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• The Somatic Mutational Landscape of Thyroid Cancer in Patients with Germline PTEN Mutations

  PTEN hamartoma tumor syndrome (PHTS) is associated with a high rate of thyroid cancer and benign thyroid disease, yet nothing is known of the genomic landscape of PHTS-associated thyroid tumors. In this study, exome sequencing was performed on 58 thyroid tumors (28 cancers, 30 benign nodules) from 19 patients with PHTS, sequenced in tumor-normal pairs. Somatic variant calling was utilized to determine the somatic mutational landscape of thyroid tumors in this population. This was then compared to the known mutational landscape of sporadic thyroid cancer in the general population using sequencing data from The Cancer Genome Atlas. The primary finding of the study was that PHTS-associated thyroid tumors had a unique genomic landscape, including a high frequency of second-hit somatic PTEN alterations compared to the sporadic thyroid tumors. Additionally, PHTS-associated thyroid cancers were found to have somatic alterations in BRAF, RAS family members, and genes associated with DNA double stranded break repair. Data available through dbGAP will include tumor BAM files for each tumor, normal BAM files for each patient, and MAF files for PHTS-associated thyroid cancer and PHTS associated benign thyroid nodules.

  Study phs003640

• Adipocytes Regulate Fibroblast Function and Their Loss Contributes to Fibroblast Dysfunction in Inflammatory Diseases

  We profiled live synovial cells from 16 individuals with no diagnosed arthritis using single-cell RNA sequencing. Our study was designed to provide a reference single cell RNA sequencing dataset for researchers interested in studying arthritic synovium, providing sequencing data on healthy synovial cells for comparison to cells from diseased synovial tissues. Synovial tissue was collected post-mortem from three different sources between 2019-2021: the National Disease Research Interchange, a collaboration with Rush University and the Gift of Hope, and the Brigham and Women's Hospital Autopsy Department. To be included in the study, patients had to be between the ages of 18 to 72 and have no diagnosed arthritis or autoimmune diseases. Additionally, this study includes bulk RNA sequencing data of cultured primary synovial fibroblasts isolated from three rheumatoid arthritis patents. Cells were stimulated with either cortisol, fat conditioned media, TGFβ, TNFα, fat conditioned media with mifepristone, TGFβ with fat conditioned media, or TNFα with fat conditioned media. Cells were harvested 4 or 22 hours later and lysates collected for sequencing. Data from this study submitted to the Gene Expression Omnibus (GEO) may be accessed via accession number GSE233504.

  Study phs003304

• Harnessing Epigenetic Regulators to improve HSC-based lentiviral gene therapy

  Curative benefits of autologous and allogeneic transplantation of hematopoietic stem cells (HSCs) have been proven for various diseases. However, the low number of true HSCs that can be collected from patients and subsequently in vitro maintenance and expansion of true HSCs for genetic correction remain challenging. Addressing this issue, we here focused on optimizing culture conditions to improve the ex vivo expansion of true HSCs for gene therapy purposes. In particular, we explore the use of epigenetic regulators to enhance the effectiveness of HSC-based lentiviral (LV) gene therapy. The HDAC inhibitor Quisinostat and the bromodomain inhibitor CPI203 each promote ex vivo expansion of functional HSCs, as validated by xenotransplantation assays and single cell RNA-sequencing analysis. We confirmed the stealth effect of LV transduction on the loss of HSC numbers in commonly used culture protocols, while addition of Quisinostat or CPI203 improved expansion of HSCs in transduction protocols. Of note, we demonstrated that addition of Quisinostat improved LV transduction efficiency of HSCs and early progenitors. Our suggested culture conditions highlight the potential therapeutic effect of epigenetic regulators in hematopoietic stem cell biology and their clinical applications to advance HSC-based gene correction.

  Study EGAS50000000175

• Programs, Origins, and Immunomodulatory Functions of Myeloid Cells in Gliomas

  Gliomas are challenging malignancies characterized by an immunosuppressive microenvironment filled with myeloid cells, whose roles in immune modulation are not fully understood. In this study, we utilized single-cell RNA sequencing (scRNA-seq) data from 85 primary human glioma tumors, related blood samples, and brain tumor organoid models. We found that nearly all glioma-associated myeloid cells express at least one of four distinct immunomodulatory activity programs. These programs include:1. Scavenger Immunosuppressive Program2. Complement Immunosuppressive Program3. Microglial Inflammatory Program4. Systemic Inflammatory ProgramAll four programs are found in both lower-grade and high-grade gliomas and are expressed across various myeloid cell types, whether derived from blood or resident origins. We validated the remarkable plasticity of myeloid cells by showing that the introduction of peripheral blood monocytes into glioma organoid models can induce the emergence of identities resembling microglia, macrophages, and dendritic cells, as well as all four immunomodulatory programs. Our study provides a valuable resource and a new framework for understanding the role of immunomodulatory myeloid cells in gliomas, laying the groundwork for developing effective immunotherapy strategies for glioma patients.

  Study phs003756

• Chronic Renal Insufficiency Cohort (CRIC) Study Metabolomics and Proteomics

  The Chronic Renal Insufficiency Cohort (CRIC study) was established in 2001 by the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) to improve the understanding of the relationship between chronic kidney disease and cardiovascular disease. The goals of the CRIC Study are to examine risk factors for progression of chronic kidney disease and cardiovascular disease among patients with chronic kidney disease and to develop predictive models to identify high-risk subgroups, informing future treatment trials and increasing application of available preventive therapies. This record includes plasma metabolomics and plasma proteomics data. Genotype data for 3527 CRIC Study partcipants is available at dbGaP in phs000524, "Chronic Renal Insufficiency Cohort (CRIC)-GWAS". Additional phenotypic, clinical, and outcomes data are available at the NIDDK Central Repository and can be linked to data available at dbGaP.More than 330 manuscripts have been published, reporting on the effects of a broad range of risk factors (from molecular biomarkers of disease pathways to clinical, demographic, and behavioral characteristics) on the progression of CKD and other health consequences. The full CRIC bibliography can be found at the BIBLIOGRAPHY for the Chronic Renal Insufficiency Cohort (CRIC) Study.

  Study phs003709

• Blood Group Genotypes and Phenotypes in Omani Blood Donors and Its Links With Susceptibility to Malaria

  The Omani population experienced endemic malaria prior to eradication in the late 1990's. Since malaria is known to be a strong selective pressure on the human genome, particularly at blood group associated loci, we aimed to understand how selective pressures from malaria may be affecting genetic variation at blood group loci. Blood samples were collected from 100 healthy, Omani blood donors. Serology testing for 10 clinically relevant blood groups and whole genome sequencing (WGS) to an average coverage of 16X were performed on all samples. Additionally, using the WGS data, genetic variants (SNPs and INDELs) were called for chromosomes 1 - 22 using GRCh38. We find signals of selection at the Plasmodium vivax associated locus, ACKR1 (the Duffy blood group), but not at any Plasmodium falciparum associated loci. We also characterized several previously undescribed blood group alleles in the Omani population affecting antigenic expression, mostly at the RHD, RHCE, and GYPB loci. The data available from this project include BAM files from 100 Omani samples aligned to GRCh38, per chromosome VCF files, and results from the serology tests for all 10 blood groups.

  Study phs003694

• Immunogenetics of BCG Vaccination and Pediatric Tuberculosis

  We examined genetic variation associated with BCG-induced innate immune responses and susceptibility to pediatric tuberculosis (TB) disease. South African study participants were enrolled at the South African Tuberculosis Vaccine Initiative (SATVI) as part of a larger BCG vaccination study. This area has one of the highest rates of TB incidence in the world. Infants were vaccinated with BCG at birth, and a nested case-control study was performed over a 2-year prospective observation period, which resulted in 135 infant TB cases and 521 controls. Whole blood was collected from BCG vaccinated infants at 10 weeks of age. Genotyping was performed with the llumina MegaEx Beadchip, and GWAS was performed against TB disease to assess for associations between genetic variants and susceptibility to TB. In addition, a subset of infants were assessed for BCG-induced innate immune responses (N=198). For these, whole blood was stimulated with BCG or media and flow cytometry was used to measure BCG-induced PDL1, CD40, and cytokine expression in myeloid (mDC) and plasmacytoid (pDC) dendritic cells, monocytes, and neutrophils. Cellular GWAS was then performed to associate genetic variants with BCG-induced immune responses.

  Study phs003406

• Genetic Studies of Homologous Recombination Deficiency in Hispanic Gastric Cancer

  Approximately 10% of gastric cancer cases show familial clustering and a hereditary cause is likely, however, only 1-3% cases result from known hereditary syndromes – which are predominantly associated with CDH1 and CTNNA1 genes. Hispanics are > 2 times more likely to be diagnosed and to die from gastric cancer compared to non-Hispanic whites. Not only does gastric cancer precision medicine lag behind other cancers – there is an urgent need to understand its etiology. Germline mutations in homologous recombination genes have been implicated as important risk factors for gastric cancer. The purpose of this study is to continue to generate knowledge to improve gastric cancer outcomes and disparities by 1) characterizing prevalence of germline mutations in homologous recombination genes and identify new genes associated with gastric cancer 2) perform molecular characterization of gastric tumors in Hispanic patients. Participants for germline analysis were enrolled from Chile, Colombia, Mexico, Portugal, Spain, Uruguay.Whole exome sequence capture was performed for all germline and somatic samples using Agilent SureSelect Human All Exon v7 Kit. All sequencing was performed on an Illumina NovaSeq 6000. Germline Analysis: Whole exome sequencing was performed on 536 Hispanic patients (290 males, 246 female)

  Study phs003251

• Synovial Fibroblast Gene Expression in Response to Fibronectin Fragment

  Osteoarthritis (OA) is a prevalent joint disease characterized by the progressive degradation of articular cartilage, hypertrophy of neighboring bone, and varying degrees of synovial inflammation. Recent research has highlighted the potential role of synovial fibroblasts in the pathogenesis of OA, particularly their inflammatory properties that disrupt cartilage homeostasis. Notably, degraded cartilage matrix components, such as fibronectin fragments (FN-f), have been identified in the synovial fluid of OA patients, suggesting that FN-f signaling influences the synovium where synovial fibroblasts reside. Despite affecting over 500 million individuals globally, our limited understanding of the underlying mechanisms of OA has significantly impeded the development of effective treatment strategies. To investigate this, we obtained deidentified surgical waste material from individuals undergoing knee replacement for OA. Synovial tissue was used to isolate synovial fibroblasts for cell culture studies. We generated bulk RNA-seq data from primary synovial fibroblasts (N=5 individuals) treated at passage 3 with either Phosphate-Buffered Saline (PBS) as control or FN-f for 18h to model the OA synovial fibroblast phenotype. We identified differentially expressed genes at an adjusted p-value of

  Study phs003999

• Leukemia Relapse via Genetic Immune Escape after Allogeneic Hematopoietic Cell Transplantation

  Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experience relapses because of the failure of the immunological responses to control leukemic outgrowth. Here we demonstrate, through a broad immunogenetic study, that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune responses and responses to immunomodulatory strategies. These findings define new molecular modes of post-transplant leukemia escape contributing to relapse.The present dataset provides HLA peripheral blood and bone marrow samples supporting the genotyping studies performed for this research. This sample set originates from patients with acute myeloid leukemia or myelodysplastic syndromes receiving allogeneic hematopoietic cell transplantation and relapsing after transplant.

  Study phs003235

• Induction of fetal meiotic oocytes from embryonic stem cells in cynomolgus monkeys

  Human in vitro oogenesis provides a framework for clarifying the mechanism of human oogenesis. To create its benchmark, it is vital to promote in vitro oogenesis using a model physiologically close to humans. Here, we establish a foundation for in vitro oogenesis in cynomolgus (cy) monkeys: cy female embryonic stem cells harboring one active and one inactive X chromosome (Xa and Xi, respectively) differentiate robustly into primordial germ cell-like cells, which in xenogeneic reconstituted ovaries develop efficiently into oogonia and, remarkably, further into meiotic oocytes at the zygotene stage. This differentiation entails a comprehensive epigenetic reprogramming, including Xi reprogramming, yet, as partly observed in vivo, Xa and Xi remain epigenetically asymmetric with incomplete Xi reactivation. In humans and monkeys, the Xi epigenome in pluripotent stem cells functions as an Xi-reprogramming determinant. We further show that developmental-pathway over-activations with suboptimal up-regulation of relevant meiotic genes impede in vitro meiotic progression. Cy in vitro oogenesis exhibits critical homology with the human system, including with respect to bottlenecks, providing a salient model for advancing human in vitro oogenesis.

