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• DNA Methylation Studies in CREW Cohorts (URECA and COAST)

  Children's Respiratory Environment Workgroup (CREW) is an NIH-funded project consisting of 12 individual U.S. cohorts and three scientific centers working together to identify phenotypes and causes of childhood asthma. CREW includes data from a large number of children and their families, with broad diversity in terms of ethnicity, family characteristics, neighborhoods and geographic locations. In this study, we identified differentially methylated regions from whole-genome bisulfite sequencing (WGBS) in nasal epithelial cells from 39 children of European or African ancestries, and with or without allergic asthma. Study participants were from two of the CREW cohorts: the Urban Environment and Childhood Asthma (URECA) cohort and the Childhood Origins of Asthma (COAST) cohort.The URECA children are also participants of a larger genetic study, in which DNA samples are derived from blood. That data is presented in the "Whole Genome Sequencing in the Inner City Asthma Consortium (ICAC) Cohorts - phs002921" study.

  Study phs003321

• Childhood Cancer Data Initiative (CCDI): Integrating Longitudinal Clinical, Sociodemographic and Genomic Data into the NCCR

  The goal of this study is to contribute clinical and genomic data from a large institutional cohort of pediatric cancer patients who had tumor genomic profiling between 2013 and 2019 at Dana-Farber/Boston Children's Hospital Cancer and Blood Disorders Center. Clinical data include demographics, diagnosis (classified according to the International Classification of Diseases for Oncology (ICD-O-3.2), stage, and biospecimen associated data. Tumors were sequenced with OncoPanel, a targeted next-generation DNA sequencing panel of up to 447 cancer genes for detection of single-nucleotide variants (SNV), insertions, and deletions, and copy number alterations (CNA), as well as selected intronic regions for up to 60 genes for the detection of structural variants (SV). This dataset includes a patient and sample identifier (GENIE ID) that can be used to link the genomic data included in this dataset to additional longitudinal clinical cancer data on a subset of patients that was submitted to the National Childhood Cancer Registry (NCCR).

  Study phs002677

• Ipilimumab and Decitabine in Treating Patients With Relapsed or Refractory Myelodysplastic Syndrome or Acute Myeloid Leukemia

  The NCI Experimental Therapeutics Clinical Trials Network (ETCTN)/Cancer Therapy Evaluation Program (CTEP) 10026 study (NCT02890329) tested combined ipilimumab and decitabine treatment in two cohorts: Arm A consisted of patients with relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation. Arm B consisted of patients with advanced myelodysplastic syndrome (MDS) or AML that did not previously undergo stem cell transplantation. During the study, peripheral blood and bone marrow samples were obtained from study participants at study entry (screening), following the first lead-in cycle of decitabine monotherapy, during combined treatment with decitabine and ipilimumab, and at the end of treatment.This study tested the combination of the CTLA-4 blocking antibody ipilimumab and the DNA methyltransferase inhibitor decitabine in advanced myeloid disease in the transplant-naive and post-transplant context. The samples were used for bulk and single cell RNA sequencing (scRNA-seq) as well as whole exome sequencing (WES).

  Study phs003015

• ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium.

  The telomeric amplicon at 8p12 is common in oestrogen receptor-positive (ER+) breast cancers. Array-CGH and expression analyses of 1172 primary breast tumours revealed that ZNF703 was the single gene within the minimal amplicon and was amplified predominantly in the Luminal B subtype. Amplification was shown to correlate with increased gene and protein expression and was associated with a distinct expression signature and poor clinical outcome. ZNF703 transformed NIH 3T3 fibroblasts, behaving as a classical oncogene, and regulated proliferation in human luminal breast cancer cell lines and immortalized human mammary epithelial cells. Manipulation of ZNF703 expression in the luminal MCF7 cell line modified the effects of TGFβ on proliferation. Overexpression of ZNF703 in normal human breast epithelial cells enhanced the frequency of in vitro colony-forming cells from luminal progenitors. Taken together, these data strongly point to ZNF703 as a novel oncogene in Luminal B breast cancer.

  Study EGAS00000000082

• Single-cell RNA sequencing of human skin tumors (BCC, SCC and Melanoma)

  Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. Here, we elucidate the yet unresolved intra-tumoral CAF variety in three skin cancer types at molecular and spatial single-cell resolution in a large cohort. We show that two out of three CAF subtypes contribute to tumor immune surveillance with distinct mechanisms. Matrix CAFs (mCAFs) ensheath tumor nests and synthesize extracellular-matrix to prevent T cell invasion. Immunomodulatory CAFs (iCAFs), which express proinflammatory and immunomodulatory factors, are only detected in high abundance in aggressive tumors. Strikingly, iCAFs but not tumor cells are (apart from immune cells) the exclusive cell type producing chemokines and, thus, play a key role in immune cell recruitment and activation. Mechanistically, we show that cancer cells transform adjacent healthy fibroblasts into cytokine-expressing iCAFs, which subsequently recruit immune cells and modulate the immune response. In conclusion, targeting CAF variants holds promise for improved efficacy of immunotherapy.

  Study EGAS50000000365

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

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

  Study EGAS50000000806

• Aberrant RNA-splicing (neojunctions) offers a new source for targets, and our neoantigen discovery platform (SNIPP) characterizes a novel class of clonally-expressed splicing-derived neoantigens that elicit a CD8+ T-cell-mediated tumor killing response.

  RESULTS: Our pipeline identified 789 public neojunctions, with 32 neojunctions concurrently identified in transcriptomic and proteomic glioma data and predicted to be presented by HLA-A*02:01 with high confidence. IVS and subsequent 10x VDJ scRNA-seq identified TCR clonotypes reactive against neojunctions in RPL22 (n=7) and GNAS (n=1), the latter being highly intratumorally-conserved (detected in > 90% of spatially-mapped biopsies across 17/56 patients (26.78%)). TCR-transduced T-cells demonstrated recognition and immunogenic activation against endogenously processed and presented neoantigens in multiple GBM PDX cell lines. Furthermore, IDH1-mutant oligodendroglioma samples demonstrated significantly elevated expression of neojunctions over IDH1-mutant astrocytoma and IDH1wt subtypes. Differential gene expression (DESeq2) identified decreased expression of splicing factors due to oligodendroglioma-specific co-deletion of Chromosomes 1p/19q. siRNA knockdown of these splicing factors (e.g. SF3A3, SNRPD2) in IDH1wt glioma cells resulted in significantly increased expression of corresponding neojunctions.

  Study EGAS00001007986

• Uncovering Gene Regulatory Differences between Human and Chimpanzee Neural Cells

  A major challenge in human evolutionary biology is to pinpoint the genetic differences that underlie phenotypic changes in the human lineage, such as increased neuron number and a prolonged period of neuronal maturation. Here, we used human-chimpanzee tetraploid cells to distinguish changes in gene expression due to cis-acting sequence variants that change local gene regulation, from trans expression changes due to species differences in the cellular environment, in neural progenitor cells and excitatory neurons using RNA-seq and ATAC-seq. Using a CRISPR inhibition screen with scRNA-seq, transcription factor motif analyses with CUT&Tag, and downstream single-locus studies with RNA-seq, we further characterized cis-acting gene regulatory differences, including changes to FOS, TNIK, FOSL2, and MAZ, that influence neurogenesis and neuronal maturation. This study identifies specific genomic changes that may contribute to human neural specializations and provides a general framework for understanding genetic differences that underlie human traits.

  Study phs004053

• Deciphering craniopharyngioma subtypes: Single-cell analysis of tumor microenvironment and immune networks

  Craniopharyngiomas, including both adamantinomatous (ACP) and squamous papillary (PCP) types, present significant challenges in treatment due to their proximity to critical pituitary structures. In this study, we conducted a single-cell RNA analysis to examine the tumor microenvironments (TME) of ACP and PCP. Single-cell clustering revealed a wide range of cell types, which were further categorized based on gene expression patterns. For ACP, these categories included developing epithelia, calcification, and immune response, while PCP showed developing epithelia, cell cycle, and immune response as prominent categories. Subclustering analysis unveiled different types of immune cells in both ACP and PCP TMEs, with specific patterns of immune responses. Interestingly, smaller tumors were associated with particular immune cell ratios. Furthermore, we identified specific cell-to-cell interactions within the tumor cells. In conclusion, our study has led to the development of a comprehensive cell atlas, shedding light on the molecular characteristics and intricate interplay of immune cells within the TMEs of ACP and PCP.

  Study JGAS000722

• Tumor inflammation and mutational burden are differentially associated with response to nivolumab or nivolumab plus ipilimumab in metastatic colorectal cancer

  Nivolumab alone and in combination with ipilimumab demonstrated durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer in the phase 2 CheckMate 142 study. Exploratory biomarker analyses of tumor and microbiome samples from CheckMate 142 were performed to evaluate associations between various biomarkers and the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab combination in these patients. Higher expression of inflammation-related gene expression signatures was associated with improved response per investigator assessment and survival benefit with nivolumab monotherapy. In contrast, higher tumor mutational burden, tumor indel burden and degrees of microsatellite instability were associated with improved response per investigator assessment and survival benefit with nivolumab plus ipilimumab. While interpretation is limited by the exploratory nature of these analyses, they suggest that tumor antigenicity rather than baseline tumor inflammation might be important for the combinatorial efficacy. Validation of these findings in larger, randomized studies is necessary.

  Study EGAS50000000416

• Measles oncolytic virus as an immunotherapy for recurrent/refractory pediatric medulloblastoma and atypical teratoid rhabdoid tumor

  Pediatric recurrent medulloblastoma (MB) and atypical teratoid rhabdoid tumor (ATRT) are largely incurable and warrant novel therapies. We investigated a) the safety of a measles virus variant, MV-NIS, in a pediatric phase 1 study and b) the mechanisms of MV-NIS and potential benefit of combination with immune checkpoint inhibition (ICI). Pediatric patients with recurrent MB or ATRT were treated with intratumoral injections for local recurrence or via lumbar puncture for disseminated recurrence. We evaluated local immune responses to MV-NIS with and without ICI via single-cell and bulk RNA sequencing in an intracranial, immunocompetent, syngeneic murine model. MV-NIS given intratumorally or via repeat intrathecal dosing was safe. MV-NIS prolonged survival in murine models but did not demonstrate additive benefit with ICI. No changes in tumor-infiltrating immune-cell composition or activation were observed in response to MV-NIS treatment; however, MV-NIS induced local expression of neutralizing antibodies, complement cascade, and phagocytosis-related genes.

