AmpliSeq HD Prostate Cancer cfDNA panel on all 68 patients. The sequencing on 42 matched FFPE tumor biopsy samples was performed using a custom-designed or an alternative commercial panel (ThermoFisher). Raw data underwent automated processing on the Ion Torrent Server v5.16.1 (ThermoFIsher) and were aligned to a hg19 reference genome using the Torrent Alignment Software (ThermoFihser).

  Dataset EGAD50000000348

• Immune profiling reveals enrichment of distinct immune signatures in oral epithelial dysplasia

  The dataset contains transcriptomic information of 36 oral potentially malignant disorders (OPMD), 14 fibroepithelial polyps (FEP), and 6 early stage oral squamous cell carcinoma (OSCC) from the Asian population. Total RNA was extracted from formalin-fixed paraffin embedded (FFPE) tissue sections. RNA libraries were prepared using the NEB NextUltra RNA kit with Illumina Ribo-Zero rRNA removal as per manufacturer’s instructions. RNA sequencing was performed on the HiSeq2500 platform to generate paired-end 150 nucleotides reads and with a coverage of 50 million reads per sample. Uploaded bam files have been mapped to the GRCh38 human genome using TopHat2. Clinical and demographic data for these patients are available from the associated publications or by request.

  Dataset EGAD00001007970

• MAESTRO-Pool Enables Highly Parallel and Specific Mutation-Enrichment Sequencing for Minimal Residual Disease Detection in Cohort Studies

  MAESTRO-Pool builds upon the technology MAESTRO (Minor Allele Enriched Sequencing Through Recognition Oligonucleotides) by pooling tumor-specific MAESTRO probes from multiple patients and applying these to all samples from all patients. In this study, MAESTRO-Pool was applied to a cohort of 9 melanoma patients where 98 plasma samples were screened for 22,333 mutations. Additionally, a new dynamic minimal residual disease (MRD) caller was used to estimate the likelihood of MRD detection based on the number mutations and cell-free DNA molecules interrogated which allowed each bespoke MRD test to be properly calibrated against false detection. These developments led to sensitive detection in patient-matched samples down to 0.78 parts per million (ppm) while limiting false detection in negative controls to 1/784 (tumor fraction=2.7 ppm). MAESTRO-Pool and the dynamic MRD caller enable a unique blend of sensitivity, specificity, and efficiency, which will improve the ability to detect MRD.The data contained in this repository consists of:Tumor and normal whole genome sequencing data used to call patient-specific tumor mutations and design the MRD Tracker and MAESTRO-Pool fingerprintsMAESTRO-Pool data (enriched duplex sequencing via hybrid capture) of tumor gDNA, normal gDNA and cfDNA MRD Tracker data (duplex sequencing via hybrid capture) of tumor gDNA, normal gDNA and cfDNA

  Study phs003447

• Data from the paper Context-specific Effects of TGFβ/SMAD3 in Cancer Are Modulated by the Epigenome. Tufegdzic et al, Cell Reports 2015

  The transforming growth factor beta (TGFβ) signalling pathway exerts opposing effects on cancer cells, acting either as a tumor-promoter or as a tumor-suppressor. Here we show these opposing effects are a result of the synergy between SMAD3, a downstream effector of TGFβ signalling, and the distinct epigenomes of breast tumor initiating cells (BTICs). These effects of TGFβ are associated with distinct gene expression programs, but genomic SMAD3 binding patterns are highly similar in the BTIC-promoting and BTIC- suppressing contexts. Our data show cell type-specific epigenetic configurations provide a modulatory layer by determining accessibility of genes to regulation by TGFβ/SMAD3. LBH, one such context-specific target gene, is regulated according to its DNA methylation status, and is crucial for TGFβ-dependent promotion of BTICs. Overall, these results reveal that the epigenome plays a central and previously overlooked role in shaping the context-specific effects of TGFβ in cancer.

  Study EGAS00001001570

• A reference map of potential determinants for the human serum metabolome

  The collection of metabolites circulating in the human blood, termed the serum metabolome, contains a plethora of biomarkers and causative agents. Although the origin of specific compounds is known, we have a poor understanding of the key determinants of most metabolites. Here, we measured the levels of 1251 circulating metabolites in serum samples from a healthy human cohort of 491 individuals, and devised machine learning algorithms to predict their levels in held-out subjects based on a comprehensive profile consisting of host genetics, gut microbiome, clinical parameters, diet, lifestyle, anthropometric measurements and medication data. Notably, we obtained statistically significant predictions for over 76% of the profiled metabolites. Despite using the strict out-of-sample prediction metric, which is a lower bound for the explained variance, diet and microbiome each explained hundreds of metabolites, with over 50% of the variance explained in some metabolites. We further validated the robustness of the microbiome related associations by showing a high replication rate in two geographically independent cohorts that were not available to us when developing the algorithms. We also demonstrate that some of these interactions are causal, as some metabolites we predicted to be positively associated with bread increased in level following a randomized clinical trial of bread intervention. Microbiome-explained metabolites were enriched with unnamed metabolites, and we devised an algorithm that accurately predicts their biological pathway, finding that they mainly include food components, aromatic amino acids and secondary bile acid derivatives. Overall, our results unravel potential determinants of over 800 metabolites, paving the way towards mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating circulating metabolite levels.

  Study EGAS00001004512

• RNA sequencing on colonic biopsies from inflammatory bowel disease patients treated with vehicle control, MEK inhibitor, or infliximab

  This dataset consists of RNA sequencing data (FASTQs) from intestinal mucosal biopsies from 9 IBD patients. All patients endoscopically active disease and were not receiving immunosuppressive or biologic therapies. All biopsies (6 per donor) were collected from a single inflamed site. Biopsies were cultured for 18 hours at an air-liquid interface in media containing either DMSO (vehicle control), PD-0325901 (0.5uM) or infliximab (10ug/ml; MSD) - two biopsies per condition. Sequencing was performed on a NovaSeq 6000 (100bp, PE reads). After 18 hours, biopsies were harvested and snap frozen. After lysis, RNA was extracted using an AllPrep DNA/RNA Mini Kit (Qiagen). Sequencing libraries were prepared from 10ng RNA using the SMARTer Stranded Total RNA-Seq Kit v2 - Pico Input Mammalian (Takara) following the manufacturer’s instructions. The quality and molarity of all libraries was assessed using a BioAnalyzer 2100 and the libraries were sequenced on a NovaSeq 6000 (100bp, PE reads).