  Study JGAS000573

• Cambridge Neoadjuvant Cancer of the Prostate (CANCAP03): A Window Study into the Effects of Olaparib ± Degarelix in Primary Prostate Cancer.

  Study: Cambridge Neoadjuvant Cancer of the Prostate (CANCAP03): A Window Study into the Effects of Olaparib ± Degarelix in Primary Prostate Cancer. EudraCT Number: 2014-004417-86 Clinicaltrials.gov Number: NCT02324998 Purpose: Investigate combined PARP and androgen inhibition in primary prostate cancer. Aim: To understand the biological mechanism(s) underlying clinical efficacy, especially in the absence of mutations in homologous recombination (HR) repair pathways. Dataset: Single-nuclear RNA sequencing data from post-treatment radical prostatectomy tissue cores for six patients, 3 from each of olaparib and olaparib and degarelix cohorts. Samples were processed for nuclear isolation and extraction, prior to single-nuclear RNA sequencing. 10x libraries were constructed using the 10x supplied protocol, briefly: individual nuclei were trapped into droplets with a single bead, and poly A transcripts were barcoded during reverse transcription. Complementary DNA was amplified, and libraries were prepared for sequencing on NovaSeq 6000 using S4 flow cell (100k reads per cell). FASTQ files were processed using CellRanger pipeline (10X Genomics). Outputs from the CellRanger pipeline were analysed using the Seurat package (v4.9.9.9049) in R (v4.2.0). Processed data is provided as a Seurat object.

  Study EGAS50000000880

• Global Anaplastic Thyroid Cancer Initiative

  Thyroid cancer is the most common endocrine malignancy. Most thyroid cancers are of the well-differentiated (non-aggressive) phenotype, and are almost always cured with standard treatments. In contrast, anaplastic thyroid cancer (ATC) is rare, accounting for only 1% of thyroid cancers, however it is perhaps the most lethal human malignancy with an average survival of 3 to 6 months. ATC presents with dramatic and rapid onset of airway and esophageal blockage with frequent spread to the lungs. Interestingly, 21–79% of ATCs have coexisting areas or a previous history of well-differentiated cancers. Although this suggests a progression from well-differentiated cancers to ATC, to date there is little molecular conformation that such a progression exists versus de novo generation of ATC. As ATC is extremely rare and most cases are inoperable, there are a paucity of tissue samples for study at any one center. The Global Anaplastic Thyroid Cancer Initiative (GATCI) aims to unite international institutions in order to pool samples (ATC with or without a paired well-differentiated component) for a comprehensive analysis of the genomic landscape of this disease.

  Study EGAS00001002234

• Distinct portrayal of lesions in synchronous multifocal lung adenocarcinoma revealed by genome sequencing

  Distinguishing multiple primary lung cancers in the synchronous multifocal intrapulmonary lesions has important significance on clinical staging and therapeutic decision. To investigate genomic aberration profiles, we applied whole genome and whole exome sequencing, and microarray-based comparative genomic hybridization on 15 intrapulmonary tumors derived from six patients with synchronous multifocal lung cancers having similar histological diagnosis. Any pair of intrapulmonary tumors in a single patient, which shared the identical genetic background and environment, showed an extinctive heterogeneity between each other. Phylogenetic relationship analysis indicated an independently branched evolution among all the tumors, suggesting they were multiple primary lung cancers. EGFR or KRAS mutations were found in 7 or 3 out of the 15 tumors, from 3 or 2 patients, respectively. Somatic mutational heterogeneity of these two genes in a single patient was also observed. Our analysis indicates genomic aberration profiling is valuable for identification of multiple primary lung cancer, especially when high histopathological concordance was observed between lesions. We also suggest a thoroughly molecular diagnosis against therapeutic target genes should be taken for each accessible nodule before making a plan for adjuvant therapy.

  Study EGAS00001001572

• Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors

  Cell-free tumour-derived DNA (ctDNA) allows non-invasive monitoring of various cancers but its utility in renal cell cancer (RCC) has not been well established. A combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n=90) with various renal tumour subtypes, were used to determine ctDNA content in plasma and urine. Our data revealed lower plasma ctDNA levels in RCC relative to other cancers, with untargeted detection of ~33% for both cohorts. A highly sensitive personalised approach, applied to plasma and urine from select patients (n=22), improved detection to ~50%, including in patients with early stage and even benign lesions. A machine-learning based model, applied to untargeted data, predicted this detection, potentially offering a means of triaging patient samples for personalised analysis. We observed that plasma, and for the first time, urine ctDNA may better represent tumour heterogeneity than a single tissue biopsy. Longitudinal sampling of >200 plasma samples revealed that ctDNA can track disease course. These data highlight low ctDNA levels in RCC but indicate potential clinical utility provided improvement in isolation and detection approaches.

  Study EGAS00001003530

• Genomic analysis of Smoothened inhibitor resistance in basal cell carcinoma

  Smoothened inhibitors are currently being investigated for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). The majority of BCC patients treated with vismodegib experience significant clinical benefit, however, a small number of patients develop resistance. Knowledge of resistance mechanisms can generate predictive biomarkers and is critical for the design of additional therapeutic strategies aimed at circumventing resistance. To investigate mechanisms of resistance to vismodegib in BCC we sequenced and profiled biopsies from patients who initially responded to treatment and subsequently progressed on drug.We find that resistance is associated with re-activation of the Hedgehog (Hh) pathway through diverse mechanisms, including concurrent copy number alterations in the downstream Hh pathway components SUFU and GLI2, as well as novel SMO mutations that reduce sensitivity to vismodegib. The latter fall into two classes: those that activate SMO and those that directly affect the vismodegib-binding pocket. Additionally, we observe evidence of clonal selection of SMO mutations and intra-tumor heterogeneity of resistance mechanisms, which implies diverse and combinatorial strategies are required to overcome resistance.

  Study EGAS00001000845

• SINGLE_CELL_ANALYSIS_OF_IN_VITRO_ERYTHROPOIESIS

  We are developing a protocol to differentiate mouse and human induced pluripotent stem (IPS) and embryonic stem (ES) cells towards the haematopoietic pathway to generate erythrocytes in vitro. This system has many applications such as the study of the role of specific genes and human polymorphisms in infectious diseases such as malaria, as well as haematological diseases such as myelodysplastic syndrome. The nature of the in vitro differentiation process means that a heterogeneous population of cells is generated. In order to understand the types of cells produced with our protocol, we have performed a single cell analysis, which has the power to reveal the different populations of cells and their characteristics. For this, a cDNA library has been made that needs to be sequenced to obtain the gene expression profiles of the different cells. With this information we will be able to assess the quality of the differentiation protocol and improve it in order to produce better cells for the downstream applications.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001000764

• Determination_of_cell_specific_regulatory_enhancers_in_hematopoetic_models

  The BLUEPRINT project is a large-scale project investigating epigenetic mechanisms involved in blood formation, in health and disease. The human variation workpackage (WP10) of the project seeks to characterize the effect of common sequence variation on the epigenome status of a cell. To do this, the project will use highly purified blood cells to minimise “experimental noise” and therefore enhance the power to discover modest effects. Two peripheral blood cell types, the CD14+CD16- monocyte (an important central orchestrator of adaptive immunity and a bridge between innate and adaptive immunity) and the CD65+CD9- neutrophilic granulocyte (the frontline cell for innate immunity) have been selected for this purpose. The two types of cells will be obtained at high purity from adult blood (AB) of 200 healthy males and females, respectively. Cells will be purified by using already validated and fully operational protocols that are based on density gradient centrifugation of the buffy coat obtained from whole blood, followed by magnetic bead-based purification using monoclonal antibodies against Cluster of Differentiation (CD) lineage-specific cell surface markers. This data set contains functional genomics data for gene expression and chromatin state.

  Study EGAS00001000586

• Whole Mitochondrial Sequencing of Gingivo-buccal Cancer: ICGC-India Project

  As a part of the ICGC, India has undertaken genomic studies on gingivobuccal cancer of the oral cavity, which is the most prevalent form of cancer among men in India. There are various known environmental (life-style) correlates of this cancer, the most important of which are tobacco chewing and HPV infection. Detailed clinical characterization of the patients, collection of data on demographic and environmental exposures, and isolation of DNA samples from blood and tumor tissues collected from each patient are being done at the Advanced Centre for Research, Treatment and Education on Cancer, Mumbai. Whole genome and other sequencing experiments are being performed at the National Institute of Biomedical Genomics, Kalyani. Whole mitochondria sequencing of 89 patients was performed in this study. The mean depth of sequencing was at least 2500X, but variable across platforms, 2689X and 9894X for amplicon sequencing in Ion Torrent PGM (Tumor-blood pairs=16) and Illumina HiSeq 2500 (Tumor-blood pairs =48), respectively; and, 14,190X for whole genome sequencing in Illumina HiSeq 2500 (Tumor-blood pairs =25). Associations of mutation data with important clinical aspects have been found.

  Study EGAS00001002425

• SHANK2 mutations associated with Autism Spectrum Disorder cause hyperconnectivity of human neurons

  Heterozygous loss-of-function mutations in the synaptic scaffolding gene SHANK2 are strongly associated with autism spectrum disorder (ASD). To investigate their effect on synaptic connectivity, we generated cortical neurons from induced pluripotent stem cells (iPSC) derived from neurotypic and ASD-affected donors. We developed Sparse coculture for Connectivity (SparCon) assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed striking increases in dendrite length, dendrite complexity, total synapse number, and frequency of spontaneous excitatory postsynaptic currents. These findings were phenocopied in gene-edited homozygous SHANK2 knockout cells and rescued by gene correction of an ASD SHANK2 muation, supporting a role for SHANK2 as a regulator of connectivity in developing human neurons. Dendrite length increases were exacerbated by IGF1, TG003, or BDNF, and suppressed by DHPG treatment. The transcriptome in these isogenic SHANK2 neurons was deeply perturbed in synapse, plasticity, and neuronal morphogenesis gene sets and ASD gene modules, and activity-dependent dendrite extension was impaired. Our unexpected findings provide evidence for hyperconnectivity and profoundly altered transcriptome in SHANK2 neurons derived from ASD subjects.

  Study EGAS00001003436

• Identification of 19 novel loci reveals gene regulatory mechanisms determining susceptibility to testicular germ cell tumour

  Testicular germ cell tumour (TGCT) is the most common cancer in young men1,2, and is characterised by strong inherited genetic risk factors3. Here we have undertaken large-scale genome wide association study (GWAS) for TGCT, encompassing ~7,500 cases and ~23,000 controls, through the Oncoarray consortium. We identified 19 novel loci, approximately doubling the number of known TGCT risk loci to 44 (P<5x10-8)4-14 and conduct deep, high-throughput functional annotation of all risk loci. We establish a network of physical interactions for all risk SNPs to candidate casual genes in 3D space, using high-throughput chromosome conformation capture techniques (HiC) in TGCT cells. Firstly, functional evidence reveals widespread disruption of developmental transcriptional regulators, consistent with failed primordial germ cell differentiation as an initiating step in TGCT oncogenesis15. We secondly observe multiple risk loci associated with defective microtubule assembly, compatible with the high level of aneuploidy observed in TGCTs, suggesting gross chromosomal instability. Finally KIT-MAPK signalling features as a recurrently dysregulated pathway. In summary our findings substantially increase the number of known TGCT risk alleles, and provides a functional basis for disease susceptibility.