  Study EGAS50000000811

• Transcriptome changes in circulating immune cells of critical COVID-19 patients predict a specific metabolic and epigenetic imprint

  The progression to severe COVID-19 arises predominantly from a dysregulated host immune response, although the underlying regulatory mechanisms still remain partially elusive. This limits a prompt prediction of disease progression and restrains our understanding of “long COVID”. Here, we analyzed the transcriptomes of peripheral blood mononuclear cells collected from COVID-19 patients experiencing different degrees of the disease and control patients. In critical COVID-19 patients, we found an altered regulatory network involving microRNAs, long non-coding RNAs, and coding genes that control mRNA translation-related genes, epigenetics, and metabolism. We also observed an upregulation of tRNA aminoacylation genes and increased expression of coding genes enriched for the cognate amino acids. Collectively, our findings indicate a broad perturbation of the gene expression landscape that characterizes the aberrant host immune response in critical COVID-19 patients and is potentially coordinated by alterations in microRNA expression and tRNA metabolism.

  Study EGAS50000000965

• Quick Guide for data submission

  Quick Guide This is a quick guide to submit data to the EGA. Please select data type to display the right detailed instructions. Sequence data Array-based data Get your submission account You first need to create your EGA user. Then, once your account has been verified by the Help Desk team, request your submission account and provide details of the data type and platform(s) in your submission. Register Study/DAC Use Submitter Portal to register your study, samples, Data Access Committee (DAC) and Policy. Upload data Encrypt your data files using the and upload it to your inbox using SFTP. Register experiments and runs Associate each data file to a registered sample and study by Linking files to samples. Details of the experimental procedure you followed must be provided. Finalise your submission Group your runs/analysis into datasets and link them to your new or existing DAC and policy using DAC Portal. Data request are done at a dataset level, thus files within a datasets must share release conditions. Release and admin When finalising the submission, set a released date to instruct our Helpdesk to release your study. All registered studies are automatically placed on hold until the named submission or DAC contact instructs our Helpdesk for the study to be released. Get your submission account Fill the submission form and provide details of the data type and platform(s) in your submission. Register Study/DAC Use EGA Programmatic submission to register your study, samples, Data Access Committee (DAC) and Policy. Upload data Encrypt your data files using the EgaCryptor and upload it using default FTP clients or Aspera. Complete the Array-Format (AF) spreadsheet Download the AF spreadsheet and complete all four sections. Return the spreadsheet to the EGA helpdesk. Release and admin Instruct our Helpdesk to release your study. All registered studies are automatically placed on hold until the named submission or DAC contact instructs our Helpdesk for the study to be released.

  Documentation submission/quickguide

• EuCANCan: EUropean-CANadian Cancer network

  The EUropean-CANadian Cancer network (EuCANCan) is a project aiming to develop a federated network of aligned and interoperable infrastructures for the homogeneous analysis, management and sharing of genomic oncology data for Personalized Medicine. This initiative, funded by the European Commission and the Canadian Institutes of Health and coordinated by the Barcelona Supercomputing Center (BSC), is expected to process and provide the scientific community with around 30-35 thousand patient samples from different types of cancer, coming from different nodes involved in this project, during the four years of the project. Data generated as part of primary studies, often in small hospitals or research centers, is hardly reused by other projects or groups. EuCANCan is proposed to foster the homogenisation and discoverability of cancer samples from very different sources for the whole community. These efforts will help paving the way to future standardised and global genomics projects, specially for those participant countries that eventually integrate the methodology and infrastructure generated during the project. “The more data we have access to the more and better discoveries. We attempt to overcome the legal and technical limitations in order to generate, gather and exploit bigger datasets as well as answer more ambitious questions”. These were some of the words Dr. David Torrents, main coordinator of the project, shared with a regional radio during the kick-off meeting of the project, on February 11th, 2019. The EUCANCan network will be composed of reference nodes in Amsterdam, Barcelona, Berlin, Heidelberg, Paris and Toronto which have established strong research and clinical programs in the field of genomic oncology. The Centre for Genomic Regulation (CRG), specifically the European Genome-phenome Archive (EGA), is among the leading institutions. Its exhaustive experience in biomedical data archival and secure distribution is considered key for crucial developments within the project. It is also notable the recent inclusion of EUCANCan in the list of GA4GH driver projects. Further information and details can be found in the following links: InsideHPC BSC official description Techweek (Spanish)

  Blog eucancan

• Frequent alterations in cytoskeleton remodeling genes in primary and metastatic Chinese lung adenocarcinomas

  The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including themost commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scalesequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.

  Study EGAS00001000982

• Transcriptional and functional profiling defines human small intestinal macrophage subsets

  Macrophages (Mf) are instrumental in maintaining immune homeostasis in the intestine, yet studies on origin and heterogeneity of human intestinal Mf are scarce. Here, we identified four distinct Mf subpopulations in human small intestine (SI). Assessment of their turnover in duodenal transplants revealed that all Mf subsets were completely replaced over time; Mf1 and Mf2, phenotypically similar to peripheral blood monocytes (PBMo), were largely replaced within 3 weeks, whereas two subsets with features of mature Mf, Mf3 and Mf4, exhibited significantly slower replacement. Mf3 and Mf4 localized differently in SI; Mf3 formed a dense network in mucosal lamina propria, whereas Mf4 was enriched in submucosa. Transcriptomic analysis showed that all Mf subpopulations subsets were markedly distinct from PBMo and dendritic cells (DC). Compared to PBMo, Mf subpopulations showed reduced responsiveness to proinflammatory stimuli, but were proficient at endocytosis of particulate and soluble material. These data provide a comprehensive analysis of human SI Mf population and suggest a precursor-progeny relationship with PBMo.

  Study EGAS00001002093

• 65 prostate cancer cases WGS and transcriptome sequencing project

  We obtained whole-genome and transcriptome sequencing of tumor-benign pairs from 65 Asian prostate cancer (PCa) patients. Taken together with the TCGA PCa cohort, our integration analysis provides the first comprehensive mutational landscape of PCas across major ethnics worldwide and reveals potential novel role of frequent altered chromatin remodeler genes in PCas without androgen receptor (AR) alteration and complex rearrangements derived from Chromoplexy. In addition, we identified 5 putative tumor suppressor genes (TSGs) chains including one on chromosome 13q with novel findings of PCDH9 (deletions in 15/65 tumors) which was implicated in aggressive progression of prostate cancer. Finally, the integrative pathway and co-expression network analysis followed by the functional study indicated the frequent altered genes, particularly focal amplifications of PLXNA1 (11/65), in semaphoring signaling of axon guidance pathway may interact with PI3K/AKT and AR signaling and also contribute to the aggressiveness and progression of prostate cancer.

  Study EGAS00001000888

• Comparison of 3 protocols for deriving pancreatic progenitors from hPSC with RNA-seq and ATAC-seq

  Several distinct differentiation protocols for deriving pancreatic progenitors (PP) from human pluripotent stem cells have been described but it remains to be shown how similar the PP are across protocols, and how well they resemble their in vivo counterparts. Here we evaluated three differentiation protocols; performed RNA and ATAC-seq on isolated PP derived with these, and compared them to fetal human pancreas populations. This enabled us to define a shared transcriptional and epigenomic signature of the PP, including several genes not previously implicated in pancreas development. Furthermore, we identified a significant and previously unappreciated cross-protocol variation of the PP through multi-omics analysis and demonstrate how such information can be applied to refine differentiation protocols for derivation of insulin-producing beta-like cells. Together, our study highlights the importance of a detailed characterization of defined cell populations derived from distinct differentiation protocols, and provides a valuable resource for exploring human pancreatic development.

  Study EGAS00001003513

• Genomic landscape and PD-1 blockade in Natural-killer/T cell lymphoma

  Natural killer/T-cell lymphoma (NKTL) is an aggressive malignancy with a predilection for Asian, Mexican and South American populations. With the exception of Japan, it is the most common mature T-cell lymphoma in Asia. NKTL presents as extranodal disease and mostly affects the upper aerodigestive tract. Neoplastic cells are invariably infected by the Epstein-Barr virus (EBV) and characterized by a cytotoxic phenotype. The genetic landscape of NKTL has been recently unraveled by discoveries describing recurring mutations altering the JAK-STAT pathway, epigenetic modifiers, the DDX3X gene and genetic predisposition in the HLA-DPB1 gene.The genomic landscape of NKTL has been interrogated by whole-exome sequencing, targeted sequencing and single nucleotide polymorphism arrays, but has yet been studied with whole-genome sequencing (WGS). In this study, we will use a combination of WGS, targeted-capture sequencing (TCS) and RNA sequencing data to explore the genetic landscape and its relevance to immunotherapy in NKTL

  Study EGAS00001003828

• Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer

  Mismatch repair deficient colorectal cancers have high mutation loads and many respond to immune checkpoint-inhibitors. We investigated how genetic and immune landscapes co-evolve in these tumors. All cases had high truncal mutation loads. Driver aberrations showed a clear hierarchy despite pervasive intratumor heterogeneity: Those in WNT/βCatenin, mitogen-activated protein kinase and TGFβ receptor family genes were almost always truncal. Immune evasion drivers were predominantly subclonal and showed parallel evolution. Pan-tumor evolution, subclonal evolution, and evolutionary stasis of genetic immune evasion drivers defined three MMRd CRC subtypes with distinct T-cell infiltrates. These immune evasion drivers have been implicated in checkpoint-inhibitor resistance. Clonality and subtype assessments are hence critical for predictive immunotherapy biomarker development. Cancer cell PD-L1 expression was conditional on loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and likely contributes to the high recurrence risk of MMRd CRCs with impaired CDX2 expression.

  Study EGAS00001005769

• Circulating tumor cells for comprehensive and multiregional non-invasive genetic characterization of multiple myeloma (arrays set)

  Multiple myeloma (MM) patients undergo repetitive bone marrow (BM) aspirates for genetic characterization. Circulating tumor cells (CTCs) are detectable in peripheral blood of virtually all MM cases and are prognostic, but their applicability for non-invasive screening has been poorly investigated. Here, we used next-generation flow cytometry to isolate matched CTCs and BM tumor cells from 42 patients and compare their genetic profile. In 8 cases, tumor cells from extramedullary plasmacytomas were also sorted and whole-exome sequencing performed in the three spatially-distributed clones. Noteworthy, ≥84% mutations present in BM and extramedullary clones were detectable in CTCs. Concordance between BM tumor cells and CTCs was high for chromosome arm-level copy-number alterations (≥94%) though not for translocations (43%). All high-risk genetic abnormalities except one t(4;14) were detected in CTCs whenever present in BM tumor cells. Altogether, these results support CTCs for non-invasive risk-stratification of MM patients based on their numbers and genetic profile.