  Dataset EGAD00001011333

• Gene Expression between PMD and Control LCLs at Baseline, E2, and E2 Withdrawal

  In this study, lymphoblastoid cell lines (LCLs) derived from women with past perimenopausal depression (PMD) (n = 8) and asymptomatic controls (n = 9) were compared via poly(A)-selected transcriptome sequencing (RNA-seq). LCLs were cultured in three experimental conditions: at vehicle baseline (ovarian steroid-free), during estradiol (E2) treatment, and following E2-withdrawal. Transcriptomic analysis revealed significant differences in transcript expression in PMD LCLs compared to controls in all experimental conditions, and significant overlap in genes that were changed in PMD regardless of experimental condition. Among these, chemokine CXCL10 was upregulated in women with PMD, but most so after E2-WD and CYP7B1, an enzyme intrinsic to DHEA metabolism, was upregulated in PMD across experimental conditions. Finally, this in vitro model identified gene networks dysregulated in PMD which included inflammatory response, early/late E2-response, and cholesterol homeostasis. Data available will include the normalized counts for each subject in the study.

  Study phs003003

• Hip OA Functional Genomics RNAseq (2017-06-09)

  From 9 patients undergoing hip joint replacement surgery for osteoarthritis, we collected 3 cartilage samples each: a low-grade sample (no obvious evidence of damage or fibrillation); a high-grade sample (damaged and fibrillated cartilage); an osteophytic sample (overlaid bony protrusions mainly around the margins of the articular surface). Multiplexed libraries were sequenced on Illumina HiSeq 2000 (75bp paired-end read length) and a cram file was produced for each sample. This dataset contains all the data available for this study on 2017-06-09.

  Dataset EGAD00001003354

• Targeted sequencing of 72 prostate cancer driver in 712 plasma cell free DNA samples

  Dataset contains targeted sequencing data of 712 plasma cell free DNA samples and 428 white blood cell samples collected from 428 men with metastatic prostate cancer. Target capture was performed using a hydridization-based custom Roche SeqCap EZ Choice kit, designed to capture all exons of 72 prostate cancer driver genes. Cell free DNA was extracted from 10 mL blood samples. Libraries were sequenced using Illumina HiSeq 2500 or Illumina MiSeq instruments to a median coverage of 750x. 62% of samples had ctDNA fraction above 2% of total cfDNA. Note that "Dataset type" is erroneously listed as "Amplicon sequencing", because "Captured-based targeted sequencing" or "Hybridization-based targeted sequencing" were not available options in EGA at the time of submission.

  Dataset EGAD00001004208

• The polarity and specificity of antiviral T lymphocyte responses determine susceptibility to SARS-CoV-2 infection in cancer patients and healthy individuals

  We monitored patient's anti SARS-CoV-2 immune responses using an in vitro cross presentation assay. The goal of this study was to identify immune correlates of clinical protection against SARS-CoV-2 infection. Briefly, peripheral blood mononuclear cells of patient were divided into a monocyte and lymphocyte. Monocyte were differentiated into monocyte derived dendritic (mo-DC)cells using GM-CSF and Interferon alpha. Mo-DC were then loaded with SARS-CoV-2 culture lysates , or VeroE86 lysates. SARS-CoV-2 loaded mo-DC were then used to stimulates their autologous lymphocytes and T cell cytokine secretion was monitored in the supernatant. We discriminated patients producing IL-2 and patients producing IL-5. RNA sequencing was performed for 18 patients, to identify gene profile associated with IL-2 or IL-5 production.

  Dataset EGAD00001008538

• DEPArray-based sorting of pure carcinoma and stromal populations from formalin-fixed paraffin-embedded (FFPE) tissues followed by shallow whole genome sequencing

  To overcome the challenges of low DNA yields, degraded DNA by formalin fixation and diluted signal of genomic aberrations by non-carcinoma components in the heterogeneous FFPE samples, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from 9 primary and metastatic breast cancer and 3 primary ovarian high-grade serous carcinomas. This was followed by downstream shallow whole genome sequencing (WGS) for copy number landscape profiling for 10 samples. Seven out of 10 samples (even some with low tumour content or of old age) produced good quality genomic data, detecting sCNA in all carcinoma population samples but not in the stromal populations.

  Study EGAS50000001328

• National Eye Institute (NEI) Age-Related Eye Disease Study 2 (AREDS2)

  The Age-Related Eye Disease Study 2 (AREDS2) was a multi-center, randomized Phase III clinical trial designed to assess the effects of oral supplementation of high doses of lutein, zeaxanthin, and omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) in reducing the risk of progression to late age-related macular degeneration (AMD), progression to cataract surgery, and/or progression to moderate vision loss in high-risk participants. The effect of the study supplements on cardiovascular outcomes and cognitive function were also examined. Other study goals included evaluation of eliminating beta-carotene and/or reducing zinc in the original AREDS formulation on the progression and development of late AMD. AREDS2 sought to validate the AREDS AMD scale developed from the photographic data obtained from AREDS, (Study Accession: phs000001).Eighty-two clinical sites across the United States enrolled 4,203 participants aged 50 to 85 (mean age 74 years) between October 2006 and September 2008. Enrollment was restricted to people at high risk of progression to late AMD with either bilateral large drusen or large drusen in 1 eye and late AMD in the fellow eye. Follow-up assessments in the clinic occurred on an annual basis for an average of 5 years, with telephone calls every six months during each year. Blood or saliva samples were also collected from 2,000+ AREDS2 participants for genetic research. Of these, samples from 1,800+ AREDS2 participants were included in the International Age-Related Macular Degeneration Genomics Consortium - Exome Chip Experiment, and have exome chip data available in the dbGaP (Study Accession: phs001039). In addition, samples from 1300+ AREDS2 participants were included in the International Age-Related Macular Degeneration Genomics Consortium - Whole Genome Sequencing Study in the dbGaP (Study Accession: TBD). Of 1363 AREDS2 participants with whole genome sequencing, 488 previously participated in AREDS.Please see "The Age-Related Eye Disease Study 2 (AREDS2) Research Group" document for a full list of AREDS2 study contributors.

  Study phs002015

• Structure and Diversity of Urinary Cell-Free DNA Informative of Host-Pathogen Interactions in Human Urinary Tract Infection

  The risk of acquiring urinary tract infection (UTI) is very high for patients who have received kidney transplants; nearly half will develop bacteriuria and an eighth viruria via BK polyomavirus in the first three years following transplantation. Current methodology for diagnosing viral and bacterial infections, while well practiced, is often limited in scope. The advent of next generation sequencing of cell-free DNA has shown promise in its ability to capture multiple perspectives of human health from discovering the origin of cell-free DNA in plasma; such a diagnostic has not been readily applied to urinary cell-free DNA. In this study, we selected 141 urine samples from a cohort of kidney transplant patients, which were collected and stored at Weill Cornell Medical College - New York Presbyterian Hospital. Of these samples, 43 samples were determined to be culture positive (> 10,000 CFU) for one or more bacterial species, including E. coli, Enterococcus, Klebsiella, Haemophilus, and Raoultella. A separate 23 samples were confirmed for BK virus nephropathy, with presence of BK polyomavirus confirmed via qPCR. We also included 29 samples from 14 patients who did not develop UTIs in the first three months following transplantation, and 11 samples that were negative for BK virus nephropathy. For a full description of samples, please see the Supplementary Data 1 in https://pubmed.ncbi.nlm.nih.gov/29925834/. From these urine samples, we aimed to capture and sequence urinary cell-free DNA using a single-stranded library preparation. In addition, we performed whole-genome bisulfite sequencing to 170 plasma samples collected from 27 hematopoietic cell transplant patients who developed graft-versus host disease and BK polyomavirus infection. We also performed Sample-Intrinsic microbial DNA Found by Tagging and sequencing (SIFT-seq) on 196 cell-free DNA (cfDNA) samples (154 plasma and 42 urine) collected from five groups of subjects. For a full description of samples, please see publications in PMID: 35864089 and PMID: 35058359.