  Study EGAS00001001836

• Familial psychosis associated with a missense mutation at MACF1 gene combined with the rare duplications DUP3p26.3 and DUP16p23.3, affecting the CNTN6 and CDH13 genes

  Psychosis is a highly heritable and heterogeneous psychiatric condition. Its genetic architecture is thought to be the result of the joint effect of common and rare variants. Families with high prevalence are an interesting approach to shed light on the rare variant's contribution without the need of collecting large cohorts. To unravel the genomic architecture of a family enriched for psychosis, with four affected individuals, we applied a system genomic approach based on karyotyping, genotyping by whole-exome sequencing to search for rare single nucleotide polymorphisms (SNPs) and SNP array to search for copy-number variants (CNVs). We identified a rare non-synonymous variant, g.39914279 C>G, in the MACF1 gene, segregating with psychosis. Rare variants in the MACF1 gene have been previously detected in SCZ patients. Besides, two rare CNVs, DUP3p26.3 and DUP16p23.3, were also identified in the family affecting relevant genes (CNTN6 and CDH13, respectively). We hypothesize that the co-segregation of these duplications with the rare variant g.39914279 C>G of MACF1 gene precipitated with schizophrenia and schizoaffective disorder.

  Study EGAS00001004791

• Profiling_the_Microbiome_of_Early_Life_Gut_Samples

  The human gut microbiome (GM), defined as the microorganisms that reside in the human gastrointestinal tract, has been identified as critical for normal intestinal development and physiology. However, to-date, the majority of studies characterizing the gut microbiome has relied on stool samples, thereby limiting insights into the regionality of the gut and how its microbiota differs along its length. As a result, this project seeks to profile the adjacent microbiota of various regions along the intestinal tract from pediatric intestinal tissue and their associated mucosal washes, enabling insights into tissue-specific microbiomes. Due to the expected low microbial biomass of these samples, donor stool (when available) will also be metagenomically profiled as positive controls, which will enable us to benchmark our low-biomass processing methods with existing protocols. By sampling pediatric patients of diverse ages and health statuses, this metagenomic data will also be valuable for understanding the gut microbiome of the developing human gut across time and space. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001008081

• ARAF Mutations Confer Resistance to RAF Dimer Inhibitor Belvarafenib in NRAS- and BRAF- Mutant Melanoma

  Belvarafenib, a potent and selective RAF dimer (type II) inhibitor, exhibits clinical activity in BRAFV600E- and NRAS-mutant melanoma patients. Here, we report the first-in-human phase I study investigating maximum tolerated dose, assessing safety and preliminary efficacy of belvarafenib in BRAF- and RAS-mutated advanced solid tumors (NCT02405065, NCT03118817). Through generation of belvarafenib resistant NRAS- mutant melanoma cells and analysis of circulating tumor DNA from patients treated with belvarafenib, we identified novel recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and kinase activity- dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Taken together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.

  Study EGAS00001005086

• Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer

  Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and methylation status. We identified five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reasoned that their strong selection should prioritise them as key biomarkers for targeted therapies. We used primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number was associated with in-vitro and clinical response to paclitaxel and in-vitro response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context of MYC-amplified HGSOC was statistically associated with increased prevalence of SCNAs in genes from the PI3K pathway. Co-occurrence of amplifications in MYC and genes from the PI3K pathway was independently observed in squamous lung cancer and triple negative breast cancer. These results suggest that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine.

  Study EGAS00001006200

• Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling (hipo_021)

  Parathyroid carcinoma (PC) is an orphan malignancy with a high risk of recurrence after surgery. Tumor-directed systemic treatments for PC are not established. We used whole-genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (i) immune checkpoint inhibition with pembrolizumab based on high tumor mutational burden and a single-base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) overactivation; (ii) multi-receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 and RET and, later in the course of disease, PARP inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome-wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra-rare cancers based on insight into disease biology.

  Study EGAS00001006747

• Transcriptional profiling and clonality analysis of small intestinal and bone marrow plasma cells

  This study contains single-cell RNA sequencing data (gene expression, VDJ and feature barcodes) for paired samples of small intestinal plasma cells and bone marrow plasma cells isolated from four patients with celiac disease. The mucosa lining the gastrointestinal tract harbors the body’s largest population of plasma cells, most of which produce dimeric IgA destined for release into the lumen. In addition, there is systemic production of monomeric IgA circulating in the blood. Little is known about the connection between systemic and mucosal IgA. To address this relationship and to explore antibody responses against the microbiota, we isolated bacteria from duodenal biopsies and assessed antibody reactivity. Systemic IgA showed reactivity to bacteria of the upper gastrointestinal tract with a preference for binding Neisseria species, while duodenal IgA showed broader reactivity. Single-cell RNA sequencing of gut and bone marrow plasma cells demonstrated limited clonal overlap between the two compartments. Yet, a few shared clones specific to bacterial antigens were identified. Overall, gut and bone marrow plasma cells have distinct V(D)J repertoires and IgA subclass distributions, and they likely depend on B-cell activation at discrete anatomical sites.

  Study EGAS50000001912

• CM067 WES - Clinical Outcomes by Tumor Mutational Burden and Inflammatory Gene Expression With Combined Nivolumab and Ipilimumab or Monotherapy in Advanced Melanoma

  Purpose Exploratory analyses of CheckMate 066 and 067 trials were conducted to investigate associations of tumor mutational burden (TMB), a 4-gene inflammatory gene expression signature, and BRAF mutation status with tumor response, progression-free survival (PFS), and overall survival (OS) in patients with advanced melanoma. Patients and Methods Patients with known programmed death ligand 1 (PD-L1) expression and BRAF mutation status received nivolumab (NIVO) or dacarbazine in CheckMate 066 and either NIVO, ipilimumab (IPI), or NIVO+IPI in CheckMate 067. Whole exome sequencing and RNA sequencing were used to determine TMB and inflammatory gene expression signature scores, respectively. These biomarkers were evaluated in terms of their association with PFS and OS. Results In the NIVO, NIVO+IPI, and IPI arms of CheckMate 067, longer survival was associated with high (> median) versus low (≤ median) TMB with hazard ratios (HRs) (95% confidence interval [CI]) for PFS of 0.45 (0.30–0.65), 0.55 (0.38–0.81), and 0.60 (0.43–0.82), and for OS of 0.46 (0.30–0.71), 0.53 (0.34–0.82), and 0.52 (0.36–0.74), respectively. For NIVO-treated patients, these results were confirmed in CheckMate 066. A survival benefit was observed with high TMB and absence of BRAF mutation. Survival was associated with high versus low inflammatory signature scores with HRs (95% CI) for PFS of 0.56 (0.34–0.94), 0.40 (0.23–0.72), and 0.43 (0.27–0.70), and for OS of 0.37 (0.20–0.66), 0.38 (0.19–0.74), and 0.46 (0.27–0.79), in the NIVO, NIVO+IPI, and IPI arms, respectively. Weak correlations were observed between PD-L1, TMB, and the inflammatory signature. Conclusions Combined assessment of TMB, inflammatory gene expression signature, and BRAF mutation status may be predictive for response to immunotherapy in advanced melanoma.

  Dataset EGAD00001007573

• NHLBI TOPMed: Outcome Modifying Genes in Sickle Cell Disease (OMG)

  Sickle cell disease (SCD) is caused by homozygosity for a single mutation of the beta hemoglobin gene. Despite the constancy of this genetic abnormality, the clinical course of patients with SCD is remarkably variable. SCD can affect the function and cause the failure of multiple organ systems through the pathophysiologic processes of vaso-occlusion and hemolysis. These pathophysiological processes are complex and expected to impact multiple organ systems in a variety of ways. This study, therefore, was designed to identify genetic factors that predispose SCD patients to develop specific end-organ complications and to experience more or less severe clinical courses. We enrolled > 700 patients with Hb SS, Hb S-beta0 thalassemia and HbSC being followed primarily at three southeastern U.S. regional institutions (Duke University Medical Center, University of North Carolina Medical Center, and Emory University Medical Center). Medical information obtained included the presence or absence of specific targeted outcomes (overall disease severity as well as specific types of end organ damage). Clinical data include medical status (history, physical, examination, and laboratory results) and information regarding potentially confounding environmental factors. Limited plasma samples are available for correlative studies (e.g. of cytokine levels, coagulation activation). Targeted SNP for candidate gene analysis as well as GWAS has been performed on most samples. Whole genome sequencing has been conducted through the TOPMed Consortium. The subjects in this analysis were collected as part of a larger study, "Outcome Modifying Genes in Sickle Cell Disease" (OMG-SCD) aimed at identifying genetic modifiers for sickle cell disease. More information about the study can be found in Elmariah et al. (2014), PMID: 24478166. Clinical and genetic data have been used to identify genetic characteristics predisposing patients with SCD to a more or less severe overall clinical course as well as to individual organ-specific complications. It is anticipated that identification of such genetic factors will reveal new therapeutic targets individualized to specific complications of SCD, leading to improved outcomes and increased life expectancy for patients with SCD.

  Study phs001608

• Genetics and Functional Studies of Autosomal Recessive Neurological Disorders

  Neurological conditions account for over 6% of the global disease burden. There are more than 600 neurological disorders, and cognitive dysfunction, also referred to as intellectual disability (ID), occupies a prominent position in this list. Cognitive dysfunction arises from the failure of neuronal cells to organize into a complex network and remodel this network in response to learning and experience. It is manifested by deficits in adaptive behaviors in everyday social and practical skills. Due to its high prevalence and the lifetime cost of care per individual, in the range of $1-2 million in United Sates (CDC), it presents a significant health burden. Genetic and functional studies of the genes and protein determinants of ID have helped to elucidate the molecular pathways of human brain development in health and disease. However, the identity of a large number of essential molecular and cellular components still remain elusive. The objectives of our study are to expand the genetic repertoire of causal ID genes and characterize their role in neuronal structure and cognitive function. The rationale is that identification and functional elucidation of causative gene variants that lead to cognitive dysfunction will be essential for understanding brain function and for developing improved diagnostic tools and efficacious preventive and therapeutic agents for neurological disorders, including ID. There are 3 aims of our comprehensive research program: 1) Ascertain and clinically phenotype members of extended families segregating autosomal recessive intellectual disability (ARID); 2) identify new ARID genes and gene products; and 3) determine the functions of prioritized novel ARID genes using multifaceted approaches, including analysis of spatiotemporal expression patterns in mouse brain, targeting in cultured rat hippocampal neurons, effects on cell morphology and synapse abundance, synaptic transmission and plasticity in neuronal cells by electrophysiology and live-cell imaging assays. The project will advantageously combine human clinical assessment, genetic and functional analyses relevant to brain development and function. Impact: Execution of the proposed studies will generate new knowledge that is clinically relevant, with high potential to impact ID molecular diagnosis, prognoses, and identify novel therapeutic targets to slow progression, delay onset, and possibly devising precision medicine approaches for ID.

  Study phs003298

• Gabriella Miller Kids First (GMKF) Pediatric Research Program in Susceptibility to Ewing Sarcoma Based on Germline Risk and Familial History of Cancer

  Ewing sarcoma (EWS) is a deadly bone cancer that occurs in children and adolescents. Mounting evidence suggests that a genetic predisposition exists for this pediatric cancer, although the specific genetic contribution has yet to be identified. EWS has never been linked to a specific cancer predisposition syndrome, although several case reports have been published that describe siblings and cousins with EWS. Furthermore, neuroectodermal tumors appear to occur more commonly in families with EWS. The two consistent epidemiology findings in EWS include a very strong Caucasian predilection and increased rates of hernia in EWS patients and their family members. Finally, the role of genetic microsatellite repeats in EWS tumorigenesis has been recently described, and these GGAA microsatellites are polymorphic in repeat size and location across the genome. The study goals of this Kids First project include (1) To identify cancer predisposition genes in EWS trios increasing disease risk, (2) To identify genome-wide GGAA microsatellite repeats in EWS trios increasing disease risk, and (3) To identity de novo mutation and structural variant rates in EWS trios reflecting underlying DNA repair defects that increase disease risk. As part of the Kids First Common Fund initiative, this study proposal will further elucidate the genetic contribution to pediatric cancer development. Around 375 of these trios were selected for whole genome sequencing as part of the Gabriella Miller Kids First fund. The EWS trios have been collected as part of the Children's Oncology Group's AEPI10N5 Study ("Genetic Epidemiology of Ewing Sarcoma"), and each trio has associated phenotypic data including a detailed family history. We will interrogate the sequence data using our genomic analysis pipeline at the University of Utah and the Utah Science Technology and Research initiative's (USTAR) Center for Genetic Discovery. We will look for the genetic contribution to EWS and the sequence data with be shared in a repository designated by the Kids First Common Fund. The WGS of these ~375 EWS trios will help us to understand the genetic origins of a deadly childhood cancer and may lead to novel strategies for prevention and treatment.