  Study EGAS00001004314

• Arriba: accurate and efficient detection of gene fusions from RNA-Seq (H021)

  The identification of gene fusions from RNA sequencing data is a routine task in cancer research and precision oncology. However, despite the availability of many computational tools, fusion detection remains challenging. Existing methods suffer from poor prediction accuracy and are computationally demanding. We developed Arriba, a novel fusion detection algorithm with high sensitivity and short runtime. When applied to a large collection of published pancreatic cancer samples (n=803), Arriba identified a variety of driver fusions, many of which affected druggable proteins, including ALK, BRAF, FGFR2, NRG1, NTRK1, NTRK3, RET, and ROS1. The fusions were significantly associated with KRAS wild-type tumors and involved proteins stimulating the MAPK signaling pathway, suggesting that they substitute for activating mutations in KRAS. In addition, we confirmed the transforming potential of two novel fusions, RRBP1-RAF1 and RASGRP1-ATP1A1, in cellular assays. These results demonstrate Arriba’s utility in both basic cancer research and clinical translation.

  Study EGAS00001003554

• Tocilizumab treatment leads to early resolution of myeloid dysfunction and lymphopenia in patients hospitalized with COVID-19

  Tocilizumab, an anti-interleukin-6 receptor inhibitor, is recommended in global treatment guidelines for patients hospitalized with severe COVID-19. Using proteomic and transcriptomic analysis, we characterized the immune profile and identified cellular and molecular pathways directly modified by tocilizumab in peripheral blood samples collected from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial, to assess the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19 pneumonia. We identified factors predicting disease severity and clinical outcomes, including markers of inflammation, lymphopenia, myeloid dysfunction, and organ injury. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysfunction associated with severe COVID-19 thus supporting an underlying anti-inflammatory mechanism of action for the beneficial effects of tocilizumab in patients hospitalized with COVID-19.

  Study EGAS00001006688

• Single-cell RNA-seq and spatial transcriptomics data for the sarcoidosis baseline project

  Granulomas are lumps of immune cells that can form in various organs. Most granulomas appear unstructured, yet they have some resemblance to lymphoid organ formation. To better understand granuloma formation, we performed single-cell sequencing and spatial transcriptomics on granulomas from patients with sarcoidosis and bioinformatically reconstructed the underlying gene-regulatory networks. We discovered an immune stimulatory environment in granulomas that repurposed transcriptional programs associated with lymphoid organ development. Granuloma formation followed characteristic spatial patterns and involved genes linked to immunometabolism, cytokine and chemokine signaling, and extracellular matrix remodeling. Three cell types emerged as key players in granuloma formation: metabolically reprogrammed macrophages, cytokine-producing Th17.1 cells, and fibroblasts with inflammatory and tissue remodeling phenotypes. Pharmacological inhibition of one of the identified processes attenuated granuloma formation in a sarcoidosis mouse model. We show that human granulomas adopt characteristic aspects of normal lymphoid organ development in aberrant combinations, indicating that granulomas constitute aberrant lymphoid organs.

  Study EGAS00001006970

• Sensitive and Frequent Identification of High Avidity Neo-epitope Specific CD8 + T-cells in Immunotherapy-naïve Ovarian Cancer

  Immunotherapy directed against private tumor neo-antigens derived from non-synonymous somatic mutations is a promising strategy of personalized cancer immunotherapy. However, feasibility in low mutational load tumor types remains unknown. Comprehensive and deep analysis of circulating and tumor-infiltrating lymphocytes (TILs) for neo-epitope specific CD8 + T cells allowed prompt identification of oligoclonal and polyfunctional such cells from most immunotherapy-naïve patients with advanced epithelial ovarian cancer studied. Neo-epitope recognition was discordant between circulating T cells and TILs, and was more likely to be found among TILs, which displayed higher functionalavidity and unique TCRs with higher predicted affinity than their blood counterparts. Our results imply that identification of neo-epitope specific CD8 + T cells is achievable even in tumors with relatively low number of somatic mutations, and neo-epitope validation in TILs extends opportunities for mutanome-based personalized immunotherapies to such tumors.

  Study EGAS00001002803

• Assessment of cannabidiol and Δ9-tetrahydrocannabiol in mouse models of medulloblastoma

  Phytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been demonstrated to exhibit anti-cancer activity in preclinical models of brain cancer leading to new clinical trials for adults with glioblastoma. We describe here the first report that has investigated a role for THC and CBD in paediatric brain cancer. Cannabinoids had cytotoxic activity against medulloblastoma and ependymoma cells in vitro, functioning in part through the inhibition of cell cycle progression and the induction of autophagy. Despite these effects in vitro, when tested in orthotopic mouse models of medulloblastoma or ependymoma, no impact on animal survival was observed. Furthermore, cannabinoids neither enhanced nor impaired conventional chemotherapy in a medulloblastoma mouse model. These data show that while THC and CBD do have some effects on medulloblastoma and ependymoma cells, are well tolerated and have minimal adverse effects, they do not appear to elicit any survival benefit in preclinical models of paediatric brain cancer.

  Study EGAS00001004963

• Pediatric Patient-Derived-Xenograft development in MAPPYACTS – international pediatric cancer precision medicine trial in relapsed and refractory tumors

  Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient’s tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Paediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This new PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and new treatments development in advanced pediatric malignancies.

  Study EGAS00001007327

• Epidemiological study comparing rates and risk factors for dementia in African Americans in Indianapolis and Yoruba living in Ibadan, Nigeria

  In 1991 collaboration between researchers at Indiana University School of Medicine and the University of Ibadan, Ibadan, Nigeria established the Indianapolis-Ibadan Dementia Project. It is a longitudinal, prospective population-based comparative epidemiological study of the prevalence and incidence rates and risk factors of Alzheimer's disease and other age associated dementias. The project compares samples of community-dwelling elderly (age > 70 years) African Americans living in Indianapolis to Yoruba living in Ibadan, Nigeria, employing the same research design, methods, and investigators. It initially reported significantly lower prevalence rates of disorders in the Yoruba compared to the African Americans. In subsequent waves of the study (1994-1995, 1997-1998) incidence rates, rates of newly diagnosed cases, were also found to be significantly lower in the Yoruba. In genetic studies, the frequency of the APOE 4 allele was about the same in the two groups. APOE 4 was a significant risk factor for Alzheimer's disease and dementia in the Americans, while no association was found for the Yoruba. The APOE 2 allele appears to be protective in the Americans, but not the Yoruba. A constellation of factors often associated with vascular risk including a history of hypertension, diabetes, and high cholesterol levels is less common in the Yoruba than in the American group. An interaction was observed between cholesterol, APOE genotype and Alzheimer's disease in both study groups. In 2001-2002 survivors of the original cohort were once again evaluated (N~800 in each site) and 2,000 additional individuals age 70 years and older were enrolled in each site. Blood samples were collected from approximately 1,500 study participants in each site for genetic studies and analysis of biochemical risk factors for vascular disease. Subsequent waves of field work were conducted in 2004, 2007, 2009, and 2011. This fieldwork followed the classic two-stage study design. The study design involves an in-home screening interview with the study participant, which includes a cognitive assessment, medical history and current medications, brief neurological examination, height and weight, blood pressure measurement and assessment of social involvement. There is also a screening interview with a close relative of the study participant to assess activities of daily living, personality change, and medical history of the study participant. On the basis of the screening interview a sample of study participants (N~500 in each site) is selected for a full clinical diagnostic dementia work up which includes a neurological test battery, extensive interview with a family member and examination by a clinician. Diagnoses are made in a consensus diagnosis conference using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III R) and International Classification of Diseases 10th Revision (ICD-10) for dementia. The criteria of the National Institute for Neurological and Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association were used to diagnose possible and probable Alzheimer's disease. The focus of the study is risk factors for dementia and Alzheimer's disease, but also of particular importance is the question of mild cognitive impairment. This refers to the condition of having some decline in cognition but the decline is not sufficient to meet the criteria for dementia. We have studied this over the course of this project. In follow up studies of individuals who have this diagnosis about one third of them are better at follow up, about a third are about the same, and about a third decline more to meet the criteria for dementia. This is a very important issue for researchers because the ultimate goal of the research is to figure out how to identify the individuals who will definitely progress to dementia. If there are clear identifiers, it would be possible to make interventions, while individuals still function well, and possibly prevent the development of dementia altogether or delay the onset significantly. This is crucial because at the moment individuals usually do not enter into the medical care system until the dementia symptoms are quite severe, and the pathological damage to the brain cannot be undone.

  Study phs000378

• Mayo Clinic and Illumina Collaborative Early Stage Ovarian Cancer (ESOC) Study

  Twenty five patients with early stage carcinoma (Stage I and II) of the ovary were consented for this study. As part of a collaborative agreement with Illumina Inc, Tumor-DNA and patient matched normal DNA from blood underwent whole genome sequencing and microarray genotyping and RNA underwent RNASeq. Tissue also underwent IHC staining for TP53 mutations. The aim of the study was to profile the genomic landscape of these early tumors to discover biomarkers for early detection or subgrouping into different genomic or outcome subgroups. Analyses performed include somatic mutation analysis, RNASeq mutation analysis, LOH analysis, structural variant detection. The current release of this study focusses on 17 patients with serous carcinoma and stage 1 or 2 and with high grade (3 or 4).

  Study phs000897

• Single-Cell Sequencing Reveals Distinct Microenvironment Cell Types Associated with Response to High Dose Melphalan and Autologous Stem Cell Transplant in Multiple Myeloma

  The aim of this study is to understand the transcriptome of microenvironment cells in pre- and post- autologous stem cell transplantation (ASCT) samples between patients with complete response and partial response to transplant. Here, we studied immune cells from 40 multiple myeloma patients who have undergone ASCT. Samples were collected from 40 multiple myeloma patients before and after ASCT. Samples were sorted using magnetic activated cell sorting (MACS) and the non-tumor CD138- fraction underwent 3' single cell RNA-sequencing (scRNA-seq) or 5' scRNA-seq + 5' T cell receptor sequencing (TCRseq), to determine the scRNA transcriptome and TCR repertoire. This study includes 24 samples with 3' scRNA-seq, 56 samples with 5' scRNA-seq, and 56 samples with 5' TCRseq data.