  Study phs001564

• Dataset for ChIP and Transcriptomic sequencing of neuroblastoma tumor samples(hipo)

  This dataset contains ChIP and Transcriptomic sequencing of 32cneuroblastoma tumor samples. The sequencing was performed on Illumina HiSeq 2000 and Illumina HiSeq 4000 respectively.

  Dataset EGAD00001015808

• Korean Young Age Diffuse Gastric Cancers

  The incidence of diffuse gastric cancers (DGC) remains steadily high, but relatively small numbers of DGCs have been evaluated with whole exome sequencing (WES). Clinicopathological features of DGC vary according to age, but the molecular basis for these variations is unclear. To identify genomic alteration in this unique subset of gastric cancers, whole exome and SNP6 analyses were performed using frozen cancer tissue. The same analyses were also performed using blood of the same patients.

  Study EGAS00001001711

• Maternal Plasma Folate and DNA Methylation in Epigenome-Wide Meta-Analysis of Newborns

  Folic acid is routinely recommended for women trying to conceive to ensure proper fetal development. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. This data represents meta-analysis results from a large epigenomics study to examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina's HumanMethyl450 (450K) Beadchip in 1,996 newborns from two European cohorts. Results for all CpGs analyzed (419,905) are provided. These data may be downloaded through the dbGaP Authorized Access portal under phg000701.v1.

  Study phs001059

• Combined Targeting of CDK4/6 and HER2 Signaling in Orthotopic Patient-Derived Xenografts of HER2-Positive Breast Cancer Brain Metastases

  Patients with metastatic HER2-positive (HER2+) breast cancer will frequently develop brain metastases (BCBMs). Here, we report that p16INK4A, a tumor suppressor, is deficient in the majority of HER2+ BCBMs. Furthermore, p16INK4A deficiency, as measured by protein immunohistochemistry, can be a predictive marker associated with response to combined treatment with tucatinib and abemaciclib in our orthotopic patient-derived xenografts (PDXs) models of HER2+ BCBMs. Our findings provide the rationale for a biomarker-driven clinical trial of combined treatment with CDK4/6- and HER2-targeted agents for patients with HER2+ BCBM.  

  Study phs002482

• 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

• Targeted re-sequencing of multi-region sampled tumors in PDAC

  Multi-region tumor samples were cut from frozen sections or FFPEs and reviewed from microdissection and H&E staining in order to select ones with high cellularity. DNA extraction was done using DNeasy Blood & Tissue Kits for frozen samples following the manufacturer’s guideline. Extracted DNAs were processed on an Illumina HiSeq 2500 in a paired end mode (100x100) using a custom targeted panel based on the list of all unique somatic mutations from the original WES data by the Integrated Genomics Operation (IGO) at Memorial Sloan Kettering Cancer Center (New York, NY).

  Study EGAS50000000239

• Karyotype Evolution in Response to Chemoradiotherapy and Upon Recurrence of Esophageal Adenocarcinomas

  The genome of esophageal adenocarcinoma (EAC) is highly unstable and might evolve over time. Here, we track karyotype evolution in EACs in response to treatment and upon recurrence through multi-region and longitudinal analysis. To this end, we introduce L-PAC, a bio-informatics technique that allows inference of absolute copy number aberrations (CNA) of low-purity samples by leveraging information of high-purity samples from the same cancer. Quantitative analysis of matched absolute CNAs reveals that the amount of karyotype evolution induced by chemoradiotherapy (CRT) is predictive for early recurrence and depends on the initial level of karyotype intra-tumor heterogeneity. We observe that CNAs acquired in response to CRT are partially reversed back to the initial state upon recurrence. CRT hence alters the fitness landscape to which tumors can adjust by adapting their karyotype. Together, our results indicate that karyotype plasticity contributes to therapy resistance of EACs.

  Study EGAS00001007711

• Osteosarcoma 3D patient derived cultures to test genome-informed personalized treatment options; a feasibility study

  Background: Improving osteosarcoma treatment beyond conventional (neo)adjuvant chemotherapy and resection remains challenging. An urgent need for novel therapeutic options, particularly personalized and targeted approaches, has emerged due to high inter-patient molecular heterogeneity. A lack of representative in vitro and in vivo models impedes therapeutic development, therefore we aimed to create 3D in vitro long term culture models directly from patient material. Methods: Tumour cells from seven osteosarcoma patients were propagated in monolayer or collagen hydrogels, while whole-exome sequencing of corresponding primary tumour tissue was performed to identify potential drug targets. Established cultures were subsequently used to assess efficacy of the identified personalized treatment options. Results: Three out of seven hydrogel cultures harboured the same genetic alterations as the corresponding primary tumours. Among these, the L6565 patient line exhibited homozygous CDKN2A loss with retained Rb expression, rendering tumour cells sensitive to CDK4/CDK6 inhibition via palbociclib. This patient line was used to evaluate genome-informed therapy and to compare cell culture models of increasing complexity. Our findings demonstrate feasibility of establishing long-term patient-derived osteosarcoma cultures with a success rate of 14%. Tumour heterogeneity was reflected in advanced culture methods producing more variability in treatment response. Conclusion: These results highlight the potential of genome-informed therapies in osteosarcoma and the importance of refining culture techniques to enhance translational research and therapeutic outcomes.

  Study EGAS50000001583

• Human tumour ChIP-seq.

  We profiled 16 patient tumour samples by ChIP-seq. H3K27ac and Input are provided for 16 samples and H3K27me3 is provided for 14 samples. Among the 16 samples, 9 are G34WT and 7 are G34R/V. The raw fastq or bam files are provided.