  Study phs001228

• Identification of Modifiers of 22q11.2 Deletion Syndrome in Whole Genome Sequence - CIDR

  This project aims to identify genetic modifiers of congenital heart disease (CHD), which occurs among 22q11.2 deletion syndrome (22q11.2DS; also known as DiGeorge syndrome/velo-cardio-facial syndrome) patients. In contrast to the prevalence of ~0.8% in the general population, about 60%-70% of 22q11.2DS patients have CHD, of which most are conotruncal heart defects, making 22q11.2DS a very ideal model to study the genetic underpins of CHD. The chromosome 22q11.2 region is susceptible to meiotic chromosome rearrangements leading to hemizygous deletions, because there are large blocks of low copy repeats, termed LCR22s, that are dispersed in the region. Non-allelic homologous recombination during meiosis can lead to specific-sized deletions. Approximately 90% have a typical hemizygous 3 million base pair (Mb) deletion between LCR22-A and -D, while some have nested deletions between LCR22-A and B or LCR22-A and C. Our goal is to perform a case-control association study, in which cases have CHD, while controls have normal heart structures, all with 22q11.2DS. All individuals are unrelated and have been collected from collaborators in the US, Canada and Europe. All subjects received a clinical diagnosis of 22q11.2DS and signed informed consent to allow a blood sample to be collected for research. The DNA samples were de-identified in 2 steps to protect their privacy. We then determined deletion type using multiplex ligation-dependent probe amplification (MLPA). This information is provided for the great majority of subjects. We also obtained cardiac phenotype information from echocardiogram reports as well as reported race and ethnicity (Hispanic vs. non-Hispanic information), which is required for the analysis. We will obtain 30X whole-genome sequence data from NIH CIDR. We will first annotate the sequence variants identified to uncover rare ( For genotype data, we will provide the raw fastq data from whole-genome sequencing as well as the called variants file in a VCF file. For phenotype data, we will provide the sample relationship files (ped files), CHD affection status, deletion type, and race.

  Study phs002514

• Epi4K: Gene Discovery in 4,000 Epilepsy Genomes

  The Epi4K project began in 2011 as an international, multi-center study that seeks to identify and characterize the genetic bases of complex epilepsies. The Center without Walls Epi4K project includes three cores and four scientific projects, as well as a steering committee comprised of the primary study investigators and representatives from the National Institute of Neurological Disorders and Stroke (NINDS). The three cores include: (1) The Administrative Core which handles the overall coordination of Epi4K activities; (2) The Sequencing, Biostatistics and Bioinformatics Core which is responsible for generating the next-generation sequence data, inferring the genetic variation in each of the study participants, and performing the primary analyses to identify epilepsy genes; and (3) The Phenotyping and Clinical Informatics Core which verifies and archives all the phenotypic data from each study participant. The proposed number of patients to be sequenced and analyzed in the scientific projects is a minimum of 4,000; thus the Center was named "Epi4K: Gene Discovery in 4,000 Genomes". Project 1 addresses the genetics of rare and severe childhood epilepsies, including epileptic encephalopathies (infantile spasms and Lennox-Gastaut syndrome), and malformations of cortical development (periventricular nodular heterotopia and polymicrogyria). Exome and genome sequence data generated from DNA collected from patients will be screened for mutations (single nucleotide substitutions, small insertion-deletions, and copy number variations) that cause or contribute to the diseases. Project 2 is focused on genetic discovery in multiplex families. This study will use next-generation sequencing to identify genomic variation that influences risk for common subtypes of epilepsy including idiopathic generalized epilepsy and nonlesional focal epilepsy. Project 3 seeks to identify genetic determinants of prognosis in patients with a range of epilepsy disorders. This study will study established epilepsy cohorts with well-characterized data on seizure outcome to look for relationships between genetic variation and pharmacological control of seizures. Project 4 will use next-generation sequencing data (exome and genome) to screen for epilepsy-associated copy number variation across all Epi4K projects using novel computational algorithms.

  Study phs000653

• German early-onset prostate cancer cohort of the Pan-Prostate Cancer Genome (PPCG) project

  Prostate cancer is the most frequent malignant tumor in males and the second most frequent cause of cancer-related death. Currently, in Germany, more than 60,000 prostate cancers are diagnosed every year. Although most of these patients are treated in a curative attempt, more than 10,000 German men die from prostate cancer annually. Owing to the demographic changes of our society, a further doubling of prostate cancer incidences during the next 20 years is expected. Prostate cancer is generally considered a tumor of elderly men. However, a fraction of prostate cancers are diagnosed at the age of 55 years or less. For several reasons, these “early onset prostate cancers” may represent a key entity for the understanding of prostate cancer biology. First, it is likely that early onset prostate cancers represent a distinct molecular subgroup of prostate cancer (PCa), potentially characterized by relatively small numbers of genetic changes, some of which may be particularly strong driver mutations for PCa development. Second, a fraction of prostate cancers in young individuals could represent classical prostate cancers that are detected at a very early stage and might therefore have accumulated molecular changes/mutations occurring that are most instrumental for prostate cancer early detection. Third, PCa with hereditary backgrounds are likely to accumulate in the age group below 55 years. A comparison with other sample sets (e.g. from other ICGC consortia), a systematic genomic analysis of young men with PCa could therefore lead to the detection of mechanisms for hereditary PCa. Fourth, a better understanding of these tumors is particularly relevant as finding optimal treatment regimens is most critical in young cancer patients. We are analyzing the entire genomic DNA sequences of at least 200 PCas (and matched non-tumorous DNA) of young men (≤ 55y), to at least 30 fold coverage, and integrate single-nucleotide variants and genomic structural variations with differential methylation, mRNA and miRNA expression data.Tissues were collected at the University Medical Center Hamburg-Eppendorf. Sequencing was performed at DKFZ and NCT (Heidelberg), EMBL (Heidelberg), and MPIMG (Berlin). Data management and bioinformatic data analyses is being conducted at DKFZ.

  Study EGAS00001003373

• Drug development for pediatric cancers: the importance of patient' s genomic data re-use

  Cancer in children is uncommon and the overall prognosis for most pediatric cancers is good. However, while the combined survival rates have improved over the last decades, certain childhood malignancies, such as high-grade gliomas or metastatic sarcomas, still remain incurable in most patients. New strategies for targeting those devastating diseases are imperative, and patient genomic data can become a key asset in the process [1]. The Pediatric Cancer Genome Project’s datasets At EGA, we store over 500 datasets with sequencing data from pediatric cancer patients. A remarkable case is the datasets belonging to the Pediatric Cancer Genome Project (PCGP) from St. Jude Children’s Research Hospital–Washington University (Table 1 - EGAS list). PCGP is an ambitious effort to identify the mutations that drive childhood cancer and find new cures. Those datasets include 600 patients with complete tumor and normal genomes from 15 different tumor types. PCGP datasets have been an important resource for various studies that pooled genomic data from different public and in-house datasets to perform extensive genomic characterizations and publish comprehensive pan-cancer pediatric studies [2],[3]. Other interesting pediatric cancer datasets are from the Pediatric Brain Tumor Consortium, Sickkids or ICGC PedBrain project. How data reuse impacts drug development for pediatric cancers Recently, in October 2024, Nature Communications published a work led by the University of Michigan where authors used data from EGA (PCGP) check the table below as part of their strategy to pursue the identification of new tumor vulnerabilities susceptible to becoming novel therapeutic targets in diffuse midline glioma. Diffuse midline gliomas (DMG) are treatment-resistant and uniformly fatal pediatric brain tumors. The prognosis of this brainstem tumor is dismal with a median overall survival of 9–12 months from diagnosis. In this study, the authors first developed a lab model of the disease and reanalyzed data from the EGA to identify genes potentially linked to tumor severity. This approach revealed involvement of specific metabolic pathways, suggesting new possibilities for therapeutic intervention. In mice, the study shows that the use of statins can improve survival. For a brief overview of the underlying science, diffuse midline gliomas present intratumor heterogeneity with subpopulations of less-differentiated oligodendrocyte precursors and more differentiated astrocytes. Authors established in vitro models to recapitulate both phenotypes and identify metabolic programs in both subpopulations. To determine the clinical relevance, the authors re-used gene expression data from 76 DMG patients identifying a gene signature predicting decreased overall survival. After extensive metabolic characterization of subpopulations, authors defined strategies to target specific metabolic vulnerabilities. Pre-clinical experiments in mice using OXPHOS inhibitors and statins showed a reduction in tumor burden and increased overall survival [4]. In this scenario, the re-use of high-quality patient’s sequencing data appeared as an advantageous strategy to support the clinical relevance of in-vitro and pre-clinical findings. On the other hand, in rare conditions such as childhood cancer, the availability of public datasets and the possibility of pooling data from different sources can be the only way to obtain impactful results that lead to improvements for patients. References Davidoff, A. M. Pediatric Oncology. Seminars in pediatric surgery 19, 225–233 (2010). Gröbner, S. N. et al. The landscape of genomic alterations across childhood cancers. Nature 555, 321–327 (2018). Venu Thatikonda et al. Comprehensive analysis of mutational signatures reveals distinct patterns and molecular processes across 27 pediatric cancers. Nature Cancer 4, 276–289 (2023). Mbah, N. E. et al. Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma. Nature Communications 15, (2024). Datasets and Studies ID Title Access Policy Year EGAD00001000134 Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma McGill-DKFZ Pediatric Brain Tumour Consortium 2016 EGAS0000100192 Somatic Histone H3 Mutations in Diffuse Intrinsic Pontine Gliomas and Non-Brainstem Paediatric Glioblastomas St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project 2017 EGAS00001000575 Whole genome sequencing and whole exome sequencing of DIPG tumors and matched normal tissue The hospital for sick children ("SickKids") 2016 EGAD00001000792 Exome sequencing reads of paediatric glioblastoma McGill-DKFZ Pediatric Brain Tumour Consortium 2016 EGAD00001002006 Whole genome sequencing of paediatric glioblastoma in the ICGC PedBrain project ICGC PedBrain project 2016