  Study phs003219

• Genomic and clinical characterization of a familial GIST kindred intolerant to imatinib

  Familial gastrointestinal stromal tumors (GIST) are rare. We present a kindred with multiple family members affected with multifocal GIST who underwent whole genome sequencing of the germline and tumor. Affected individuals with GIST harbored a germline variant found within exon 13 of the KIT gene, (c.1965T>G; p.Asn655Lys, p.N655K) and a variant in the MSR1 gene (c.877C>T; p.Arg293*, pR293X). Multifocal GISTs in the proband and her mother were treated with preoperative imatinib, and resulted in severe intolerance. The clinical features of multifocal GIST, cutaneous mastocytosis, allergies and gut motility disorders seen in the affected individuals may represent manifestations of the multifunctional roles of KIT in interstitial cells of Cajal or mast cells and/or may be suggestive of additional molecular pathways which can contribute to tumorigenesis.

  Study EGAS50000000372

• Two lung cancer cell lines with EGFR mutations, PC-9 and KHM-3S, were either treated with Tarceva for 24 hours or left untreated. The gene expression profiles were examined by RNAseq, and the genome wide binding profiles of total STAT3 and pSTAT3 were characterized by ChIPseq.

  Lung cancers harboring activating EGFR mutants show dramatic responses to EGFR TKIs, such as Tarceva. However, nearly all patients show relapse within 1 year after initial treatment. To investigate the early signaling switches that are involved in the formation of drug resistance, and the role of STAT3 in the early signaling switches involved in the formation of drug resistance, we have treated two lung cancer cell lines with EGFR mutations, PC-9 and KMH-3S, with Tarceva for 24hours. The RNA samples with and without treatment were collected in triplicate for RNAseq experiment.The total STAT3 and pSTAT3 chromatinIP were done on samples with and without treatment for ChIPseq.

  Study EGAS00001000793

• Open Targets 020 Epigenomes of Cell Lines (2018-10-23)

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. 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 2018-10-23.

  Dataset EGAD00001004415

• Radiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B

  Long-term complications such as radiation-induced second malignancies occur in a subset of patients following radiation-therapy, particularly relevant in pediatric patients due to the long follow-up period in case of survival. Radiation-induced gliomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies such as acute lymphoblastic leukemia (ALL) and medulloblastoma (MB). We perform comprehensive (epi-) genetic and expression profiling of RIGs arising after cranial irradiation for MB (n=23) and ALL (n=9). Our study reveals a unifying molecular signature for the majority of RIGs, with recurrent PDGFRA amplification and loss of CDKN2A/B and an absence of somatic hotspot mutations in genes encoding histone 3 variants or IDH1/2, uncovering diagnostic markers and potentially actionable targets.

  Study EGAS00001005243

• Genomic Landscape and Clonal Architecture in Pediatric Myeloid Neoplasms with Chromosome 7 Deletions

  Full and partial loss of chromosome 7 (del7, 7q-) are prevalent cytogenetic abnormalities in pediatric myeloid neoplasms resulting in haploinsufficiency of key hematopoietic regulators on chromosome 7. While the genomic landscape of myeloid neoplasms in adults with del7 and 7q- has been described, pediatric patients with similar chromosome 7 losses have not been compiled into a single, comprehensive study utilizing modern sequencing strategies. To this end, we assembled a cohort of 108 pediatric and young adult patients representing a mixture of diagnoses. Using WGS, WES, and RNAseq, we compared the co-occurring mutations and gene expression levels in our cohort to those found in pediatric and young adult patients with two intact copies of chromosome 7. We also performed single-cell multi-omics on a subset of eight samples.

  Study EGAS00001008055

• Multiregional sequencing of IDH-WT glioblastoma reveals high genetic heterogeneity and a dynamic evolutionary history

  Glioblastoma is the most common and aggressive primary brain malignancy in adults. In addi-tion to extensive inter-patient heterogeneity, glioblastoma shows intra-tumor extensive cellular and molecular heterogeneity, both spatially and temporally. This heterogeneity is one of the main reasons for the poor prognosis and overall survival. Moreover, it raises the important question of whether the molecular characterization of a single bioptic sample, as performed in standard di-agnostics, actually represents the entire lesion. In this study, we sequenced the whole-exome of nine spatially different cancer regions of three primary glioblastomas. We characterized their mutational profiles and copy number alterations, with implications for our understanding of tu-mor biology in relation to clonal architecture and evolutionary dynamics, as well as therapeuti-cally relevant alterations.

  Study EGAS00001005128

• Phase Ib of olaparib and capivasertib

  Background: Combining poly(ADP-ribose) polymerase (PARP) with phosphatidylinositol-3-kinase (PI3K) pathway inhibitors is supported by strong preclinical rationale. We sought to assess safety and a recommended phase 2 dose (RP2D) for the PARPi olaparib combined with the AKT inhibitor, capivasertib, and evaluate molecular markers of response and resistance. Methods: As part of a larger phase 1b trial, we performed a safety lead in of olaparib and capivasertib followed by expansion (n=24) in endometrial, triple negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300mg orally twice daily and capivasertib orally twice daily on a 4 day on/3 day off schedule were evaluated. Two dose levels (DL) were planned: capivasertib 400mg (DL1); capivasertib 320mg (DL-1). Patients underwent biopsies at baseline and after 28 days.

  Study EGAS00001004930

• Genetic Diseases of Immune Homeostasis and Autoimmunity Caused by GIMAP Deficiency

  We investigated 17 affected individuals in 9 kindreds with lymphopenia, splenomegaly, liver disease, thrombocytopenia, lymphadenopathy, severe recurrent lung infections, skin diseases, and lymphoma. Whole-exome sequencing of the cohort revealed mutations in GIMAP5. We also found another patient from one kindred with a unique mutation in the gene GIMAP6, discovered by whole-exome sequencing. A comprehensive investigation of this gene mutation through in vivo and in vitro experiments revealed that GIMAP6 deficiency results in defects in autophagy in patient T cells and interruption of GIMAP7 and GABARAPL2 interactions. GIMAP6 deficiency leads to affected patients to present with clinical phenotypes such as recurrent infections, lymphoproliferation, autoimmunity, and inflammation.

  Study phs002816

• Supraphysiologic MDM2 Expression Impacts P53-Independent Chromatin Networks and Therapeutic Responses in Sarcoma

  We collected multiple liposarcoma samples from different patients, including different subtypes (DD, WD) and normal adipose tissue as control. This study provides the biggest liposarcoma cohort to date, and examined the molecular regulatory circuits associated with MDM2 overexpression. To this end, we obtained not only RNA-seq data, but also ChIP-seq from Jun, RUNX, MDM2, P53 and H3K27ac, as well as hiChIP from tumor samples and cell lines. We found that MDM2 binds to thousands of genes involved in cellular growth and stress response in a P53-independent manner. Furthermore, we described these active genes engaged in multi-way topological interactions that resemble transcriptional hubs.

  Study phs003272

• Whole Exome Sequencing of Colorectal Cancer Patients from the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS)

  Colorectal cancer is a molecularly heterogeneous disease. Whole Exome Sequencing from patients diagnosed with colorectal cancer in the NHS and HPFS cohorts will extend our understanding of the genetic changes occurring in specific clinical contexts in the disease. This effort has the potential to discover novel recurrently mutated genes and pathways in colorectal cancer that can be functionally validated and give further insights to colorectal cancer pathogenesis. All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Agilent SureSelect Human All Exon Kit v2 and sequencing was performed on an Illumina HiSeq 2000.

  Study phs000722

• Melanoma and Cancer-Associated Fibroblast Short-Term Cultures Derived from Patient Metastases

  The purpose of this study was to obtain tissue specimens derived from patients with melanoma to generate research tools to advance our understanding of the genetics, pathogenesis, and therapeutics of melanoma. Briefly, tissue was obtained from metastatic lesions and used to generate clonal primary cell lines from melanoma cells and fibroblasts from the tumor microenvironment. RNA was extracted from low passage cell lines using Trizol reagent. cDNA libraries were prepared using the TruSeq mRNA sample preparation kit, v2 (Illumina) and sequenced on the HiSeq 2000 platform (Illumina). The submitted files are bam files that contain both unaligned and aligned reads (human genome, build hg19).

  Study phs001115

• Phase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients with Recurrent Triple Negative Breast Cancer or High Grade Serous Ovarian Cancer

  We analyzed massive parallel sequence data from patients with breast and ovarian cancer and identified single base substitution mutational signature 3 (Sig3) - extracted using SigMA - as a biomarker of homologous recombination deficiency (HRD) and predictive for response to PARP inhibitors. Participants were patients enrolled in clinical trials as 2 independent datasets: (1) high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) from a Phase 1b trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120) (NCT01623349), and (2) TNBC patients who received neoadjuvant olaparib in the Phase II PETREMAC trial (NCT02624973).

  Study phs003019

• DNA methylation in rhabdomyosarcoma PDX and PDX-derived primary cells

  Conditions to maintain primary tumor cells in culture are largely unknown for most tumor entities including rhabdomyosarcoma. In this collaborative study with Dr. Beat Schäfer's laboratory, we performed DNA methylation profiles of rhabdomyosarcoma patient-derived xenograft (PDX) and their matching PDX-derived primary cells (PPC), where the PPCs were developed and maintained under optimized culture conditions. We further compared DNA methylation profiles between these PDXs and PPCs. Exome sequencing and copy number analysis between these rhabdomyosarcoma PDXs and PPXs were also carried out. These analyses may help us to evaluate a feasibility of in vitro profiling of primary rhabdomyosarcoma cells from a genomic perspective.

  Study phs002051

• Derivation and Investigation of The First Human Cell-Based Model of Beckwith-Wiedemann Syndrome

  Beckwith-Wiedemann Syndrome (BWS) is the most common human imprinting disorder, and phenotypes include hepatomegaly and hepatoblastoma development. In approximately 20% of patients, this syndrome is caused by uniparental isodisomy of the paternal allele across chromosome 11p15 (pUPD11). From fibroblasts cultured from 2 BWS patients with pUPD11, we derived induced pluripotent stem cells (iPSC) and differentiated to hepatocytes to study a model of the BWS liver transcriptome through RNA-Seq. Compared to 2 similarly derived controls, we observed differential expression in insulin signaling, cell proliferation, and cell cycle pathways, indicating their potential importance in the liver overgrowth and oncogenesis associated with BWS.