  Dataset EGAD00001006100

• Comprehensive Omics Analysis of Pediatric Solid Tumors and Establishment of a Repository for Related Biologic Studies (10C0086)

  This study (10-C-0086) collected and analyzed tumor and circulating tumor omics of pediatric and young adult patients with relapsed rhabdomyosarcoma who were co-enrolled in and receiving treatment on the interventional study 17-C-0049. We sought to describe the summary genomic findings of tumors, and report on the detection of circulating tumor DNA (ctDNA) in serial samples. Tumor tissue and blood were collected and analyzed. Tumor samples were subjected to whole exome and/or whole genome sequencing paired with RNA-Seq. Cell free DNA (cfDNA) was extracted from serially collected blood samples and sequenced. Fusion status, mutations, and IGF1R and YES1 expression from tumor samples revealed the presence of a PAX3 fusion in most samples, a number of common mutations, and universal but heterogeneous expression of IGF-1R and YES1. ctDNA was detected above the 3% threshold in a majority of patients and analysis of cfDNA demonstrated an ability to monitor tumor clonal evolution.

  Study phs003243

• 5- FU treated organoids

  5-Fluorouracil (5-FU) is a chemotherapeutic drug component that is commonly used for the treatment of solid cancers. The anticancer properties of 5-FU have been attributed to interference with nucleotide synthesis and through direct incorporation into the DNA as being a pyrimidine analog. As both mechanisms of action may have a mutational impact on surviving tumor cells, we performed three independent analyses to characterize the genomic consequences of 5-FU treatment: i) in vitro treatment of intestinal organoids with 5-FU followed by whole genome sequencing, ii) genome-wide mutation analyses in tumor samples from 5-FU treated patients with breast or colorectal cancer, and iii) analysis of paired biopsies from patients treated with 5-FU between biopsies. Our results demonstrate that both in vitro and in vivo 5-FU causes a mutational pattern that is dominated by T>G substitutions in a CTT context and with strong resemblance to COSMIC signature 17. Interestingly, this signature is also found in non 5-FU treated patients, most prominently in esophageal tumors, indicating that distinct endogenous and exogenous triggers can converge into highly similar mutational signatures. Furthermore, our results suggest that 5-FU may have adverse mutagenic effects on healthy cells and contributes to genetic variability in surviving cancer cells thereby contributing to tumor evolution.

  Study EGAS00001003592

• Exome sequencing for paired tumor/normal samples from patients with corticotropin-independnet Cushing's syndrome

  Exome sequencing was performed for paired tumor/normal samples from patients with corticotropin-independnet Cushing's syndrome. Tumor DNA was extracted from adrenocortical adenomas and normal DNA was extracted from adjacent adrenal tissues or periphral blood.

  Dataset EGAD00001000715

• 4 - transcriptome (.bam) files, 2 -called somatic mutations (.vcf) files and 2 coverage (.csv) files

  The dataset contains 4 .bam whole transcriptome files that were generated from 2 tumor samples (one .bam file per sample was created using exome-capture (hybrid capture) and the other .bam file was created using ribo-repletion (inverse mRNA selection) library preparation technology). The dataset also contains 2 somatic mutations (.vcf - sample) files (one per sample) which serve as input for Vardetector package (vardetector/vardetector at main · julijselb/vardetector) to produce somatic coverage over those mutations from the .bam file. Therefore, the dataset also contains 4- .csv files (number of reads per somatic mutation that contain the somatic mutation variant and the ones that do not contain the somatic mutation variant) that serve as outputs of the Vardetector package.

  Dataset EGAD50000002055

• 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

• 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

• InterPregGen-GWAS-UZB-1

  GWAS genotype data for maternal and fetal (baby) cases of preeclampsia and controls from Uzbekistan. This dataset is a component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium members in Tashkent, Uzbekistan at the Institute of Immunology, Uzbek Academy of Sciences and at the Republic Specialized Scientific Practical Medical Centre of Obstetrics and Gynecology

  Dataset EGAD00010001918

• 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

• Single-Cell RNA-Seq Profiling of Peripheral Immune Responses to Severe Infection in Uganda

  We conducted a prospective observational study (RESERVE-U-2-TOR) of adults admitted to Tororo General Hospital in eastern Uganda with severe, undifferentiated infection (i.e., suspected sepsis). Peripheral blood mononuclear cells (PBMCs) were isolated from freshly collected heparinized whole-blood samples (4 - 5 mL) using a standard density-gradient protocol (STEMCELL Technologies). PBMCs were aliquoted, cryopreserved in CryoStor CS10 (STEMCELL Technologies), stored overnight at -80°C, and transferred to liquid nitrogen for longer-term storage. Upon thawing, viability was assessed using the Nexcelom Cellaca Cell Counter, and cells were diluted to optimal concentrations for loading onto the Chromium Controller (10X Genomics). Each sample targeted the capture of ~10,000 GEMs (gel bead-in-emulsions). Single-cell RNA libraries were prepared using the Chromium Single Cell 3' Reagent Kit v3.1 following the manufacturer's standard protocol. Libraries were quality-assessed using an Agilent TapeStation and quantified using both Qubit 2.0 Fluorometer (Invitrogen) and qPCR (Applied Biosystems). Sequencing was performed on the NovaSeq X Plus platform (Illumina) using a 28×91 read configuration per 10X guidelines, targeting ~50,000 reads per cell. Data from this study available through dbGaP include raw single-cell RNA-seq data generated from PBMC samples collected from a subset of RESERVE-U-2-TOR participants at study enrollment (N=8).

  Study phs004100

• Australia and New Guinea haplotype phasing (2017-06-27)

  Whole-genome sequencing and phasing of admixed Aboriginal Australian genomes and Papua New Guinean genomes using 10x Genomics Chromium technology. 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 please see http://www.sanger.ac.uk/datasharing/ This dataset contains all the data available for this study on 2017-06-27.

  Dataset EGAD00001003407

• Genome-Wide Scan for Genetic Variants Associated with Early-Onset Prostate Cancer

  This is a genome-wide association scan of 931 early-onset prostate cancer cases of European ancestry. The samples were selected from prostate cancer studies at the University of Michigan. Controls were previously genotyped individuals selected from the Cancer Genetics Markers of Susceptibility (CGEMS) and Illumina's iControlDB database.

  Study phs001185

• Genomic analysis of head and neck squamous cell carcinoma upon acquired resistance to cetuximab

  Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab) remain the only FDA-approved targeted therapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Unfortunately, most patients develop acquired resistance to cetuximab and there is currently no further therapeutic option for these patients (unmet clinical need), thereby highlighting the need to better understand resistance-causing mechanisms. Here, we carried out whole-exome sequencing on 2 cetuximab-sensitive and -resistant patient-derived xenograft models of HNSCC. Our data reveal several genetic alterations (mutations and copy number variations) associated with acquired resistance to anti-EGFR therapy.