  Blog drug-development-for-pediatric-cancers

• Download Metadata

  Metadata Distribution Welcome to the realm of Metadata Distribution within the EGA ecosystem! Our Metadata REST API empowers you to effortlessly retrieve metadata from the expansive landscape of EGA. By utilising this API, you gain access to publicly available insights across various EGA domains, including studies, samples, experiments, runs, analyses, policies, DACs, and datasets. Furthermore, this API facilitates cross-referencing of objects, enabling you to gather, for example, all the datasets associated with a specific DAC, seamlessly. In addition, we have added the ability to query private data using the metadata API. If you possess the necessary permissions, you can access behind-the-login private data for a specified list of datasets. Metadata Distribution Index Identifiers Dataset Mappings Website Download Metadata API - Private Identifiers At the core of EGA's organisational structure are unique accessions that serve as essential tags for our diverse objects. Here's a quick overview of the accessions and their corresponding object types: EGA Accession ID EGA Object description EGAS EGA Study Accession ID EGAC EGA DAC Accession ID EGAP EGA Policy Accession ID EGAN EGA Sample Accession ID EGAR EGA Run Accession ID EGAX EGA Experiment ID EGAZ EGA Analysis Accession ID EGAD EGA Dataset Accession ID EGAB EGA Submission ID EGAF EGA File Unique Accession ID For further information check our metadata schema documentation. Dataset Mappings For authorised datasets, comprehensive mappings reveal meaningful connections: Sample_file: This file presents information about the linkage between samples and files available in the dataset. Study_experiment_run_sample: This file presents information about the linkage between studies, experiments, runs, and samples within the dataset. Study_analysis_sample: This file presents information about the linkage between studies, analyses, and samples contained within the dataset. Run_sample: This file presents information about the linkage between runs and samples within the dataset. Analysis_sample: This file presents information about the linkage between analyses and samples within the dataset. An empty file indicates the absence of corresponding information. Website Download Our website serves as your gateway to downloading metadata. Simply navigate to the dataset page, and you'll find a blue Metadata button. Once authenticated, you can click this button for authorised datasets. If you lack permissions for a particular dataset, request access by clicking the 'Request Access' button. For authorised datasets, choose your preferred metadata format: CSV, TSV, or JSON. Metadata API - Private Leverage the power of programmatic metadata downloads! Start by authenticating yourself with your credentials to obtain an access token. With this token, programmatically query private information. Queries mirror the structure of the Public Metadata API. However, behind the login, you can delve into specific mapping information (as mentioned above in dataset mappings) alongside object-level exploration. Authentication An active session is required to work with the API. Each time you log in with your credentials a new session is started, which is identified by an access_token. Below an example on how to obtain one using curl: curl https://idp.ega-archive.org/realms/EGA/protocol/openid-connect/token \ -d 'client_id=metadata-api' \ -d 'username=...' \ --data-urlencode 'password=...' \ -d 'grant_type=password' All responses from the API are in JSON format. A successful response should include a new token to be used for the session: {"access_token":"eyJhbGciOiJSUzI1NiIsInR5cCIgOiA...TNw", "expires_in":300, "refresh_expires_in":1800, "refresh_token":"eyJhbGciOiJIUzI1NiIsInR5cCIgOiA...pTX10", "token_type":"Bearer", ... } Save the access_token value and include it in the API call headers. Example query usage Below you can find some example of queries available behing authentication and authorisation. Querying study-experiment-run-sample mappings: curl https://metadata.ega-archive.org/datasets/{datasetID}/mappings/study_experiment_run_sample \ -H 'Authorization: Bearer access_token' Querying run-sample mappings: curl https://metadata.ega-archive.org/datasets/{datasetID}/mappings/run_sample \ -H 'Authorization: Bearer access_token' Querying study-analysis-sample mappings: curl https://metadata.ega-archive.org/datasets/{datasetID}/mappings/study_analysis_sample \ -H 'Authorization: Bearer access_token' Querying analysis-sample mappings: curl https://metadata.ega-archive.org/datasets/{datasetID}/mappings/analysis_sample \ -H 'Authorization: Bearer access_token' Querying sample-file mappings: curl https://metadata.ega-archive.org/datasets/{datasetID}/mappings/sample_file \ -H 'Authorization: Bearer access_token' You can get a different output format by adding one of these options to the curl command: -H 'Accept: text/tsv' -H 'Accept: application/json' -H 'Accept: text/csv' For more detailed information, refer to the Metadata API Specification.

  Documentation access/download/metadata

• UK10K NEURO GURLING

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. This sample set consists of DNA from multiply affected schizophrenia families. The families have been diagnosed using the SADS-L clinical instrument which gives diagnoses at the probable level of the research diagnostic criteria (RDC). In addition all diagnoses are available using DSMIIIR criteria. These criteria are widely accepted as being valid and reliable for the diagnosis of schizophrenia. All families have been collected to ensure that they are uni-lineal for transmission of schizophrenia, i.e. they have only one affected parent with schizophrenia, or a relative of only one transmitting or obligate carrier parent with schizophrenia. Families with bi-lineal transmission of schizophrenia (i.e. with both parents being affected) were not sampled for this study. All families have multiple cases of schizophrenia and related disorders. The families have been selected to ensure there are no cases of bipolar disorder within them and that they do not contain bipolar disorder in any relatives on either side of the family.For further information on this cohort please contact Hugh Gurling (h.gurling@ucl.ac.uk).

  Study EGAS00001000225

• Germline elongator mutations in sonic hedgehog medulloblastoma

  Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHHa subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

  Study EGAS00001004126

• Effects of 2DG, Galactose, or Oligomycin on the epigenome remodeling induce by T cells activation.

  T cell activation is known to require a metabolic shift towards glycolysis, triggered by TCR-engagement . To substantiate the role of glycolysis in transcriptional reprogramming during antigen-driven T cell activation, we utilized a well-established ex-vivo model to recapitulate the process of antigen stimulation without the requirement for additional antigen-presenting cells . We initially explored and validated the conditions for both metabolic and epigenetic reprogramming. Antigen-mediated CD4+ T cells activation initiates context-specific gene-expression programs that drive effector functions and cell fates through changes in the epigenetic landscape . To evaluate global changes in histone modifications, we isolated CD4+ T cells from peripheral blood (PB) of healthy control (HC) human donors and either maintained them in resting conditions or stimulated with anti-CD3/CD28 for 24h. Rapid changes in the CD4+ epigenome and transcriptome were observed within 24h as measured by RNA-sequencing (RNA-seq) and H3K27ac chromatin immunoprecipitation followed by DNA-sequencing (ChIP-seq).To explore the requirement for metabolic reprogramming in regulating transcriptional responses after initial TCR engagement, CD4+ T cells from PB of healthy donors were isolated and activated in either the presence or absence of oligomycin (inhibitor of ATP synthase blocking the production of ATP by OXPHOS), 2-deoxyglucose (2DG; competitively inhibiting production of glucose-6-phosphate from glucose), or replacement of glucose with galactose. Galactose is metabolized through glycolysis, utilizing the Leloir pathway which is energy neutral, forcing cells to use all the pyruvate production to sustain the TCA cycle for OXPHOS and ATP synthesis at the expense of lactate production. Employing ChIP-seq and RNA-seq, inhibition of OXPHOS-mediated ATP production by oligomycin had only a limited effect on H3K27-acetylation or activation-induced transcription during the first 24h of activation. In contrast, inhibition of glycolysis by 2DG treatment compromised both H3K27-acetylation and transcriptional changes. However, under conditions of galactose-metabolism where lactate production is abrogated, activated CD4+ T cells were still able to globally remodel H3K27 acetylation and reprogram the transcriptome.

  Study EGAS00001007115

• Mapping the epigenomic landscape of human monocytes following innate immune activation reveals context-specific mechanisms driving endotoxin tolerance

  Background Monocytes are key mediators of innate immunity to infection, undergoing profound and dynamic changes in epigenetic state and immune function which are broadly protective but may be dysregulated in disease. Here, we aimed to advance understanding of epigenetic regulation following innate immune activation, acutely and in endotoxin tolerant states. Methods We exposed human primary monocytes from healthy donors (n=6) to interferon-γ or differing combinations of endotoxin (lipopolysaccharide), including acute response (2hr) and two models of endotoxin tolerance: repeated stimulations (6+6hr) and prolonged exposure to endotoxin (24hr). Another subset of monocytes was left untreated (naïve). We identified context-specific regulatory elements based on epigenetic signatures for chromatin accessibility (ATAC-seq) and regulatory non-coding RNAs from total RNA sequencing. Results We present an atlas of differential gene expression for endotoxin and interferon response, identifying widespread context specific changes. Across assayed states, only 24-29% of genes showing differential exon usage are also differential at the gene level. Overall, 19.9% (6884 of 34616) of repeatedly observed ATAC peaks were differential in at least one condition, the majority upregulated on stimulation and located in distal regions (64.1% vs 45.9% of non-differential peaks) within which sequences were less conserved than non-differential peaks. We identified enhancer-derived RNA signatures specific to different monocyte states that correlated with chromatin accessibility changes. The endotoxin tolerance models showed distinct chromatin accessibility and transcriptomic signatures, with integrated analysis identifying genes and pathways involved in the inflammatory response, detoxification, metabolism and wound healing. We leveraged eQTL mapping for the same monocyte activation states to link potential enhancers with specific genes, identifying 1,946 unique differential ATAC peaks with 1,340 expression associated genes. We further use this to inform understanding of reported GWAS, for example involving FCHO1 and coronary artery disease. Conclusion This study reports context-specific regulatory elements based on transcriptomic profiling and epigenetic signatures for enhancer-derived RNAs and chromatin accessibility in immune tolerant monocyte states, and demonstrates the informativeness of linking such elements and eQTL to inform future mechanistic studies aimed at defining therapeutic targets of immunosuppression and diseases.

  Study EGAS00001007362

• CRU-Ukrainian National Research Center for Radiation Medicine Trio Study

  Data on transgenerational effects following nuclear accidents are important for understanding fully the consequences of parental exposure to ionizing radiation. Few studies to date have had adequate statistical power to detect effects of the magnitude expected based on animal data, and most have not been of low-dose, protracted exposures associated with nuclear accidents and their aftermath. Although, to date, scant use has been made of the new genomic technologies, in Chernobyl-exposed areas of Ukraine and Belarus, excess minisatellite mutations have been seen in children born after the accident. We propose a study of parent-child trios in which at least one parent was exposed to Chernobyl radiation as a clean-up worker (mean dose>=100 mGy) and/or evacuee from a contaminated area (mean >=50 mGy). The specific aims are to investigate the transgenerational and de novo mutation rates of the spectrum of genetic variants in trios, in particular looking at effects in children and mapping them to possible parental origin of the chromsoome. Together with long-term collaborators at the Research Center for Radiation Medicine (RCRM) in Kiev, epidemiologic data will be collected for up to 450 trios of parents with preconceptional doses and their unexposed offspring. We will use state-of-the-art genomic technologies to characterize the landscape of the genomes of the trios to determine whether parental radiation exposure is associated with genetic mutations transmitted to the offspring, by examining de novo mutation rates, minisatellite mutations, copy number alterations, and variations in telomere length. The analysis will be conducted in peripheral blood and/or buccal samples (when blood is not available) from complete father-mother-child trios. Doses to the gonads from the time of the accident to the time of conception will be reconstructed for all parents using existing records supplemented by interview data. Trio subjects will be selected from representative populations exposed to radiation from Chernobyl who are under active follow-up in the Clinico-Epidemiologic Registry at RCRM. To help identify specific effects of paternal and maternal radiation exposure, we will initially select sets of trio subjects in five categories: (1) exposed father, unexposed mother; (2) unexposed father, exposed mother; (3) both parents exposed; (4) both parents unexposed; and (5) a group of high dose "emergency workers" with acute radiation syndrome. All trio members will be invited to the RCRM outpatient clinic for collection of a 20 ml blood sample (or buccal cells for those who refuse phlebotomy). Both parents will be asked to complete a general questionnaire to obtain demographic and lifestyle data. Then one or both will complete detailed dosimetry questionnaires, based on forms used in previous collaborations with RCRM and administered by specially trained interviewers. Once 50 trios have been recruited (10 from each of the 5 exposure categories), we will conduct an interim evaluation of participation rates, sample collection and quality, and dose reconstruction in order to modify the protocol as needed. The analytical approach will be to correlate the extent, especially for de novo events of genetic alterations in the offspring with parental pre-conceptional radiation dose overall and by parental origin. The statistical power in relation to de novo mutations is very high, in excess of 90%, but somewhat lower for trends in minisatellite mutations. Study findings will contribute importantly to knowledge of the heritable effects of moderate- and low-dose radiation exposure in humans and to radiation risk projection. Eventually data from the Trio Study may be shared with the international community through dbGap.

  Study phs001163

• A Genome-Wide Association Comparative Analysis of Response of AF Patients to Rate Control Therapy; A Collaboration between the NIH Pharmacogenomics Research Network and the RIKEN Yokohama Institute Center for Genomic Medicine

  The goal of this study was to identify genetic predictors of response to rate control therapy in patients with AF. We conducted a genome-wide association study (GWAS) focusing on subjects with a history of atrial fibrillation. Rate control therapy for AF uses a range of drugs (beta-adrenergic receptor blockers, calcium channel blockers, and digitalis) to depress conduction through the AV node, thereby preventing rapid rates and minimizing symptoms. In large groups of patients, such as the Vanderbilt AF Registry (a clinical and genetic repository with over 1200 patients with ECG-confirmed AF) from which these study subjects were drawn, approximately 5% display failure of aggressive AV nodal-blocking therapy to control ventricular rate. In these patients, interruption of the AV node by ablation and pacemaker implantation are necessary for adequate rate control. Study cases were individuals who underwent AV node ablation and pacemaker implantation after combined therapy with 3 AV nodal-blocking agents was ineffective in rate control. Controls for this study were individuals who met standardized rate-control efficacy criteria (as described in AFFIRM study, Wyse et al, NEJM 2002; PMID: 12466506) for optimal rate control with 2 or fewer AV nodal-blocking agents. Two additional groups were genotyped by RIKEN: An additional group of patients with AF as well as subjects undergoing cardiac surgery in whom AF did not occur post-operatively. All study participants were recruited and treated/evaluated at Vanderbilt University Medical Center. This study was conducted by the Pharmacogenomics of Arrhythmia Therapy subgroup of the Pharmacogenetics Research Network, a nationwide collaboration of scientists studying the genetic contributions to drug response variability. Genotyping was performed by the RIKEN research institute in Japan using the Illumina 610 Quad Beadchip platform.