  Study phs002365

• Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and is Associated with Worse Outcomes

  Small-cell lung cancer (SCLC) is a very aggressive neuroendocrine lung cancer often associated with oncogenic MYC amplifications, which are known to drive SCLC heterogeneity marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states. The genetic mechanisms of MYC amplification and phenotypic plasticity between cell states is not known. Using data from cell-lines and a few patient-derived samples along with integrated whole-genome sequencing, long-range optical mapping, single-cell DNA sequencing, and fluorescence in situ hybridization, we have attempted to successfully characterize extrachromosomal DNA (ecDNA) as the primary source of MYC amplifications and driver fusions in SCLC.

  Study phs003190

• IκBε deficiency accelerates disease development in chronic lymphocytic leukemia

  The NFKBIE gene, which encodes the NF-κB inhibitor IκBε, is mutated in 3-7% of patients with chronic lymphocytic leukemia (CLL). The most recurrent alteration is a 4-bp frameshift deletion associated with NF-κB activation in leukemic B cells and poor clinical outcome. To study the functional consequences of NFKBIE gene inactivation, both in vitro and in vivo, we engineered CLL B cells and CLL-prone mice to stably down-regulate NFKBIE expression and investigated its role in controlling NF-κB activity and disease expansion. We found that IκBε loss leads to NF-κB pathway activation and promotes both migration and proliferation of CLL cells in a dose-dependent manner. Importantly, NFKBIE inactivation was sufficient to induce a more rapid expansion of the CLL clone in lymphoid organs and contributed to the development of an aggressive disease with a shortened survival in both xenografts and genetically modified mice. IκBε deficiency was associated with an alteration of the MAPK pathway, also confirmed by RNA-sequencing in NFKBIE-mutated patient samples, and resistance to the BTK inhibitor ibrutinib. In summary, our work underscores the multimodal relevance of the NF-κB pathway in CLL and paves the way to translate these findings into novel therapeutic options.

  Dataset EGAD50000000754

• Evolutionary Pressures Shape Undifferentiated Pleomorphic Sarcoma Development and Radiotherapy Response

  To study tumor evolution during tumorigenesis and in response to radiotherapy, we performed whole exome sequencing of 120 spatially distinct tumor regions and matched germline DNA from 20 patients with undifferentiated pleomorphic sarcoma. This data was utilized to generate personalized capture probes for targeted resequencing of the tumor and normal samples along with 17 matched plasma samples for circulating tumor DNA analysis. We found evidence of subclonal selection prior to treatment that was increased after radiotherapy. In addition, circulating tumor DNA analysis was able to measure the abundance of subclones before, during, and after treatment. This dbGaP submission includes whole exome sequencing and targeted resequencing from the study.

  Study phs003830

• Targeted DNA sequencing and mRNA sequencing data from patients with peritoneal metastasis from colorectal cancer

  Patients with peritoneal metastasis from colorectal cancer (PM-CRC) have inferior prognosis and respond particularly poorly to chemotherapy. This study aims to identify the molecular explanation for the observed clinical behavior and suggest novel treatment strategies in PM-CRC. Tumor samples (230) from a Norwegian national cohort undergoing surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC) for PM-CRC were subjected to targeted DNA sequencing, and associations with clinical data were analyzed. mRNA sequencing was conducted on a subset of 30 samples to compare gene expression in tumors harboring BRAF or KRAS mutations and wild-type tumors.

  Study EGAS50000000404

• Study for establishment for effective screening and diagnosis of Lynch syndrome

  The purpose of this study is to establish efficient diagnostic procedure of the Lynch syndrome in Japan and to determine the MMR gene mutation spectrum and clinicopathologic characteristics.The person who is suspected Lynch Syndrome and gives informed consent for participation in this study .To carry out the project ?Construction of clinical and genetic integral information database to help Lynch syndrome management?, the following three are required. 1) screening for Lynch syndrome-suspected cases, 2) genetic testing to define Lynch syndrome, 3) integration of detailed clinical data of Lynch syndrome, and 4) The case which has not been diagnosed Lynch syndrome, is investigated causing gene.

  Study JGAS000638

• Development of hunanized mice for human hematopoisis and immunity research

  We obtained peripheral blood or bone marrow samples from 112 acute myeloid leukemia patients and examined sensitivity and resistance of the AML samples to molecular targeting drugs. By doing RNA sequencing using AML cells, we found heterogenous gene expression patterns in AML with different mutational landscapes. From the RNA sequencing, we identified anti-apoptosis, cell cycle progression, and immune-related signals as pathways up-regulated in AML cells as compared with normal CD34+ cells. From the pathway analyses, we further setup in vitro experiments to find vulnerability genes in clinically-aggressive AML. BIRC, BCL2, MCL1, AURKB, and KIF10 may be essential molecules for AML cell survival and proliferation.

  Study JGAS000253

• Transcriptomic analysis of membranes from proliferative vitreoretinal diseases and isolated human retinal pigment epithelium

  This study investigates the transcriptomic profiles of proliferative vitreoretinal diseases (PVD) membranes, including proliferative vitreoretinopathy and epiretinal membranes collected from patients undergoing surgery, as well as human retinal pigment epithelial cells isolated from post-mortem donor eyes. Total RNA was extracted using AllPrep DNA/RNA Micro Kit (Qiagen) and cDNA libraries were prepared using the Ovation Solo RNA-seq Kit (Tecan). Multiplexed libraries were loaded onto a NovaSeq 6000 platform (Illumina), and sequences were generated using a 200-cycle kit. This study includes over 80 pathological and healthy samples to allow comparison of gene expression profiles and gain insights into the molecular mechanisms of PVD.

  Study EGAS50000001253

• How are we funded?

  How are we funded? The EGA is provided infrastructure, administrative support, advisory input, and other relevant and necessary aspects by: CRG The EGA at the CRG is funded and supported by “La Caixa Foundation”, The Generalitat de Catalunya (Catalan Government), the Spanish Ministerio de Asuntos Económicos y Transformación Digital (Spanish Government) and the Instituto de Salud Carlos III. The Generalitat de Catalunya contributes with funding to the CRG and to the Barcelona Supercomputing Centre (BSC). The Barcelona Supercomputing Center is decisively contributing to EGA by providing the required compute, storage and networking resources, as well as key personnel for shared operations of EGA infrastructure. EMBL-EBI As part of the European Molecular Biology Laboratory (EMBL), the EGA at EMBL’s European Bioinformatics Institute receives funding from the governments of EMBL’s member states. The UK government, via UK Research and Innovation, also continues to support EMBL-EBI technical infrastructure, with EMBL supporting operational costs. A major source of funding for the EGA both at CRG and EMBL-EBI are competitive projects.The EGA resource continues to be funded through strategic engagement in collaborative partnerships and projects. Please see our projects page for more information. Other funders include the European Commission, the US National Institutes of Health, the Wellcome Trust, UK Research Councils, and our Industry Programme partners. Last updated on October, 2024.

  Documentation about/projects-and-funders/funders

• Partner independent fusion gene detection by multiplexed CRISPR Cas9 enrichment and long read Nanopore sequencing (FUDGE)

  Targeted long-read nanopore sequencing. Abstract: Fusion genes are hallmarks of various cancer types and important determinants for diagnosis, prognosis and treatment. Fusion gene partner choice and breakpoint-position promiscuity restricts diagnostic detection, even for known and recurrent configurations. To accurately and impartially identify fusions, we developed FUDGE: FUsion Detection from Gene Enrichment. FUDGE couples target-selected and strand-specific CRISPR/Cas9 activity for fusion gene driver enrichment - without prior knowledge of fusion partner or breakpoint-location – to long-read Nanopore sequencing with the bioinformatics pipeline NanoFG. FUDGE has flexible target-loci choices and enables multiplexed enrichment for simultaneous analysis of several genes in multiple samples in one sequencing run. We observe on-average 665 fold breakpoint-site enrichment and identify nucleotide resolution fusion breakpoints - within two days. The assay identifies cancer cell line and tumor sample fusions irrespective of partner gene or breakpoint-position. FUDGE is a rapid and versatile fusion detection assay, providing unparalleled opportunity for diagnostic pan-cancer fusion detection.

  Dataset EGAD00001006111

• Host genotyping data from Dutch adult bacterial meningitis patients and linked bacterial genome sequences

  Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. This study includes 1146 samples of host genotyping data (genotyped and imputed) from Illumina Omni arrays. Samples were collected from adults (>16 yrs) patients with CSF confirmed bacterial meningitis in the Netherlands between 2006 and 2015. Metadata includes patient outcome, species of bacteria, and for 467 samples a link to an ENA run with the associated bacterial genome (S. pneumoniae only).

  Study EGAS00001005993

• Genome-wide genetic and epigenetic dataset of pancreatic acinar cell carcinomas

  Pancreatic acinar cell carcinoma (ACC) is an aggressive exocrine tumor with largely unknown biology. To identify potential targets for personalized treatment, integrative genome- and epigenome-wide analyses were performed. The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures suggesting defective DNA repair. In contrast to pancreatic ductal adenocarcinoma, no recurrent point mutations are known. The tumor suppressors ID3, ARID1A, APC, and CDKN2A are frequently impaired also on the protein level and thus potentially affect ACC tumorigenesis. Consequently, this work identifies potential novel therapeutic targets in ACC for drugs recently approved for precision cancer therapy.

  Study EGAS00001002533

• A spatial human thymus cell atlas mapped to a continuous tissue axis

  T cells develop from circulating precursor cells, which enter the thymus and migrate through specialised sub-compartments that support their maturation and selection. In humans, this process starts in early fetal development and is highly active until thymic involution in adolescence. To map the micro-anatomical underpinnings of this process in pre- and early postnatal stages, we established a novel quantitative morphological framework for the thymus, the Cortico-Medullary Axis, and used it to perform a spatially resolved analysis. By applying this framework to a curated multimodal single-cell atlas, spatial transcriptomics, and high-resolution multiplex imaging data, we demonstrate establishment of the lobular cytokine network, canonical thymocyte trajectories and thymic epithelial cell distributions within the first trimester of fetal development. We pinpoint tissue niches of thymic epithelial cell progenitors and distinct subtypes associated with Hassall’s corpuscles and uncover divergence in the timing of medullary entry between CD4 vs. CD8 T cell lineages. These findings provide a basis for a detailed understanding of T lymphocyte development and are complemented with a holistic toolkit for cross-platform imaging data analysis, annotation, and Organ Axis construction (TissueTag), which can be applied to any tissue.