  Study EGAS50000000800

• Revealing active mutational processes in tumours using DigiPico/MutLX at unprecedented accuracy

  Active mutational processes in a tumor result in genetic micro-heterogeneity that can determine the tumor’s evolutionary trajectory. Identification of these processes by studying micro-heterogeneity can unveil novel aspects of tumor evolution with potential therapeutic implications. Such studies, however, are inherently problematic because of the discovery of excessive false positive mutations. Here we report the optimization and validation of a robust whole genome sequencing and analysis pipeline (DigiPico/MutLX) that virtually eliminates false positive results. Using our method, we identified, for the first time, a sub-clonal local hyper-mutation (kataegis) event in a recurrent ovarian carcinoma, which was unidentifiable from the bulk WGS data of the same tumor. Overall, we propose DigiPico/MutLX method as a powerful framework for the reliable study of genetic micro-heterogeneity in tumor and normal tissues.

  Study EGAS00001003555

• Single Cell Genotypic and Phenotypic Analysis of Measurable Residual Disease in Acute Myeloid Leukemia

  Acute myeloid leukemia (AML) is a group of blood cancers with high mortality. Even though complete remission is often achieved, majority of the AML patients still relapse. Measurable residual disease (MRD), defined as the population of cancer cells which persists following chemotherapy, is responsible for AML relapse. Understanding the biology enabling MRD clones to resist therapy is necessary to guide the development of curative treatments more effectively. Discriminating residual leukemic clones, preleukemic clones, and normal precursors remains a challenge with current MRD tools. We developed a single cell MRD (scMRD) assay by combining flow cytometric enrichment of the targeted precursor/blast population with integrated single cell DNA sequencing (scDNA-seq) and immunophenotyping (Tapestri, Missionbio). The platform utilizes a custom amplicon panel covering 109 amplicons across 31 genes frequently mutated in AML and a panel of 42 oligo-conjugated antibodies against surface makers. We applied our scMRD assay to sequence 30 MRD samples (multiplexed into 6) from 29 AML patients to study the clonal architecture and protein correlation. In addition, 2 MRD samples were sequenced with scDNA+protein sequencing technology without enrichment or multiplexing. Five patients with AML at diagnosis were also sequenced with scDNA+protein sequencing technology without enrichment or multiplexing. In order to establish the sensitivity of our scMRD assay, we spiked AML cells into normal bone marrow cells. We sequenced 12 such spiked samples after multiplexing.

  Study phs003233

• Whole exome sequence analysis in multiple system atrophy

  To identify a susceptible gene for multiple system atrophy, exome sequence analysis was conducted in 14 patients and 7 controls.

  Study JGAS000009

• Genome-Wide Environment Interaction Study on Neurodevelopment in Children from Mexico and Bangladesh

  Cognitive development is known to be highly heritable, but various genome wide association studies (GWAS) have failed to find common single nucleotide polymorphisms (SNPs) which can explain a large proportion of the variance in cognitive ability. We hypothesized that an interaction between genes and exposure to potentially toxic metals may account for some proportion of this missing heritability. We genotyped 749 infants in Mexico and 636 infants in Bangladesh. Criteria for inclusion into the study are given below. We then performed a Genome Wide Environmental Interaction Study (GWEIS) with neurodevelopment outcomes. There were 552,487 SNPs in common between the two cohorts.

  Study phs000996

• Xenium analysis on Crohn's disease and control specimen

  Xenium analysis was performed on surgically resected Crohn's disease specimens and control specimens. The purpose of this study was to characterize the different features between intra-lymphatic antigen-presenting cells in Crohn's disease and those in controls.

  Study JGAS000697

• Resolving_the_Genetic_Architecture_of_Aseptic_Loosening_After_Total_Hip_Replacement

  This is a genome-wide association scan of aseptic loosening after total hip replacement in a Norwegian population. 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 please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001001883

• Single-cell multi-omics of relapse/refractory multiple myeloma patients (Hipo K08K/H067/K43R)

  Therapy resistance in cancers is ingrained in complex clonal dynamics. While the major clonal population in a tumour might respond well to the employed intervention, minor clones will eventually mutate, consequently acquiring a selective advantage and drug resistance. Hence, to improve cancer therapy, it is crucial to understand the mechanisms behind clonal evolution. Here, we applied single-cell transcriptomics and epigenomics, as well as whole-genome sequencing to 15 patients with relapsed/refractory multiple myeloma (RRMM). By profiling longitudinal samples throughout varying treatment regimens, we were able to interrogate patterns of evolution across patients. In particular, by defining clones based on copy number aberrations (CNAs), we found evidence for the majority of clones being diminished but not fully eradicated during treatment.

  Study EGAS00001006538

• Whole exome sequencing of an invasive diffuse intrinsic pontine glioma sampled from different sites

  The lateral ventricle subventricular zone (SVZ) is a frequent site of high-grade glioma (HGG) spread and tumor invasion of the SVZ is a predictor of a worse clinical prognosis. A range of HGG types invade the stem cell niche of the SVZ, including both adult glioblastoma and pediatric high-grade gliomas such as diffuse intrinsic pontine glioma (DIPG). The cellular and molecular mechanisms mediating this frequent invasion of the SVZ are poorly understood. Here we demonstrate that neural precursor cell (NPC):glioma cell communication underpins the propensity of glioma to colonize the SVZ. SVZ NPCs secrete chemoattractant signals toward which glioma cells home. Biochemical and proteomic analyses of factors secreted by SVZ NPCs revealed a discrete list of candidate proteins. Necessity and sufficiency testing implicated the neurite outgrowth-promoting factor pleiotrophin, along with three required binding partners (secreted protein acidic and rich in cysteine (SPARC), SPARC-like protein 1, and heat shock protein 90B), as key mediators of this chemoattractant effect. Pleiotrophin protein expression is strongly enriched in the SVZ, and knockdown of pleiotrophin expression starkly reduced glioma invasion of the SVZ in the adult murine brain. Pleiotrophin, in complex with the three binding partners, activated the Rho/ROCK pathway in DIPG cells, and inhibition of ROCK resulted in decreased DIPG invasion toward SVZ neural precursor cell-secreted factors. These findings demonstrate a pathogenic role for neural precursor cell – glioma interactions and potential therapeutic targets to limit glioma invasion.

  Study EGAS00001002326

• DirectHRD Enables Sensitive Scar-Based Classification of Homologous Recombination Deficiency (HRD)

  Homologous recombination deficiency (HRD)-induced genomic scars are an FDA-approved biomarker for identifying cancers likely to respond to PARP inhibitors. However, detecting HRD scars from blood biopsies has been challenging due to the low tumor content in blood samples. To address this limitation, we developed DirectHRD, a genomic scar-based HRD classifier leveraging whole-genome sequencing (WGS) data for non-invasive blood biopsy testing. DirectHRD was applied to 90 cell-free DNA (cfDNA) samples across four cancer types: breast, ovarian, prostate, and pancreatic. The method achieved an AUC of 0.87 and demonstrated the ability to detect HRD at tumor fractions as low as 1%, offering a tenfold increase in sensitivity compared to state-of-the-art methods.