  Study phs000439

• CaBagE: a Cas9-Based Background Elimination Strategy for Targeted, Long-Read DNA Sequencing

  While repeat-expansion polymorphisms are known to underlie several developmental and neurological disorders, technological limitations have inhibited the ability to resolve accurate genotypes for these variants. A pertinent example is the (CCCCGG)n repeat expansion in C9orf72 that segregates with up to 40% of familial amyotrophic lateral sclerosis (ALS) cases. There is a clear relationship between this repeat expansion and neurodegeneration. However, widely-used short-read sequencing is ill-suited to characterize the C9orf72 repeat expansion due to polymerase slippage over low complexity sequences and the inherently limited mapping/haplotype resolution of redundant short sequences. Consequently, researchers and physicians must rely on crude variant characterization methods (e.g. Southern blots), which limit direct genotype-phenotype associations and create challenges for the diagnosis of disease in patients with atypical clinical presentation. In contrast, ultra-long (e.g., 10-150kb) sequencing reads generated by Oxford Nanopore Technologies (ONT) enable direct measurement of loci containing complex structures without being subject to amplification or alignment bias. We are therefore developed a molecular and computational framework for targeted sequencing and quantification of pathogenic repeat expansions by combining Cas9 and amplification-free sequence capture methods with Nanopore long-read sequencing technology. First, extracted high molecular weight DNA is bound by Cas9 on either side of a DNA target. Bound Cas9 protects the target DNA from challenge by processive exonucleases. Unprotected (off-target) DNA is degraded with exonucleases and the remaining sample is sequenced using the ONT MinION sequencer. Then, base-called reads are aligned to the target locus and repeat copy number genotypes are estimated using a Gaussian Mixture Model. We applied this molecular and computational framework to 2 ALS patients with C9orf72 repeat expansions with biospecimens available from the NINDS collection from Coriell. Genotype estimates produced with CaBagE were commensurate with genotypes derived from repeat-primed PCR for each individual.

  Study phs002368

• Cardiovascular Health Study (CHS) Cohort: an NHLBI-funded observational study of risk factors for cardiovascular disease in adults 65 years or older

  The Cardiovascular Health Study (CHS) is a prospective study of risk factors for development and progression of CHD and stroke in people aged 65 years and older. The 5,888 study participants were recruited from four U.S. communities and have undergone extensive clinic examinations for evaluation of markers of subclinical cardiovascular disease. The original cohort, enrolled in 1989-90, totaled 5,201 participants. A supplemental cohort of 687 predominantly African-American participants was enrolled in 1992-93. Clinic examinations were performed at study baseline and at annual visits through 1998-1999, and again in 2005-2006. Examination components included medical and personal history, medication inventory, ECG, blood pressure, anthropometry, assessment of physical and cognitive function, and depression screening. Other components done less frequently included phlebotomy, spirometry, echocardiography, carotid ultrasound, cerebral magnetic resonance imaging, measurement of ankle-brachial index and retinal exam. Participants were contacted by telephone annually between exams to collect information about hospitalizations and potential cardiovascular events. Since 1999, participants have been contacted every six months by phone, primarily to identify cardiovascular events and to assess physical and cognitive health. Standard protocols for the identification and adjudication of events were implemented during follow-up. The adjudicated events are myocardial infarction, angina, heart failure (HF), stroke, transient ischemic attack (TIA), claudication and mortality. The Cardiovascular Health Study Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000287 Cardiovascular Health Study (CHS) Cohort: an NHLBI-funded observational study of risk factors for cardiovascular disease in adults 65 years or older. phs000226 STAMPEED: Cardiovascular Health Study (CHS) phs000301 PAGE: CaLiCo: Cardiovascular Health Study (CHS) phs000377 CARe: Candidate Gene Association Resource (CARe) phs000400 GO-ESP: Heart Cohorts Exome Sequencing Project (CHS) phs000667 CHARGE: Cardiovascular Health Study (CHS)

  Study phs000287

• Center for Craniofacial and Dental Genetics (CCDG): Genetics of Orofacial Clefts, Sub-types, and Subclinical Phenotypes - CIDR

  The purpose of this project is to identify the genetic factors contributing to nonsyndromic orofacial clefts (OFCs), common subtypes, and related subclinical phenotypes. The most common subtypes of OFCs are cleft lip alone (CL), cleft lip with cleft palate (CLP), and cleft palate alone (CP). CL and CLP can be unilateral (left or right) or bilateral. Related subclinical phenotypes include occult lip muscle defects, characteristics of craniofacial morphology, and subtle speech abnormalities, which are distributed within families of affected individuals, and may reflect the underlying genetic susceptibility revealing clues about OFC etiology. The multi-ethnic dataset comprises participants recruited from Pennsylvania, Puerto Rico, Colombia, Philippines, Nigeria, and Ghana, and includes individuals with OFCs (cases), their unaffected relatives, and unrelated healthy controls. The specific aims of this project are to perform genome-wide association (GWAS) scans of (1) OFCs, (2) cleft subtypes (CL, CLP, CP, and laterality subtypes), and (3) cleft-associated subclinical phenotypes to identify variants associated with manifestations across the cleft-risk spectrum. Phenotyping for participants involved characterization of the overt clefts in cases, including affected structures (lip, alveolus, hard and soft palates), visible microforms, completeness, and laterality. Individuals with syndromic forms of OFCs were excluded from participation. Subclinical features were collected for all participants, including unaffected relatives and controls. Orbicularis oris (upper lip muscle) defects were assessed by high-resolution ultrasonography and scored by three independent raters. Lip print patterns were assessed by digital photography and scored for paramedical whorls by three independent raters. Velopharyngeal insufficiency was assessed with perceptual screening by a speech-language pathology expert. This dataset has potential to improve knowledge of the genetic contributors to OFCs, subtypes, and associated subclinical phenotypes by facilitating genetic association discovery, meta-analysis, and replication efforts. Findings may ultimately be useful for predicting OFC risk and recurrence, and may enhance our understanding of OFC biology.

  Study phs002815

• A Scalable, GMP-Compatible, Autologous Organotypic Cell Therapy for Dystrophic Epidermolysis Bullosa

  Gene editing in induced pluripotent stem (iPS) cells has been hailed for enabling new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa (DEB). However, manufacturing, efficacy, and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies. Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), is a new generation, Good Manufacturing Practice-compatible (cGMP), reproducible, and scalable platform to produce autologous clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts to treat incurable wounds of patients lacking type VII collagen (C7). DEBCT uses a single step, combined, high-efficiency reprogramming, and CRISPR-based genetic correction to generate genome scar-free, COL7A1 corrected clonal iPS cells from primary patient fibroblasts. Validated iPS cells are converted into epidermal, dermal, and melanocyte progenitors with a novel 2D organoid differentiation protocol, followed by CD49f enrichment and expansion to minimize maturation heterogeneity. iSC product characterization by single cell transcriptomics was followed by mouse xenografting for disease correcting activity at 1 month and toxicology analysis at 1-6 months. Culture-acquired mutations, potential CRISPR-off target effects, and cancer-driver variants were evaluated by targeted and whole genome sequencing. iPS cell-derived iSC grafts were reproducibly generated from four recessive DEB patients with different pathogenic mutations. Organotypic iSC grafts onto immune-compromised mice developed into stable stratified skin with functional C7 restoration. Single cell transcriptomic characterization of iSCs revealed prominent holoclone stem cell signatures in keratinocytes and the recently described Gibbin-dependent signature in dermal fibroblasts. The latter correlated with enhanced graftability. Multiple orthogonal sequencing and subsequent computational approaches identified random and non-oncogenic mutations introduced by the manufacturing process. Toxicology revealed no detectable tumors after 3-6 months in DEBCT-treated mice. In conclusion, DEBCT successfully overcomes previous roadblocks and establishes a robust, scalable, and safe cGMP manufacturing platform for the production of a CRISPR-corrected autologous organotypic skin graft to heal DEB patient wounds.

  Study phs003271

• Direct Transposition of Native DNA for Sensitive Multimodal Single-Molecule Sequencing

  STUDY GOALS: This study focuses on elucidating the epigenetic modulators of prostate cancer progression and metastasis at high resolution. This is achieved by applying a novel, high-sensitivity single molecule sequencing assay that measures chromatin state on single DNA molecules (SMRT-Tag) to matched primary and metastatic tumor samples from the same patient. Samples are obtained from patient derived xenograft (PDX) models. STUDY DESIGN: Individuals diagnosed with primary and metastatic prostate cancer in the course of routine care were consented and enrolled, and biopsies of primary and/or metastatic lesions performed to obtain sample material used for generating PDX models. Samples collected from these models were processed with a novel strategy developed for highly-sensitive multimodal profiling of single chromatin fibers using the third generation long-read sequencing. The resulting data indicates genetic variants, chromatin organization, and m5dCpG methylation status across the genome. PRINCIPLE FINDINGS: We determined characteristic single-molecule patterns of chromatin organization (spacing of nucleosomes, presence and absence of m5dCpG marks, etc.) that were altered in the transition from primary malignancy to metastasis. Broadly, global chromatin organization was severely disrupted in metastatic samples, resulting in increased accessibility at CTCF motifs, which may be relevant for disease progression. We further identified specific genomic domains including constitutive heterochromatin significantly enriched for irregular or hyper-accessible chromatin. Together, these findings suggest the involvement of ATP-dependent chromatin remodelers in evicting nucleosomes as a facet of metastatic prostate cancer. DATA AVAILABILITY: SAMOSA-Tag, the assay used in this study, is a sequencing assay that uses the third generation long read sequencing, specifically the SMRT sequencing platform from Pacific Biosciences. Demultiplexed raw SMRT sequencing BAM files generated in this study are deposited. Individual raw subread BAM files correspond to replicate sequencing assays performed on either primary or metastatic PDX prostate tumors.

  Study phs003511

• Somatic Mutations and Their Etiological Determinants for Breast Cancer in African American Women (B-CAUSE Study)

  The breast cancer health disparity between women of African ancestry (AA) and European ancestry (EA) remains a major public health challenge in the United States. AA women are afflicted by higher rate of triple-negative breast cancer (TNBC) and bear the highest mortality rate of all populations from the disease. Even within TNBC, some data suggest that AA women have poorer outcomes than EA women. Mounting evidence points to population differences in cancer biology, a fundamental question that remains unsettled. The disparity also manifests in representativeness in tumor sequencing projects, due to the low inclusion of AAs in genomic studies. A recent analysis of The Cancer Genome Atlas (TCGA) data revealed that the number of AA cases sequenced was sufficient only for studying frequently mutated genes (≥10%), and the power was worse for TNBC as a separate disease entity. As a result, the breast tumor mutational landscape elucidated to date is derived mostly from EA cases, and may not necessarily represent AA cancer genomes. Moreover, as discovery potential for new driver genes has come close to a plateau, cancer in AAs derived from distinct genetic and environmental contexts may provide a powerful venue for discovering mutations that are rare in EA cases. This is showcased in recent studies in colon and prostate cancer. Thus, we carried out a collaborative project, B-CAUSE, to characterize the mutational landscape of AA breast cancer genomes by pooling resources from five established studies, including the Women's Circle of Health Study (WCHS), the Black Women's Health Study (BWHS), the Southern Community Cohort Study (SCCS), the Nashville Breast Health Study (NBHS), and the Southern Tri-State Breast Health Study (STSBHS). This effort has created the largest AA-specific breast tumor mutation dataset to date in an efficient manner. The data deposited here are from the whole-exome sequencing (WES) of matched tumor-normal pairs of 462 TNBC in AA women from the B-CAUSE Study.