  Dataset EGAD00001015384

• Genome-Wide Association of Type 2 Diabetes in Africans: The AADM Study

  The Africa America Diabetes Mellitus (AADM) study is a genetic epidemiological study of type 2 diabetes in Sub-Saharan Africa. Study participants were enrolled through university medical centers in Nigeria, Ghana, and Kenya. Ethical approval for the study was obtained from the Institutional Review Board (IRB) of each participating institution. All subjects provided written informed consent for the collection of samples and subsequent analysis. The case definition of type 2 diabetes was based on the American Diabetes Association (ADA) criteria. After providing informed consent, participants underwent the same enrollment procedures, which included collection of demographic information, medical history, clinical examination and a blood draw. Genome-wide SNP genotyping was done on either the Axiom™ PanAFR SNP array (n=1,808) or the Multi-Ethnic Global Array (MEGA) (n=3,423). After appropriate quality control, in silico imputation was done using the African Genome Resources Haplotype Reference Panel (at the Sanger Imputation Service). Imputed genotypes were filtered for variants with minor allele frequency (MAF)≥ 0.01 and information score (info) ≥ 0.3 for genetic association analysis. Genome-wide association analysis between type 2 diabetes and the imputed genotype dosages was done using a generalized linear mixed model, which adjusted for age, gender, body mass index, the genetic relatedness matrix and the first three principal components (PCs) of the genotypes.Metabolomics profiling of plasma samples of type 2 diabetes (T2D) cases and controls in Nigerians (West Africa) was done in the AADM Study. Plasma metabolites were measured in a total of 580 individuals (N=310 for the discovery phase and N=270 for the replication stage) using the global/untargeted approach on the Metabolon platform and following the manufacturer's standard operation protocols. The analytic methods are described in detail in Doumatey et al. [Genome Med 2024]. The measured metabolites level represented by peak areas are relative values. The peak area data were batch-normalized to remove the instrument batch effects (batch variability) and the batch-normalized data correspond to the median-scaled raw data. For each identified metabolite, the minimum value across all batches in the batch-normalized was imputed for the missing values. The batch-normalized and imputed data are natural log-transformed and consist of 1116 metabolites for the discovery cohort and 1071 metabolites for the replication. Welch's two-sample t-test on the log-transformed data was used to identify metabolites differentially expressed between T2D cases and controls . All other statistical analyses conducted on both the replication and discovery cohorts used the log-transformed data. To merge the discovery and replication, the same quality control samples (bridge samples) were run with each batch of the experimental samples in both cohorts and used to correct for additional variability and uniformize the procedures. The resulting merged data is the QC-normalized and imputed data that contains only metabolites that were common to both cohorts and successfully bridged for all batches (n= 891 metabolites).

  Study phs001844

• Washington University PDX Development and Trial Center

  This data set is a collection of patient specimens from common and rare cancers that have been developed into patient-derived xenograft (PDX) models at the Washington University PDX Development and Trial Center (WU-PDTC). The goal of the PDTC is to develop and characterize PDX models, gaining insight into tumor biology, and validating biomarkers across all major tumor types. Pre-clinical experiments in these PDX models will be used to advance our ability to predict clinical responses to new molecularly targeted agents under development.

  Study phs002305

• A Phenotypic and Genomics Approach in a Multi-Ethnic Cohort to Subtype Systemic Lupus Erythematosus

  Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organ systems and varies in severity across different populations. To examine the clinical heterogeneity of SLE, we sought to identify different lupus subtypes within our multi-ethnic cohort using a clustering approach. Additionally, with genome-wide methylation and genotype data generated for our cohort, we applied integrative methods to investigate genetic and epigenetic risk factors. This integrative and computational approach revealed molecular differences associated with phenotypic clusters.

  Study phs001850

• Genomics and Modification of Pain: A peripheral component identified using iPSCs with the S241T mutation

  We have capitalized on inherited erythromelalgia (IEM) as a well-characterized genetic model of chronic pain, and studied IEM patients carrying Nav1.7 mutations which affect channel activation and often produce hyperexcitability of DRG neurons. Whole exome sequencing was used to discover multiple gene variants that might contribute to neuronal excitability and that might serve as modifiers of sensory neuron firing, and identified the Kv7.2 channel as a contributor to differences in pain profiles between individuals.

  Study phs001724

• Single Suture Craniosynostosis: Gene and Pathway Discovery

  Craniosynostosis is the premature fusion of one or more of the calvarial sutures. In this work, we used genomics and network modeling to reveal genetic and developmental pathways which, when disrupted, result in premature calvarial fusion. Calvarial bone explants were obtained from children undergoing surgery for single suture craniosynostosis. Primary osteoblast cell lines were established from calvarial explants and used as an RNA source.  The data available includes subject sex, affected suture, RNA sequence variants and counts.

  Study phs002684

• Genome and transcriptome sequencing of cancer of unknown primary tumours

  Genome and transcriptome sequencing of cancer of unknown primary tumours was used to determine yield of clinical biomarkers for a molecular guided trial or for resolving cancer type of origin. This study includes profiling of germline DNA and tumour DNA by whole genome sequencing of tissue and cfDNA biopsies, as well as targeted genome sequencing using two panels, including Comprehensive cancer panel (CCP) and TruSight Oncology 500 (TSO500). This study also includes profiling of tumour RNA by whole transcriptome sequencing.

  Study EGAS50000000452

• Integrated Exome and RNA Sequencing of Dedifferentiated Liposarcoma

  Multiomics analysis of rare cancers to identify genetic alterations related with pathogenesis and prognosis. To identification of genetics alterations of Dedifferentiated liposarcoma, DNAs and RNAs were extracted from dedifferentiated liposarcoma and paired non-cancer (normal) tissues. NGS libaraies were prepared by using Agilent SureSelect XT Human All Exon V5 + IncRNA kit for whole exome sequencing (WES) and TruSeq Stranded mRNA Prep kit or TruSeq RNA Access Library Prep kit (RNA seq). Sequencing was perfomred by Illumina HiSeq 2500.

  Study JGAS000177

• Transcriptome sequencing of fibroblast-dependent alveolar organoids derived from patient-specific iPS cells with SFTPC^Y104H variant and their gene-corrected (monoallelic wild type SFTPC) ones.

  A disease-specific iPS cell line derived from a pulmonary fibrosis patient with SFTPC^Y104H and its gene-corrected (monoallelic wild type SFTPC) one were established. Then lung progenitor cells were differentiated from each cell line and co-cultured with human fetal lung fibroblasts to generate alveolar organoids, respectively. Alveolar epithelial cells and fibroblasts were isolated by fluorescence-activated cell sorting and each RNA was extracted. We performed transcriptome analysis of those samples by RNA-sequencing.

  Study JGAS000617

• Spatial Profiling of Patient-Matched HER2 Positive Gastric Cancer Reveals Resistance Mechanisms to Trastuzumab and Trastuzumab Deruxtecan Sequencing

  HER2-positive gastric cancer (HER2+ GC) exhibits significant intra-tumoral heterogeneity and frequent development of resistance to HER2-targeted therapies. This study aimed to characterize the spatial tumor microenvironment (TME) and identify mechanisms of resistance to HER2 blockade including trastuzumab and trastuzumab deruxtecan (T-DXd) in HER2+ GC, with the goal of informing novel therapeutic strategies. We performed spatial transcriptomics on pre- and post-treatment samples from patients with HER2+ metastatic GC who received trastuzumab-based therapy.

  Study EGAS50000000636

• snRNA and snATAC analysis of cocaine use disorder in human caudate nucleus

  We investigated cell type specific changes of gene expression and chromatin accessibility in the caudate nucleus of N=6 individuals with and N=8 individuals without cocaine use disorder using postmortem human brain samples. We performed single-nuclei RNA-sequencing and single-nuclei ATAC sequencing in the same cells using the 10xMultiome platform. The N=14 tissue donors were of African-American ancestry. The cohort consists of N=5 female and N=9 male individuals.

  Study EGAS50000000480

• The mutational landscape of human somatic and germline cells

  During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

  Dataset EGAD00001006642

• The mutational landscape of human somatic and germline cells

  During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

  Dataset EGAD00001006643

• Characterization of MCSP+ melanoma DCC and MelDCC lines

  To dissect the sequence of genotypic and phenotypic progression during early metastatic colonization, we searched for the earliest detectable disseminated cancer cells (DCC) and identified MCSP+ melanoma cells as strong candidates for metastasis founder cells (MFC) in lymph nodes. We isolated MCSP+ DCC from various stages of metastatic colony-formation, performed scRNA-seq and unravelled their phenotypic progression. Further we performed bulk sequencing on patient-derived DCC models (MelDCC) and showed that they exhibit an immunosuppressive activity on CD8 T cells.

  Study EGAS00001006702

• Celiac disease-specific intestinal T cells analyzed with HLA-class II tetramers, RNA-seq and mass cytometry have a narrow, autoimmune-associated phenotype

  Celiac disease (CD) is an HLA-DQ2/8-associated autoimmune enteropathy driven by activation of gluten-specific CD4+ T lymphocytes upon gluten consumption. Much less is known about the phenotype and function of these cells or their correlation, if any, to disease-relevant cells in other autoimmune disorders. Here we use mass cytometry and RNA seq to show that gluten-specific blood and gut T cells occupy a small and phenotypically distinct T-cell subset.

  Study EGAS00001003017

• RNA sequencing data of 66 matched primary and recurrent high grade serous ovarian cancer

  Gene expression profiles of matched primary and recurrent fresh frozen tumor tissues from 66 HGSOC patients were obtained by RNA sequencing. RNA libraries were created using the Illumina TruSeq RNA sample preparation kit V2 according to the manufacturer’s instructions and sequenced on a HiSeq2000 (Illumina, California, USA) using a V3 flowcell generating 1 x 50 bp reads. Raw sequencing reads were mapped to the transcriptome and the human reference genome (NCBI37/hg19) using TopHat 2.0 and Bowtie 2.0.

  Study EGAS00001002660

• Genomic characterization of co-existing biliary tract intraepithelial neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer

  Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we performed whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients.

  Study EGAS00001005402

• Induced pluripotent stem cell lines (iPSC lines) produced from skin and blood cells.