  Study phs003760

• Pediatric Papillary Thyroid Carcinoma Whole Exome Sequencing

  BACKGROUND: Pediatric papillary thyroid carcinoma (PPTC) is distinct from adult-onset disease. Despite higher rates of regional and distal metastases and more frequent recurrence, there is, paradoxically, a highly favourable prognosis. Historically, only 40-50% of childhood PTC are driven by genomic variants common to adult PTC, while the oncogenic drivers in the remainder are unknown. METHODS: Fifty-two PPTCs were genotyped by candidate gene testing, followed, in a subset (n=32), by whole exome (WES) and transcriptome sequencing (RNASeq) to identify oncogenic variants in driver-unknown tumors and to explore gene expression patterns. FINDINGS: Thirty-one tumors (60%) carried variants identified by candidate gene testing, specifically: BRAFV600E(22%), NRASQ61R(2%), RET-CCDC6(19%), RET-NCOA4(15%) and PAX8-PPARG. Among the 21 remaining tumors with negative first-line genotyping, oncogenic variants were identified in 19 (90%). These were enriched with oncogenic fusions, with 11 non-recurrent fusion transcripts identified, including two that had not been previously described: STRN-RET and TG-PBF. Most fusions were associated with 3’ receptor tyrosine kinase (RTK) moieties: RET, MET, ALK and NTRK3. Gene expression analysis defined three distinct clusters, which demonstrated differing expression of genes involved in thyroid differentiation and MAPK signaling. INTERPRETATION: Exome and transcriptome-wide sequencing identify genomic drivers of PPTC in 98% of tumors, whereas conventional genotyping leaves many tumors genetically unexplained. PPTC is driven, in the majority of cases, by oncogenic fusion transcripts involving one of a limited number of RTKs. These observations have broad implications for diagnostic testing and for therapeutic options in children with advanced disease.

  Study EGAS00001005187

• Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

  SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn’s disease (CD), suggesting a role in inflammation. We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD68+ CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte differentiation into inflammatory macrophages and lipopolysaccharide (LPS)-induced inflammatory activation. SP140 preferentially occupies transcriptional start sites (TSS) in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduced SP140 binding and thereby expression of SP140-bound genes. GSK761 inhibited the spontaneous expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal-mucosa. This study identifies SP140 as a druggable epigenetic therapeutic target for CD.

  Study EGAS00001004460

• Human dorsal root ganglia after plexus injury - RNA-fragment sequencing from histological slices

  Human dorsal root ganglia from patients with brachial plexus injury and from subjects from forensic autopsy were extracted and fixed with paraformaldehyde. The cellular composition of these DRG was analysed in histopathological slices. From some of the slices, total RNA was extracted and total RNAseq was performed. The RNA sequencing data represent DRG with neuronal preservation (n=6) or neuronal loss (n=2) versus control (n=6). Details can be found in the corresponding publication and supplement to this publication.

  Study EGAS50000000682

• Ultra-sensitive ctDNA monitoring required for predicting response and resistance to immunotherapy in advanced melanoma

  Circulating tumor DNA (ctDNA) monitoring in peripheral blood has shown promise for disease surveillance and prognostication of ICI response. Yet even in the metastatic context, ctDNA signals can be missed, suggesting the need for increased assay sensitivity. We used a tumor-informed ctDNA assay capable of detection down to 1 part-per-million (PPM) ctDNA to profile 188 plasma samples from 23 melanoma patients receiving ICI over several years. Residual disease was detected in ctDNA over a broad range, from 130,000 PPM down to 2.3 PPM, with approximately a quarter of detections below 50 PPM. Early on-treatment increases in ctDNA level, and both ctDNA-based molecular clearance (mCR) and molecular progression (mPD) were all prognostic of both OS and PFS. Additionally, mCR consistently preceded radiographic imaging. Our results show the importance and utility of an ultra-sensitive ctDNA assay in advanced melanoma treated by ICI with potential implications for other cancers.

  Study EGAS50000000550

• Stressors and Health Study

  ObjectivesThe objectives of the Stressors and Health Study were to: (1) examine the prevalence of stressors and health outcomes and (2) assess differences in the associations between multi-level stressors and health outcomes, and (3) explore the protective and adaptive factors in the associations between multi-level stressors and health outcomes. Background Stressors have been posited to explain disparities in health. However, no surveys to our knowledge have simultaneously collected multiple stressors at various levels and the coping strategies used to deal with these stressors. Measuring these factors can provide a better understanding of the stressors experienced by specific groups and the impact that these experiences have on their health and health practices. In addition, exploring the various resilience and coping strategies employed to deal with stressors can help design appropriate interventions to reduce health disparities. Participants Participants included 1000 White, 1000 Black or African American, 1000 Latino or Hispanic, 1000 Asian, 500 American Indian or Alaska Native, 500 Native Hawaiian or Pacific Islander, and 500 mixed or multi-race adults (≥18 years) across the United States. Design The Stressors and Health Study is a cross-sectional online survey of adults across the US. A sampling frame (target population) of US residents based on the American Community Survey (ACS) was constructed using a rigorous two-step sampling matching approach to establish national representation.

  Study phs004019

• Transcriptome profiling of patient derived neural stem cells highlights the importance of CTNND2 and WNT signaling in early neuralization

  Loss of CTNND2/δ-catenin function is implicated in neurodevelopmental disorders, including Cri-du-chat syndrome, autism spectrum disorder and attention deficit hyperactivity disorder. CTNND2, the encoded protein, is crucial for the cadherin-catenin cell adhesion complex in the brain. However, the specific impact on neurodevelopment remains unclear. To investigate, we used neuroepithelial stem cells (NESCs) derived from patient-specific induced pluripotent stem cells (iPSCs) with loss of CTNND2. In monolayer cultures, we observed abnormal neural rosette formation and failure to establish stable neural stem cells. 3D organoid cultures confirmed delayed neurogenesis and slower growth in patient-derived iPSC lines. We have built a transcriptomic catalog and observed a dysregulation of the WNT signaling pathway linked to our observed cellular phenotypes. To validate we excluded the WNT activator CHIR99021 from the media, which partially rescued the transcriptomic and morphological phenotype of the patient neural induction. This study enhances our understanding of how CTNND2 loss affects early neurogenesis and neuronal maturation in patient specific cells.