  Study phs003962

• Everything you need to know about Federated EGA Affiliates: Q&A

  Addressing common questions about Federated EGA (FEGA) Affiliates and providing answers. FEGA Affiliates have recently been defined as the third tier within the newly approved “Federated EGA Structure and Organisation” document, alongside Central EGA (CEGA) and the FEGA Nodes. In this blog post, we aim to answer the questions that may arise on this topic. For more general information about FEGA Affiliates, you can refer to this blog post. Let's now start with the questions and answers! What is the difference between a FEGA Affiliate and a FEGA Node? FEGA Nodes A FEGA Node is a national-level service that accepts submissions and provides archiving and access services within a single country's jurisdiction. Nodes provide end-to-end services for submitters in that jurisdiction, including submission support, processing, permissions management, and distribution. FEGA Affiliates A FEGA Affiliate is not a national submission service. Instead, it archives data from its own legal entity and/or selected partner institutions (for example, consortium partners). Affiliates are designed for organisations and consortia that need to keep data stewardship and access decisions within their own governance model, while still enabling discovery through the broader FEGA ecosystem. What do Affiliates commit to? Here is a practical checklist of the core expectations for a FEGA Affiliate. FEGA Affiliate checklist Discovery and metadata Submit non-personal metadata to CEGA to obtain EGA accessions and enable discovery (with metadata validation handled by the CEGA Helpdesk). Operations and resilience Maintain a data storage system and a defined backup/recovery approach. Ensure operational capacity (personnel and infrastructure) to deliver Affiliate services. Maintain systems and practices that support local data security and align with EGA best-practices. Access and user support Provide data distribution or access (e.g in a trusted research environment) to authorised users to datasets hosted at the Affiliate. Provide permissions management for datasets archived by the Affiliate (the CEGA DAC (Data Access Committee) Portal is always at your disposal to use). Provide a minimal helpdesk with sufficient capacity to support relevant DACs and approved users. Membership term Commit to a minimum membership term of four years. Governance and participation (lightweight by design) Affiliates integrate into the FEGA network operationally, but without the committee obligations associated with Nodes. When is becoming an Affiliate the right fit? Consider the Affiliate tier if: You host (or plan to host) controlled-access datasets that must be managed under your organisation’s or consortium’s governance, you want studies to be discoverable through EGA, but need access control and/or distribution to remain local, and you are not aiming to operate a national submission service tier.. What if a FEGA Node already exists in my jurisdiction? We encourage any potential Affiliate to reach out to their national FEGA Node to explore collaboration at the national level. Why? Federated models within a country already exist in FEGA, where a national Node operates like a Central EGA for their country. FEGA Nodes can also represent the interests of any Affiliates within their jurisdiction at the FEGA Committees. FEGA Nodes have experience and can support you on your FEGA journey. Ready to join as a FEGA Affiliate? We’re excited to open this formally defined pathway for organisations and consortia to participate in the federation. If you think the FEGA Affiliate tier fits your needs, start by assessing: Your scope (organisation/consortium-held data rather than public external submissions), Your ability to provide the core services (permissions, distribution/access, helpdesk, monitoring), and Your readiness to submit non-personal metadata to CEGA for accessioning and discovery. To express interest, please contact us here, and we'll help you understand the onboarding steps and how Affiliates integrate into the FEGA network.

  Blog fega-affiliates-q&a

• Reduced Representation Bisulfite Sequencing (RRBS) in various tissues to discover DNA methylation markers for the diagnosis of breast and ovarian cancer.

  Despite a myriad of attempts in the last three decades to diagnose ovarian cancer (OC) earlier, this clinical aim still remains a significant challenge. In addition, monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant methylation patterns of linked CpGs analyzed in DNA fragments shed by cancers into the bloodstream (i.e. cell-free DNA) can provide highly specific signals indicating cancer presence.In order to discover the most relevant CpG regions, we used RRBS and analysed several tissue samples: 11 prospectively collected invasive epithelial ovarian cancer samples (high grade serous n=8, low grade serous n=1, endometrioid n=1, mucinous n=1, mean age = 54.7 years), 8 prospectively collected invasive ductal breast cancer samples (2/8 triple negative; mean age = 56.6 years), one benign tumor (papillary serous cystadenoma, age = 86 years), 18 non-neoplastic tissue samples (breast n=7 and adnexal n=11, mean age = 60.2 years), two non-neoplastic endometrial tissues (mean age = 68 years) and twenty three white blood cell samples (mean age = 57.8 years) were assessed by RRBS. Genome wide methylation analysis was performed by Reduced Representation Bisulfite Sequencing (RRBS) at GATC Biotech. DNA was digested with MspI followed by size selection of the library, providing enhanced coverage for the CpG-rich regions. The digested DNA was adapter ligated, bisulfite modified and PCR amplified. The libraries were sequenced on Illumina’s HiSeq 2500. Analysis of the first samples sequenced with 100bp paired-end mode showed that the library insert size was small. Therefore, the remaining samples were sequenced with 50 bp paired-end mode. Using Genedata Expressionist® for Genomic Profiling v9.1, we established a bioinformatics pipeline for the detection of cancer specific differentially methylated regions (DMRs). The most promising DMRs were taken forward for the development and validation of serum based clinical assays.

  Study EGAS00001002609

• mRNA capture sequencing and RT-qPCR for the detection of pathognomonic, novel and secondary fusion transcripts in formalin-fixed paraffin-embedded tissue: a sarcoma showcase

  RNA sequencing is widely used to study gene abundance patterns, but less frequently to assess structural alterations such as fusion transcripts. In this study, we assess the performance of messenger RNA (mRNA) capture sequencing to identify fusion transcripts in formalin-fixed paraffin-embedded (FFPE) tissue of different types of sarcoma, followed by orthogonal confirmation using RT-qPCR. To validate our workflow, we used the TruSight RNA Pan-Cancer Panel to analyze a first cohort of 6 positive control tumors for which the diagnostic workup demonstrated the presence of a specific chromosomal rearrangement. Fusion transcript calling by FusionCatcher confirmed all known aberrations and enabled the identification of both fusion gene partners and breakpoints. Next, whole transcriptome TruSeq RNA Exome sequencing was applied to a second cohort of 17 patients, diagnosed with fusion gene-negative alveolar rhabdomyosarcoma (ARMS) or undifferentiated round cell sarcoma (URCS), for whom fluorescence in situ hybridization (FISH) did not identify the classical pathognomonic rearrangements. Remarkably, for 6 out of 17 patients, mRNA capture sequencing readily detected a pathognomonic fusion transcript, i.e. PAX3-FOXO1 in 2 ARMS patients, and EWSR1-FLI1, EWSR1-ERG or EWSR1-NFATC2 in 4 URCS patients. These data show that RNA capture sequencing may enhance the detection rate of pathognomonic fusion genes in sarcoma. For the 11 patients with no known pathognomonic fusion transcript, 11 newly identified fusion transcripts were confirmed by RT-qPCR, including COPS3-TOM1L2, NCOA1-DTNB, WWTR1-LINC01986, PLAA-MOB3B, AP1B1-CHEK2 and BRD4-LEUTX fusion transcripts in ARMS patients. Additionally, recurrently detected secondary fusion transcripts in two patients diagnosed with EWSR1-NFATC2-positive sarcoma were confirmed (COPS4-TBC1D9, PICALM-SYTL2, SMG6-VPS53 and UBE2F-ALS2). Our results provide new insights into the underlying genetic causes of these malignancies.

  Study EGAS00001005202

• Repurposing azacitidine and carboplatin to prime immune checkpoint blockade-resistant melanoma for anti-PD-L1 re-challenge

  Purpose: Drug repurposing offers the opportunity for chemotherapy to be used to re-establish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (Avelumab) in patients with advanced ICB-resistant melanoma. Experimental Design: 20 participants with ICB resistant metastatic melanoma received 2 x 4-week cycles of azacitidine and carboplatin followed by ICB re-challenge with anti-PD-L1 avelumab. The primary objective was overall response rate after priming and ICB re-challenge. Secondary objectives were Clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS). Translational correlation analysis of HLA-A and PD-L1 expression, RNA-seq and reduced representation bisulfite sequencing (RRBS) of biopsies at baseline, after priming and after 6 cycles of avelmuab was performed. Results: The ORR determined after azacitidine and carboplatin priming was 10% (2/20) with 2 partial responses (PR). The ORR determined after priming followed by 6 cycles of avelumab (week 22) was 10%, with 2/20 participants achieving iPR. The CBR for azacitidine and carboplatin priming was 65% (13/20) and after priming followed by 6 cycles of avelumab CBR was 35% (n = 7/20). The median PFS was 18.0 weeks (95% CI: 14.87 – 21.13 weeks) and the median OS was 47.86 weeks (95% CI: 9.67 – 86.06 weeks). Translational correlation analysis confirmed HLA-A generally increased after priming with azacitidine and carboplatin, particularly if it was absent at the start of treatment. Average methylation of CpGs across the HLA-A locus was decreased after priming and T-cells, in particular CD8+, showed the greatest increase in infiltration. Conclusions: Priming with azacitidine and carboplatin can induce disease stabilization and re-sensitisation to ICB for metastatic melanoma.

  Study EGAS00001006419

• Repurposing azacitidine and carboplatin to prime immune checkpoint blockade-resistant melanoma for anti-PD-L1 re-challenge

  Purpose: Drug repurposing offers the opportunity for chemotherapy to be used to re-establish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (Avelumab) in patients with advanced ICB-resistant melanoma. Experimental Design: 20 participants with ICB resistant metastatic melanoma received 2 x 4-week cycles of azacitidine and carboplatin followed by ICB re-challenge with anti-PD-L1 avelumab. The primary objective was overall response rate after priming and ICB re-challenge. Secondary objectives were Clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS). Translational correlation analysis of HLA-A and PD-L1 expression, RNA-seq and reduced representation bisulfite sequencing (RRBS) of biopsies at baseline, after priming and after 6 cycles of avelmuab was performed. Results: The ORR determined after azacitidine and carboplatin priming was 10% (2/20) with 2 partial responses (PR). The ORR determined after priming followed by 6 cycles of avelumab (week 22) was 10%, with 2/20 participants achieving iPR. The CBR for azacitidine and carboplatin priming was 65% (13/20) and after priming followed by 6 cycles of avelumab CBR was 35% (n = 7/20). The median PFS was 18.0 weeks (95% CI: 14.87 – 21.13 weeks) and the median OS was 47.86 weeks (95% CI: 9.67 – 86.06 weeks). Translational correlation analysis confirmed HLA-A generally increased after priming with azacitidine and carboplatin, particularly if it was absent at the start of treatment. Average methylation of CpGs across the HLA-A locus was decreased after priming and T-cells, in particular CD8+, showed the greatest increase in infiltration. Conclusions: Priming with azacitidine and carboplatin can induce disease stabilization and re-sensitisation to ICB for metastatic melanoma.

  Study EGAS00001006420

• Data Access Commitee for the project : Methylome profiling of human mesenchymal chondrosarcoma

  Dac EGAC00001003217

• Data Access Commitee for single-cell analysis of multiple myeloma and precursors

  Dac EGAC00001002920

• Data Access Committee for the Metastatic Breast Cancer Whole-exome sequencing study

  Dac EGAC00001000434

• DAC for Direct Detection of Early-stage Cancers Using Circulating Tumor DNA

  Dac EGAC00001000701

• Data Access Committee for desmoplastic small round cell tumor (DSRCT) RNAseq data.