  The IMBA stem cell bank, iPSC Biobank, is a collection of induced pluripotent stem cell lines (iPSC lines) produced from skin and blood cells. The iPSC Biobank is integrated into the IMBA Stem Cell Core Facility. It stores and provides high-quality reference control panels of iPSC clones as a tool to the research community. The resource is available to all scientists and commercial institutions. The ethical guidelines of the iPSC Biobank are always based on prevailing laws and internal regulations.

  Study EGAS00001006262

• Germline RUNX1 Variation and Predisposition to Childhood Acute Lymphoblastic

  Somatic mutations of RUNX1, which encodes the myeloid and lymphoid transcriptional factor RUNX1, are common in both B- and T- acute lymphoid leukemia (ALL) and are associated with poor prognosis of T-ALL. However, there has been no comprehensive investigation of the pattern or prevalence of RUNX1 germline mutation in both B- and T-ALL. Here we report germline RUNX1 variants in 1.23% of B-ALL and 2.11% of T-ALL, identifying 31 unique variants in 62 B-ALL and 18 unique variants in 26 T-ALL children. The majority of frameshift and nonsense variants affected RUNX1 function in transcriptional regulation, hematopoiesis, and cellular proliferation. We identified JAK3 as the most frequent somatic mutation in T-ALL with RUNX1 variants. These results not only identify RUNX1 as a leukemia predisposition gene but also further underline the importance of germline genetic variants to the development of ALL

  Dataset EGAD00001007793

• Exome sequencing of early and late passage Patient Derived Xenogratf Tumoroids with matched Patient Derived Xenogratfs and matched normal liver

  The breadth and depth at which cancer models are interrogated contribute to successful translation of drug discovery efforts to the clinic. In colorectal cancer (CRC), model availability is limited by a dearth of large-scale collections of patient-derived xenografts (PDXs) and paired tumoroids from metastatic disease, the setting where experimental therapies are typically tested. XENTURION is a unique open-science resource that combines a platform of 129 PDX models and a sister platform of 129 matched PDX-derived tumoroids (PDXTs) from patients with metastatic CRC, with accompanying multidimensional molecular and therapeutic characterization. In this specific dataset we focused our attention on early (passage 3) and late (passage 8-12) PDXTs with their matched PDXs and normal liver

  Dataset EGAD50000000266

• Myocardial Infarction Genetics Exome Sequencing Consortium: University of Lubeck

  MI cases were recruited from the German MI Family Study and the Angio-Lub study. Controls were recruited from the German MI Family Study and the Angio-Lub study. All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Illumina's ICE Capture reagent and sequencing was performed on an Illumina HiSeq 2000 or 2500.

  Study phs000990

• 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

• Genomic-Enabled Medicine for Recurrent Glioblastoma

  In this prospective study, we performed genome-wide tumor/normal exome sequencing and tumor RNA-sequencing for recurrent glioblastoma patients. A subset of patients had both enhancing tumor and non-enhancing tissue sequenced to investigate spatial heterogeneity of this disease. Together, this information builds our understanding of the genomic underpinnings of glioblastoma, and contributes toward the knowledge base for identifying and developing more effective treatments for patients with glioblastoma.

  Study phs001460

• Dana-Farber Cancer Institute (DFCI) Brown Lab CLL Sequencing Study

  Chronic Lymphocytic Leukemia (CLL) is a hematological malignancy characterized by accumulation of CD5+CD19+ B cells in peripheral lymphoid organs, bone marrow and blood. In this study we analyze matched whole genome sequencing and RNA-seq data from CLL patients to characterize the mutational processes operative throughout tumor evolution. Source of tumor and normal DNA used is patient PBMC or B cells and saliva respectively.

  Study phs000879

• Cellular Heterogeneity in Early Human Development at Stage CS16

  In this study, we applied 10x Genomics Multiome assays for single-nucleus profiling of gene expression and chromatin accessibility simultaneously to a Carnegie stage 16 (37-42 days) specimen. These data can be used to identify and characterize diverse human cell types and annotate them with respect to marker genes, expression, and regulatory modules. These data comprise a rich resource for the exploration of human biology.

  Study phs003532

• Molecular profiles in early onset prostate cancer

  Paired germline (blood) and tumour samples were collected from prostate cancer cases <65 years at diagnosis to identify genetic changes in early onset prostate cancer.  Whole exome sequencing was performed on these samples. The aim was to determine if these changes are associated with more aggressive disease and to identify targets for treatment and screening by identifying associations with family history, DNA repair germline mutations, and clinical features.

  Study EGAS50000001467

• Oropharynx cancers sequencing study (RNA-seq from FFPE)

  This is a study of transcriptomics in HPV-associated oropharynx tumors. The goals of this study were to characterize HPV+ oropharynx tumor subtypes and to examine HPV integration events and their downstream effects. HPV-host fusion transcripts and recurrent HPV integration genes were identified. Various alternative isoforms and splicing events of HPV genes were also studied. Multiple potential biomarkers of prognosis were associated with clinical outcomes.

  Study EGAS50000000893

• Transcriptomic insights into IPMN-associated PDAC progression

  This study investigates the transcriptomic heterogeneity and evolutionary progression of intraductal papillary mucinous neoplasms (IPMNs) and their associated pancreatic ductal adenocarcinomas (PDAC). Multi-region tumour sampling was performed to characterise spatial variation in gene expression and to identify transcriptional changes associated with malignant transformation. The project aims to improve understanding of tumour evolution in pancreatic cancer and to identify molecular pathways involved in IPMN-to-PDAC progression.

  Study EGAS50000001540

• Transcriptomic profiling of myeloid cells from secondary lymphoid organs (lymph nodes and tonsils) from lymphoma patients and controls.

  Despite their recognized impact on the pathogenesis and prognosis of B-cell lymphoma, tumor-associated macrophages (TAM) have not been extensively explored in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). We investigated mononuclear phagocyte (MNP) heterogeneity using single cell RNA sequencing (scRNAseq) in B-cell lymphoma lymph nodes compared to reactive secondary lymphoid organs (lymph nodes and tonsils).

  Study EGAS50000001135

• Breast_Cancer_Exome_Resequencing

  Agilent whole exome hybridisation capture was performed on genomic DNA derived from Chondrosarcoma cancer and matched normal DNA from the same patients. Next Generation sequencing performed on the resulting exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes. Now we aim to re find and validate the findings of those exome libraries using bespoke pulldown methods and sequencing the products.

  Study EGAS00001000207

• Exome_sequencing_of_Congenital_Heart_Disease_families_from_the_Competence_Network_Berlin

  This project aims to study exomes from families and trios withcongenital heart disease (CHD). The samples have been collected underthe Competence Network - Congenital Heart Defects in Berlin, Germany.The phenotypes are mainly left ventricular outflow obstruction (aorticstenosis, bicuspd aortic valve disease coarctation and hypoplasticleft heart), but will also include samples with hypoplastic rightheart and atrioventricular septal defects. We will perform whole exomesequencing using Agilent sequence capture and Illumina HiSeqsequencing.

  Study EGAS00001000368

• Gastric_and_Esophageal_tumour_rearrangement_screen

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from gastric and esophageal tumours and subjected to total of two lanes of 50 bp, paired end sequencing on the llumina HiSeq. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions.

  Study EGAS00001000037

• Cancer_Genome_Project_Exome_Sequencing

  Agilent whole exome hybridisation capture was performed on genomic DNA derived from cancer and matched normal DNA from the same patients. Next Generation sequencing performed on the resulting exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes. Now we aim to re find and validate the findings of those exome libraries using bespoke pulldown methods and sequencing the products.

  Study EGAS00001000301

• Chondrosarcoma_Validation_Study

  Agilent whole exome hybridisation capture was performed on genomic DNA derived from Chondrosarcoma cancer and matched normal DNA from the same patients. Next Generation sequencing performed on the resulting exome libraries and mapped to build 37 of the human reference genome to facilitate the identification of novel cancer genes. Now we aim to re find and validate the findings of those exome libraries using bespoke pulldown methods and sequencing the products.

  Study EGAS00001000181

• Single cell transcriptomes of of primary tumors and normal endometrial derived organoids treated with DBZ

  Endometrial carcinoma, the most common gynecologic cancer, develops from endometrial epithelium which is composed of secretory and ciliated cells. Pathologic classification is unreliable and there is a need for prognostic tools. We used single cell sequencing to study organoid model systems derived from normal endometrial endometrium to discover novel markers specific for endometrial ciliated or secretory cells. We performed single cell sequencing on endometrial and ovarian tumours, and on organoids both treated with DBZ and normal and found both secretory-like and ciliated-like tumour cells.

  Dataset EGAD00001006280

• Preeclampsia InterPregGen Consortium: Whole Genome Sequencing of 100 unrelated Uzbeks (DNA samples from the Institute of Immunology, Uzbek Academy of Sciences, Tashkent, Uzbekistan; Republic Specialized Scientific Practical Medical Centre of Obstetrics and Gynecology, Tashkent, Uzbekistan)

  Whole genome sequencing of 100 unrelated Uzbeks in order to impute genotypes into PE cases and controls from Uzbekistan and to provide genetic data and infrastructure for future genetic studies in Uzbekistan and Central Asia more generally and to fill a gap in worldwide information as Central Asia is not adequately represented in available genomic data. This dataset is one component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium collaborators 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 EGAD00001005466

• SDH_deficient_renal_tumours___RNA_

  Succinate dehydrogenase (SDH) deficient renal cancers are a rare and understudied subtype of renal cancer. As such they represent an unmet need in kidney cancer research. Here, we seek to describe the genomics and transcriptomics of SDH deficient renal cancers by sequencing five such tumours. We document their mutational burden, define driver mutations, demonstrate typical patterns of structural variants, and estimate the cell of origin and cellular composition.

  Study EGAS00001004103

• Immunological hallmarks for clinical response to BCG in bladder cancer

  Intravesical Bacillus Calmette-Guerin (BCG) is an effective immunotherapy for non-muscle invasive bladder cancer (NMIBC). However, recurrence and progression remain frequent warranting deeper insights into its mechanism. We herein comprehensively profiled blood and tissues obtained from NMIBC patients before, during and after BCG treatment using cytometry by time-of-flight (CyTOF) and RNA sequencing to identify the key immune subsets crucial for anti-tumour activity.

  Study EGAS00001004764

• Gut metagenome/FINRISK 2002 (Salosensaari et al. Nature Comms 2021)

  The main goal of the project is the study the associations between the gut metagenome and human health. The dataset contains data for n=7211 FINRISK 2002 participants who underwent fecal sampling. Demultiplexed shallow shotgun metagenomic sequences were quality filtered and adapter trimmed using Atropos (Didion et al., 2017), and human filtered using Bowtie2 (Langmead and Salzberg, 2012).