  Study EGAS50000000323

• Partner-independent fusion gene detection by multiplexed CRISPR/Cas9 enrichment and long-read Nanopore sequencing

  Fusion genes are hallmarks of various cancer types and important determinants for diagnosis, prognosis and treatment possibilities. The promiscuity of fusion genes with respect to partner choice and exact breakpoint-positions restricts their detection in the diagnostic setting, even for known and recurrent fusion gene configurations. To accurately identify these gene fusions in an unbiased manner, we developed FUDGE: a FUsion gene Detection assay from Gene Enrichment. FUDGE couples target-selected and strand-specific CRISPR/Cas9 activity for enrichment and detection of fusion gene drivers (e.g. BRAF, EWSR1, KMT2A/MLL) - without prior knowledge of fusion partner or breakpoint-location - to long-read Nanopore sequencing. FUDGE encompasses a dedicated bioinformatics approach (NanoFG) to detect fusion genes from Nanopore sequencing data. Our strategy is flexible with respect to target choice and enables multiplexed enrichment for simultaneous analysis of several genes in multiple samples in a single sequencing run. We observe on average a 508-fold on-target enrichment and identify fusion breakpoints at nucleotide resolution - all within two days. We demonstrate that FUDGE effectively identifies fusion genes in cancer cell lines, tumor samples and on whole genome amplified DNA irrespective of partner gene or breakpoint-position in 100% of cases. Furthermore, we show that FUDGE is superior to routine diagnostic methods for fusion gene detection. In summary, we have developed a rapid and versatile fusion gene detection assay, providing an unparalleled opportunity for pan-cancer detection of fusion genes in routine diagnostics.

  Study EGAS00001003964

• The Microbial Ecology of Bacterial Vaginosis: A Fine Scale Resolution Metagenomic Analysis

  Archived self-collected vaginal swabs were utilized from a pilot study of vaginal douching cessation (NIH/NIAID R03-AI061131). Thirty-nine non-pregnant, reproductive-age women who reported the use of vaginal douche products in the two months prior to screening were enrolled. Thirty-three of these successfully completed the 16-week longitudinal study. Participants self-collected vaginal swabs and smears twice weekly. We report sequences based on the analysis of 16S rRNA gene sequences amplified from whole genomic DNA isolated from the swabs. Bacterial vaginosis (BV) is defined by Gram's stain of vaginal fluid (Nugent's score =7). The large body of information generated will facilitate understanding of vaginal microbial community dynamics, the etiology of BV, and drive the development of better diagnostic tools for BV. Furthermore, it is hoped that the information will enable a more personalized treatment of BV and ultimately, prevent adverse sequelae associated with BV.

  Study phs000261

• A Proteogenomic Analysis of Clear Cell Renal Cell Carcinoma in a Chinese Population

  Clear cell renal cell carcinoma (ccRCC) is a common and aggressive subtype of renal cancer. Here we conduct a comprehensive proteogenomic analysis of 232 tumor and adjacent non-tumor tissue pairs from Chinese ccRCC patients. By comparing with tumor adjacent tissues, we find that ccRCC shows extensive metabolic dysregulation and an enhanced immune response. Molecular subtyping classifies ccRCC tumors into three subtypes (GP1–3), among which the most aggressive GP1 exhibits the strongest immune phenotype, increased metastasis, and metabolic imbalance, linking the multi-omics-derived phenotypes to clinical outcomes of ccRCC. Nicotinamide N-methyltransferase (NNMT), a one-carbon 38 metabolic enzyme, is identified as a potential marker of ccRCC and a drug target for GP1. We demonstrate that NNMT induces DNA-dependent protein kinase catalytic subunit (DNA-PKcs) homocysteinylation, increases DNA repair, and promotes ccRCC tumor growth. This study provides insights into the biological underpinnings and prognosis assessment of ccRCC, revealing targetable metabolic vulnerabilities.

  Study EGAS00001006005

• Cross-tissue transcriptomic analysis of human secondary lymphoid organ residing ILC3 reveals a default quiescent state in the absence of inflammation

  A cross tissue transcriptional comparison of human ILC3 isolated from non-inflamed lymph nodes (LN) and spleens, inflamed tonsils and the peripheral blood (PB). Using uniform gating and high-purity cell-sorting, ILC3 were sorted as Lineage(CD3,CD19,CD34,CD14,CD94)-CD45intCD127+CRTH2-CD117+. From LN, spleen, tonsils and PB, NKp44- ILC3 were isolated and, in addition, NKp44+ ILC3 were sorted from spleen and tonsils. RNA quality was measured on a RNA 6000 Pico Kit (Agilent Technologies) using a 2100 Bioanalyzer (Agilent Technologies). 100 pg high-quality RNA was isolated and cDNA was generated using the SMART-Seq (v3) Ultra Low Input RNA Kit (Clontech) with 15 cycles of amplification. Amplified and Covaris-fragmented cDNA was quality-checked on a High Sensitivity DNA chip (Agilent Technologies) and further processed according the TruSeq Nano DNA Library Preparation Kit (Illumina). Data was processed as follows: SMARTer adapters were trimmed with cutadapt and the resulting sequences were aligned to the human RefSeq transcriptome using 14 TopHat2 (Kim et al., 2013). Normalization and quantification was performed using Cufflinks (Trapnell et al., 2012). FPKM counts were determined per gene with HTSeq-count.

  Study EGAS00001002636

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

  Cohort DescriptionHispanic Community Health Study/Study of Latinos (HCHS/SOL) is an ongoing population-based prospective cohort study of 16,415 community dwelling Hispanic/Latino adults aged 18-74 years at baseline, recruited from four urban field centers with large populations of Hispanics/ Latinos (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA). The primary goals of the HCHS/SOL are to describe: (1) the prevalence and incidence of cardiovascular, pulmonary, and other major chronic conditions (2) the risk and/or protective factors associated with these conditions; and (3) the relationships between the initial sociodemographic and health profiles and future health events in the target population. Data Being Submitted Wave 1 questionnaire data includes 397 variables for up to 9817 HCHS/SOL participants in C4R. Wave 2 questionnaire data includes 448 variables for up to 7536 HCHS/SOL participants in C4R. Derived data includes 43 variables for up to 11182 HCHS/SOL participants in C4R. Phenotype data includes 113 variables for up to 11182 HCHS/SOL participants in C4R.

  Study phs002908

• National Institutes of Health The Cancer Genome Atlas (TCGA)

  The Cancer Genome Atlas (TCGA) is a comprehensive and coordinated effort to accelerate our understanding of the molecular basis of cancer through the application of genome analysis technologies, including large-scale genome sequencing. TCGA is a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), which are both part of the National Institutes of Health, U.S. Department of Health and Human Services. TCGA projects are organized by cancer type or subtype. Click here for a current list of cancer types selected for study in TCGA. Data from TCGA (e.g., gene expression, copy number variation and clinical information), are available via the Genomic Data Commons (GDC). Data from TCGA projects are organized into two tiers: Open Access and Controlled Access. Open Access data tier contains data that cannot be attributed to an individual research participant. The Open Access data tier does not require user certification. Data in Open Access tier are available in the TCGA Data Portal. Controlled Access data tier contains individual-level genotype data that are unique to an individual. Access to data in the Controlled Access data tier requires user certification through dbGaP Authorized Access. Controlled Access data types consist of the following: Individual germline variant data (SNP .cel files) Primary sequence data (.bam files), which are available at GDC Clinical free text fields Exon Array files (for Glioblastoma and Ovarian projects only) NOTE: TCGA strives to release most data in the open access tier. Individual genotype or sequence files are prominent exceptions. Commonly requested files such as descriptions of somatic mutations or clinical data are open access. Please go to this page: https://tcga-data.nci.nih.gov/docs/publications/ to access all data associated with TCGA tumor specific publications. The TCGA study is utilized in the following dbGaP substudies. To view genotypes and other molecular data collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000178 TCGA study. phs000854 Genome-wide Analysis of Noncoding Regulatory Mutations in Cancer

  Study phs000178

• Single-cell transcriptome analysis of B-cell development in the ABO platform

  The dataset includes samples from four individual donors, pooled at each cell-harvesting time point (days 21, 28, and 35). Single-cell RNA sequencing was performed on the 10x Genomics Chromium platform using GEM-X Single Cell 5′ v3 and GEM-X Single Cell V(D)J v3 for BCR profiling. For each timepoint, paired libraries were constructed: a 5′ GEX library and a V(D)J-B library. Per reaction 350,000-400,000 cells were loaded, aiming for 60,000 cells per reaction. Pooled libraries were sequenced on an Illumina NovaSeq X sequencer. 50,000 read pairs per cell for GEX and 5,000 read pairs per cell for V(D)J were targeted.

  Dataset EGAD50000002433

• Dataset for H3K27me3 ChIP-seq data for neuroblastoma cell lines (Neuroblastoma_CL)

  Dataset for H3K27me3 ChIP-seq data of 31 neuroblastoma tumor samples. The sequencing was performed on Illumina HiSeq 2000 and Illumina HiSeq 2500

  Dataset EGAD00001015809

• Head and neck tumor organoid biobank for modelling individual responses to radiation therapy according to the TP53/ HPV status

  Head and neck cancers (HNC) represent an extremely heterogeneous group of diseases with a poorly predictable therapy outcome. Here, we have established a comprehensive molecularly and functionally characterized head and neck organoid biobank recapitulating the clinically relevant subtypes of TP53 mutant and human papillomavirus type 16 (HPV 16) infection-driven HNC. Organoids were exposed to radiotherapy and genetically engineered normal and tumor organoids were used for testing the direct functional consequences of TP53-loss and HPV infection. We identified subtype-associated transcriptomic signatures and pathological features, including sensitivity to TP53 stabilization by the MDM2 inhibitor Nutlin-3. TP53 loss-of-function alone was insufficient to promote radiation resistance, whereas HPV 16 oncogenes E6/E7 mediated radiosensitivity via induction of cell cycle arrest.

  Study EGAS50000001219

• Myelodysplastic cells in patients re-program mesenchymal stromal cells to establish a transplantable stem cell-niche disease unit.

  Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms with defects in hematopoietic stem/progenitor cells (HSPCs) and possibly the HSPC niche. Here we show that patient-derived mesenchymal stromal cells (MDS MSCs) display a disturbed differentiation program and are essential for the propagation of MDS-initiating lin-CD34+CD38- stem cells in orthotopic xenografts. Overproduction of niche factors such as N-Cadherin, IGFBP2, VEGFA and LIF is associated with the ability of MDS MSCs to enhance MDS expansion. These factors represent putative therapeutic targets to disrupt critical hematopoietic-stromal interactions in MDS. Finally, healthy MSCs adopt "MDS-MSC like" molecular features when exposed to hematopoietic MDS cells, indicative of an instructive remodeling of their microenvironment. This patient-derived xenograft model therefore provides functional and molecular evidence that MDS is a complex disease involving both the hematopoietic and stromal compartments. The resulting deregulated expression of niche factors may well also be a feature of other hematopoietic malignancies.

  Study EGAS00001000716

• Molecular Phenotyping to Accelerate Genomic Epidemiology (MolPAGE)

  MolPAGE is an integrated EU project that aims to develop methods and tools for discovery of biomarkers associated with diabetes (see www.ocdem.ox.ac.uk for MolOBB and www.twinsuk.ac.uk for MolTWIN).

  Study EGAS00000000102

• An exome sequencing study of the HIV elite-long term non progressors and rapid progressors (CASCADE cohorts)

  Background: A rare subgroup of HIV infected individuals naturally controls infection without treatment. These ?elite controllers? constitute an important model for the natural control of HIV infection. Indeed, the study of these individuals may provide insights into strategies for the development of HIV vaccines. Although several HLA and chemokine alleles are known to be over-represented in elite controllers, only a small portion of HIV phenotypic variation is explained by known genetic variants. The elite controller phenotype is rare and distinct, representing the extreme of an infectious disease trait. As such, this phenotype may be partly explained by variation in host immune control, which may be characterized by differences in rare functional genetic variants. Genomic regions underlying elite control can be potentially identified by comparing the presence or frequency of variants in this group to that representing the opposite extreme. In this context, ?rapid progressors? is a group defined by its rapid immunological and clinical disease progression. Aim: To extend an existing study, in order to identify DNA sequence variants involved in the control of HIV infection with greater statistical resolution. Specifically, we aim to sequence up to 200 exomes from multiple cohort studies within the EuroCoord CASCADE collaboration (a collaboration of 25 HIV seroconversion cohort studies across Europe).

  Dataset EGAD00001002179

• OncoArray: Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)

  The Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) was one of five projects funded in 2010 as part of the NCI's Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative (http://epi.grants.cancer.gov/gameon/). FOCI represents a collective effort that builds upon the strengths and history of collaboration inherent in the Ovarian Cancer Association Consortium (OCAC), a multidisciplinary group comprised of epidemiologists, genetic epidemiologists, statistical geneticists, molecular and cell biologists and clinicians that was formed in 2005. The other four funded GAME-ON projects were: the ColoRectal TransdisciplinaryStudy (CORECT), Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE), Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE), and Transdisciplinary Research in Cancer of the Lung (TRICL). As part of our aim to discover, expand, and replicate ovarian cancer susceptibility loci, the GAME-ON projects and other consortia formed the OncoArray network (http://epi.grants.cancer.gov/oncoarray/) to develop and genotype a new custom genotyping array in large numbers of cancer cases and controls (over 400,000 samples) across multiple cancer types. The FOCI data includes over 50,000 ovarian cancer cases and controls genotyped with the Oncoarray at the Center for Inherited Disease Research (CIDR). Genotype calling and quality control procedures were performed under a standardized protocol across the Oncoarray consortium, and over 490,000 SNPs passed QC and are included under this dbGaP submission.

  Study phs001882