  Study EGAS00001005020

• The transcriptomic response of skeletal muscle in life-long high-level trained and untrained men and women after acute exercise

  To investigate the influence of lifelong exercise training on the response of skeletal muscle to a bout of acute exercise we generated global transcriptomic data from long-term endurance (8 men, 8 women) and strength (8 men, 8 women) trained individuals and healthy age-matched untrained controls (8 men, 8 women). Skeletal muscle biopsies were taken from M. vastus lateralis before, directly after, and after 1h and 3hrs following acute exercise. All subjects completed one bout of acute endurance exercise and one bout of acute resistance exercise, separated by 4-8 weeks. All 384 samples were multiplexed in 4 lanes and sequenced (2x250bp paired end) on the Illumina NovaSeq 6000.

  Dataset EGAD00001008663

• Pooled Single-Cell RNA-Seq of iPSC-Derived Neural Stem Cells from ADHD and Control Individuals

  This dataset contains FASTQ files from pooled single-cell RNA sequencing (scRNA-seq) of neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs). The iPSCs were reprogrammed using the non-integrative Sendai virus system (CytoTune-iPS 2.0), introducing OCT3/4, SOX2, KLF4, and cMYC. Donor somatic cells included keratinocytes, PBMCs, and lymphoblastoid cell lines from individuals with ADHD and age-matched healthy controls (6–18 years). iPSCs underwent standard quality control, including immunocytochemistry, qRT-PCR, mycoplasma testing, and SNP genotyping. NSCs were produced via neural induction and validated by qRT-PCR and immunostaining for PAX6, SOX2, NESTIN, TUJ1, and FOXG1. Sequencing was performed on the Illumina NovaSeq 6000.

  Dataset EGAD00001015644

• Cooperative Study of Sickle Cell Disease (CSSCD)

  The Cooperative Study of Sickle Cell Disease was initiated in 1977 to determine the natural history of sickle cell disease (SCD) from birth to death in order to identify those factors contributing to the morbidity and mortality of the disease. Specific objectives included: 1) to study the effect of sickle cell disease on growth and development from birth through adolescence 2) to study the conditions or events that may be related to the onset of painful crises 3) to obtain data on the nature, duration, and outcome of major complications of SCD 4) determine the nature, prevalence, and age- related incidence of organ damage due to SCD, and 5) study the role of SCD and its interaction with selected health events.Phases 2 and 3 of the study involved followup of the infant cohort. A total of 709 infants (age less than 6 months) were enrolled during Phase 1 of the Cooperative Study of Sickle Cell Disease (CSSCD), and Phases 2 and 3 of the CSSCD was designed to follow these children for an additional 10 years. The study objectives included: 1) define prospectively the natural history of sickle cell disease; 2) determine the relationships between cognitive and academic functioning and brain status as determined by MRI; 3) determine the cognitive or behavioral markers of silent infarct; 4) determine the relationship of family functioning on the Family Environment Scale (FES) to brain status, cognitive functioning, and social and demographic factors; 5) continue studies that will enhance the state of knowledge on the influence of sickle cell disease on the psychosocial adjustment of children and adolescents. Phase 2A of the study sought to examine the progression of organ damage in the heart, lung, kidney, and liver in adult cohort patients (born before 1/1/56) enrolled in phase 1 of the study between 3/79 and 5/81. A total of 620 patients from 11 centers were eligible for phase 2A.Instructions for requesting individual-level data are available on BioData Catalyst at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BioData Catalyst. For questions about availability, you may contact the BioData Catalyst team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs002362

• A Case-Controlled Study for Genotype-Phenotype Associations in Multiple Sclerosis (MS)

  This is a multi-centre, case-controlled study to develop a dataset containing 1000 MS cases and 1000 matched controls and to associate DNA sequence (allelic) variations with MS phenotypes. Study subjects were enrolled through a prospective effort initiated in 2003. Three MS clinical centres were involved in subject recruitment and biological specimen collection using identical inclusion/exclusion criteria, two in Europe (Vrije Universiteit Medical Center, Amsterdam; and University Hospital Basel) and one in the US (University of California San Francisco). This study recruited subjects of northern-European ancestry with a diagnosis of MS (McDonald et al., 2001), with dissemination in time and space. Patients with Clinically Isolated Syndromes (CIS) were also included if they fulfilled 3 of the 4 Barkhof criteria for dissemination in space as per application of the McDonald criteria (McDonald et al., 2001). While recruitment predominantly included subjects with a relapsing onset of MS, individuals with all clinical subtypes of the disease participated, including clinically isolated syndrome (CIS), relapsing remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PRMS). The control group consisted of unrelated individuals, primarily spouses/partners, friends, and other volunteers. Control subjects were of northern-European ancestry and matched as a group, proportionally with cases according to age (&#177;5 years) and gender. A familial history or current diagnosis of MS as well as a relation to another case or control subject were considered exclusionary for this group. Protocols were approved by the Committees on Human Research at all Institutions and informed consent was obtained from all participants prior to participation in the study. Primary Study Objective:To identify DNA sequence variations (genotype) and flanking sequences that are associated with clinical factors (phenotype) which differ between study subjects with and without MS. Secondary Study Objectives: To develop a clinical dataset including quantitative measures of 1000 well-characterized cases with MS, and 1000 ethnically matched controls. To identify other genotype-phenotype associations in MS study subjects such as magnetic resonance imaging (MRI) measures of disease burden and/or severity. To identify or confirm candidate surrogate markers of neurodegeneration using a variety of techniques including biochemical assays, blood transcriptome analysis, plasma proteomics and MRI*. GenotypingGenotyping of the complete dataset was performed at the Illumina facilities using the Sentrix&#174; HumanHap550 BeadChip. *MRI results are not available on dbGaP.

  Study phs000171

• Singapore Adult Metabolism Study - Phase 2 (SAMS2)

  Singapore Adult Metabolism Study - Phase 2 (SAMS2) was an interventional study where hundreds of donors aged 21-45 were recruited to participate in a 16-week weight loss program. Study individuals selected (see below for more detailed selection standards) were sedentary (exercise 1 or fewer times a week), obese or overweight with a body fat mass greater than 24% and a BMI between 23-35 kg/m2. For this study, we adjusted BMI definition for Asian population, based on the WHO Consultation 2002, and the BMI cut-off is 23 kg/m2 for overweight and 27.5 kg/m2 for obese. The weight loss program included a combination of dietary interventions, structured exercise sessions, and additional physical activity performed in participants' own time. Energy and protein requirements were calculated based on each participant's weight, height, and physical activity level, with the goal of achieving a 40% calorie deficit. Participants' calorie intake was tracked using food recalls and questionnaires. Additionally, subjects attended structured exercise sessions at least three times per week, supervised by a coach. Each session consisted of 90 minutes of aerobic and strength training exercises, designed to burn approximately 500 kcal per session. To monitor daily physical activity, participants wore pedometers throughout the study. In total, the exercise sessions (500 kcal per session) and daily physical activity (targeting an additional 500 kcal) were aimed at achieving a total caloric expenditure of 2000 kcal per week. We collected clinical data and skeletal muscle biopsies from 54 overweight/obese Asian individuals before and after a 16-week lifestyle intervention, which resulted in an average ~10% weight loss, accompanied by a ~30% increase in insulin-stimulated glucose uptake. Improvements were observed in 118 of 252 clinical traits and six blood lipids. Transcriptomic analysis of paired skeletal muscle biopsies identified 505 differentially expressed genes enriched in mitochondrial function and insulin sensitivity. Thousands of muscle-specific e/sQTLs were detected pre- and post- intervention, including hundreds of lifestyle-responsive e/sQTLs. Notably, approximately 4.2% of eQTLs and 7.3% of sQTLs showed Asian specificity. Joint analysis with GWAS identified 16 putative metabolic risk genes. Our study reveals gene-by-lifestyle interactions and how lifestyle modulates gene regulation in skeletal muscle.

  Study phs004078

• Exome Sequencing of Alcohol-Associated Hepatitis

  Alcoholic hepatitis (AH) is a clinically severe, acute disease that only afflicts a fraction of patients with alcohol use disorder (AUD). Although recent genomic studies of alcoholic cirrhosis (AC) and steatosis have revealed that several genes of large effect are shared between these disorders, the genetic and environmental sources of variation that lead to AH, AC or alcohol fatty liver disease (AFLD) in some AUD patients remain largely unknown. In order to investigate the genetic determinants of AH, we sequenced a 58 Mb exome target to high genotype accuracy (0.996) and completeness (0.941) in 1,735 patients with AH (N=784) and heavy drinking controls without alcohol-associated liver disease (ALD) (N=951), detecting 1,085,982 unique single nucleotide variants (SNVs). Analysis of common SNPs that comprised 17.5% of those SNVs, we observed exome-wide significant association of PNPLA3 (rs738409-G allele: odds ratio [OR]=1.73, 95% confidence interval [CI]: 1.44-2.08, p =3.75e-9), as had previously been seen for AH in candidate gene contexts, and as previously observed for PNPLA3 to AC and nonalcohol steatohepatitis in GWAS. Other genes previously implicated in AC did not strongly contribute to AH, and the only prominently implicated (but not exome wide significant) gene overlapping with AUD was ADH1B, also a known liver disease gene. However, SNPs at ICOSLG (Chr 21) and TOX4/RAB2B (Chr 14), were also exome-wide significant and of large effect-size (ICOSLG rs13052840-C allele: OR=1.67, 95% CI: 1.39-2.02, p = 4.59e-8; TOX4/RAB2B rs17516362-C allele: OR = 0.61, 95% CI: 0.50-0.74, p=1.25e-7). ICOSLG encodes a co-stimulatory signal for T-cell proliferation and cytokine secretion and induces B-cell proliferation and differentiation, and thus could be tied to the inflammatory component of AH. TOX4 was previously implicated in diabetes and immune system and its linked SNP is a cis eQTL for TOX4 and RAB2B. A polygenic signal was visible on the exome-wide quantile-quantile graph, where there was modest p value inflation (lambda = 1.040). Ranking p values of all 18,705 genes evaluated versus a list of 227 genes objectively precompiled for relationship to liver diseases (via GWAS), we observed a strong (pThe data generated here also represents a resource that can be used cumulatively or meta-analytically with future datasets.

  Study phs003659