  Dac EGAC00001000851

• DAC for Oncogenic fate conversion by PRDM16s causes acute myeloid leukemia

  Dac EGAC00001001023

• EMBL genome biology research group for structural variation (Strand-seq application)

  Dac EGAC00001001091

• DAC for Integrated Genomic, Epigenetic, and Expression Analyses of Ovarian Cancer Cell Lines

  Dac EGAC00001001101

• Stanford Data Access Committee for Multi-Region WES of Metastatic Colorectal Cancer

  Dac EGAC00001001164

• DAC for the study of tumor-derived somatic mutation detection in cfDNA

  Dac EGAC00001001569

• Nicola Murray Centre for Ovarian Cancer Research Data Access Committee

  Dac EGAC00001001588

• Cancer Clinical Research Trust DAC for WES of HER2+ metastatic cancer samples

  Dac EGAC00001001632

• Data Access Commitee of the Princess Maxima Center for Pediatric Oncology

  Dac EGAC00001001948

• Data access committee for Gut microbiome of BA patients and normal controls

  Dac EGAC00001002146

• "DAC for RNAseq from regions of insitu and invasive human mammary ductal disease"

  Dac EGAC00001002538

• Chromatin Profiles in PRAD - Englander Institute for Precision Medicine - Weill Cornell Medicine

  Dac EGAC00001002559

• Single cell multi-omics group for somatic structural variation in human blood lineages

  Dac EGAC00001002852

• DAC for Tuebingen-Stuttgart cohort

  Dac EGAC00001000317

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Jackson Heart Study (JHS)

  Study phs002907

• DAC for Clonal driver neoantigen loss under EGFR TKI and immune selection pressures

  Dac EGAC00001003522

• SGMedical Data Acess Committee

  DAC for SG Medical Inc. of South Korea

  Dac EGAC50000000636

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

  Study EGAS00001007008

• A multi-center genome-wide association study for nasopharyngeal carcinoma

  Study EGAS00001006062

• bed_files

  Bed files as whitelist for Tapestri Insights analysis

  Dataset EGAD00010002560

• irish_fineSTRUCTURE

  SNP data for 991 Irish individuals

  Dataset EGAD00010001479

• DNA Methylation data for EGAS00001002592

  Islet_HumanMethylation450K_ThurnerEtAl

  Dataset EGAD00010001695

• EGAD00010000831

  BLUEPRINT EpiMatch: harnessing epigenetics for haematopoietic stem cell transplantation

  Dataset EGAD00010000831

• DAC for patient-derived cell line samples

  Dac EGAC00001000594

• Research Program on Genes, Environment and Health (RPGEH)

  The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) is a resource developed to facilitate research on genetic and environmental factors on common diseases and healthy aging. The RPGEH resource links biospecimens, health surveys, and comprehensive electronic medical records on broadly consented adult members of Kaiser Permanente Medical Care Plan, Northern California Region (KPNC). KPNC is an integrated health care delivery system with a membership of approximately 3.3 million people in northern California. The membership of KPNC is representative of the general population in the 14 county area in which facilities are located, although extremes of income are underrepresented. At the end of 2013, the RPGEH resource included: (1) demographic and behavioral surveys from over 430,000 participants; (2) biospecimens (DNA, serum, plasma, and/or saliva) from over 204,000 participants, including over 13,000 pregnant women; (3) genome-wide genotype data (70 billion SNP genotypes) on over 100,000 participants, including the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort; and (4) the longitudinal electronic medical records of the participants. The RPGEH was developed beginning in 2005 at the Division of Research of Kaiser Permanente Northern California by Catherine Schaefer (Director), Neil Risch (Co-Director), Lisa Croen, Eric Jorgenson, Lawrence Kushi, Charles Quesenberry, Sarah Rowell, Carol Somkin, Stephen Van den Eeden, Larry Walter, and Rachel Whitmer. Funding of the RPGEH was provided to C. Schaefer (PI) and N. Risch (co-PI) by the Wayne and Gladys Valley Foundation, The Ellison Medical Foundation, the Robert Wood Johnson Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Regional Community Benefit Programs. The GERA cohort was funded by a grant from NIH to RPGEH and UCSF (RC2 AG036607; C. Schaefer and N. Risch, PIs). At the time of the award of the RC2 project in late 2009, the RPGEH had established a cohort of about 140,000 individuals who had answered a detailed survey, provided saliva samples for extraction of DNA, and given broad consent for the use of their data in studies of health and disease. Survey and Cohort Recruitment. Initially, the RPGEH developed electronic disease registries to enable identification of phenotypes, using algorithms applied to EMR data. In 2007, the RPGEH mailed a four page survey to 1.9 million adult (≥ 18 years old) members of KPNC who had been members for two years or more, to obtain data on demographic and behavioral factors complementary to the clinical data in the EMR. The survey materials included a cover letter introducing the RPGEH, a two page list of Frequently Asked Questions, and the survey, which included questions on demographic factors such as education, race-ethnicity, income and marital status, dietary factors, physical activity, smoking, and alcohol consumption, as well as reproductive history and reproductive health. Members whose electronic medical records indicated a preference for written communications in Chinese or Spanish received survey materials both in English and a Chinese or Spanish translation. Approximately 400,000 completed surveys were returned. Saliva Sample Collection. Beginning in July 2008, respondents to the survey were asked to sign and return a consent form and authorization for use and disclosure of protected health information. The consent form authorized broad use of biospecimens, survey data, and data from participants' electronic health records for use in studies of genetic and environmental influences on health and disease. Respondents who returned completed consent forms were mailed (Oragene) saliva collection kits; more than 132,000 saliva samples were collected in two years. Completed saliva kits were scanned and archived in a temporary biorepository at the KPNC Division of Research. In late 2009, the RPGEH began collection of saliva samples from the California Men's Health Study (CMHS), a cohort that had been previously assembled in 2002-2003 and had been excluded from the RPGEH survey mailing with the intent of later adding CMHS participants to the assembled RPGEH cohort. The CMHS was developed to facilitate research on prostate cancer and other conditions in older men; the study protocol is described in Enger, et al., 2006. It enrolled and surveyed more than 40,000 men in KPNC, ages 45-69 years, who were members of KPNC during 2002-2003. CMHS men completed two mailed surveys with demographic and behavioral data similar to that of the RPGEH. The data on analogous variables were reconciled and integrated with the data derived from the RPGEH cohort for use in the RPGEH resource. By 2011, RPGEH collected approximately 15,400 saliva samples from men participating in the CMHS. RPGEH Access and Collaborations Website and Procedures. The RPGEH maintains a web portal for inquiries and applications for collaboration and access to data. The url is: https://rpgehportal.kaiser.org/. RPGEH has an application process and an Access Review Committee that reviews applications for collaboration and use. For more information, please contact RPGEH through the website.

  Study phs000788

• A Genome-Wide Association Study of Heroin Dependence

  This collaboration of Australian and American investigators aims to identify genes associated with liability for heroin dependence. The project uses a case-control design in which cases met lifetime DSM-IV criteria for heroin dependence. Controls included assessed individuals who did not meet DSM-IV heroin dependence criteria and unassessed general population controls. Cases and controls were obtained from the several large investigations including: The Comorbidity and Trauma Study, Heroin Dependence in Western Australia, the OZ-ALC Study, a Twin Study of Mole Development in Adolescence, and ongoing genetic studies of substance dependence conducted by investigators at Yale and collaborating institutions. These projects are briefly described below. The Comorbidity and Trauma Study (PI: Elliot Nelson), a retrospective case-control study examining genetic and environmental factors contributing to heroin dependence liability. The study was funded by the National Institute on Drug Abuse (NIDA), and was run in collaboration with Washington University, the Queensland Institute of Medical Research (QIMR), and the National Drug and Alcohol Research Centre (NDARC), University of New South Wales. Case participants were recruited from maintenance clinics in the greater Sydney area. Control participants were recruited from employment centres and community centres, open street malls, and local press servicing the same geographical area as the opioid maintenance treatment clinics and either denied recreational use of opioids or had used these drugs recreationally fewer than 11 times lifetime. The prevalence in these individuals of non-opioid licit drug dependence and illicit drug dependence as well as childhood trauma exposure and other psychiatric disorders is elevated considerably versus estimates of similar measures in Australian general population samples. Participants provided blood samples as a source of DNA and completed a comprehensive psychiatric diagnostic interview based on the Semi-Structured Assessment of the Genetics of Alcoholism - Australia (SSAGA-OZ) augmented with sections drawn from other instruments assessing childhood trauma exposure, family history, and screening for borderline personality disorder. Heroin Dependence in Western Australia (PI: Sybille Schwab) is a study focusing both on genetic contributions to heroin dependence and response to naltrexone treatment of the disorder. Participants completed a clinical assessment and provided blood samples during their treatment at the Perth Naltrexone Clinic now name as the Fresh Start Recovery Programme. Funding for the project was provided by the Australia Government's National Health and Medical Research Council (Grant # 513862; PI: Sybille Schwab) Affected subjects from ongoing genetic studies of substance dependence conducted by investigators at Yale (PI: Joel Gelernter) and collaborating institutions were collected in the course of several NIDA-funded studies. Those included in the current set were assessed by means of the SSADDA (Semi-Structured Assessment for Drug Dependence and Alcoholism). All are opioid dependent European-Americans, and all list heroin as the opioid must used. Most were collected at Yale University School of Medicine or University of CT School of Medicine under the supervision of Drs Joel Gelernter and Henry Kranzler. Control subjects were also collected in the course of several NIDA- and NIAAA-funded studies. Those included in the current set were assessed by means of the SSADDA (Semi-structured Assessment for Drug Dependence and Alcoholism). Most were collected at Yale University School of Medicine or University of Connecticut School of Medicine under the supervision of Drs Joel Gelernter and Henry Kranzler. The OZ-ALC Study (PI: Andrew Heath) consists of a large group of twins and their family members ascertained from the general population Australian Twin Registry who have participated in ongoing research projects. For the control investigation, we have selected individuals who do meet criteria for illicit drug dependence who have had GWAS genotyping with the Illumina Human CNV370-Quad. Inclusion of individuals with alcohol dependence or nicotine dependence was minimized. For a more detailed description of the study, please see: http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000181.v1.p1 The Twin Study of Mole Development in Adolescence (PI: Nick Martin) is an ongoing investigation of melanocytic naevi funded by the Australian Government's National Health and Medical Research Council (Grant # 389891; PI: Nick Martin). For the current project, unassessed parents of these twins will serve as a control group. These individuals will either have been previously genotyped with the Illumina Human 610-Quad BeadChip or will be genotyped as part of the current project. Parents have largely survived the period of risk for heroin dependence and, by virtue of their participation in this research, are very likely to have a prevalence of heroin dependence lower than that in the general population (i.e., <0.7%). In order to understand the immune modulatory effect of opioids across peripheral blood immune populations, a second study (PI: Christine S. Cheng) analyzed single cell RNA-seq profiles from the PBMCs of a subset of case participants and control participants from the Comorbidity and Trauma Study (PI: Elliot Nelson). The study assessed and identified transcriptional changes between opioid dependent and control samples across naive and LPS stimulated immune populations.

  Study phs000277

• National Human Genome Research Institute (NHGRI) GENEVA Genome-Wide Association Study of Venous Thrombosis (GWAS of VTE)

  Overview: Our overall long-term goal is to determine risk factors for the complex (multifactorial) disease, venous thromboembolism (VTE), that will allow physicians to stratify individual patient risk and target VTE prophylaxis to those who would benefit most. In this genome-wide association case-control study (1300 cases and 1300 controls) we hope to identify susceptibility variants for VTE. Mutations within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic, and innate immunity pathways are risk factors for VTE. We hypothesize that other genes within these four pathways or within other pathways also are VTE disease-susceptibility genes. Therefore, we performed a genome wide association (GWA) screen and analysis using the Illumina 660W platform to identify SNPs within 1,300 clinic-based, non-cancer VTE cases primarily from Minnesota and the upper Midwest USA, and 1300 clinic-based, unrelated controls frequency-matched on patient age, gender, myocardial infarction/stroke status and state of residence. This is a subset of a slightly larger candidate gene study using 1500 case-control pairs to identify haplotype-tagging SNPs (ht-SNPs) in a large set of candidate genes (n~750) within the anticoagulant, procoagulant, fibrinolytic, and innate immunity pathways. Study Populations. Cases. VTE cases were consecutive Mayo Clinic outpatients with objectively-diagnosed deep vein thrombosis (DVT) and/or pulmonary embolism (PE) residing in the upper Midwest and referred by Mayo Clinic physician to the Mayo Clinic Special Coagulation Laboratory for clinical diagnostic testing to evaluate for an acquired or inherited thrombophilia, or to the Mayo Clinic Thrombophilia Center. Any person contacted to be a control but discovered to have had a VTE was evaluated for inclusion as a case. Cases were primarily residents from Minnesota, Wisconsin, Iowa, Michigan, Illinois, North or South Dakota, Nebraska, Kansas, Missouri and Indiana. A DVT or PE was categorized as objectively diagnosed when (a) confirmed by venography or pulmonary angiography, or pathology examination of thrombus removed at surgery, or (b) if at least one non-invasive test (compression duplex ultrasonography, lung scan, computed tomography scan, magnetic resonance imaging) was positive. A VTE was defined as: Proximal leg deep vein thrombosis (DVT), which includes the common iliac, internal iliac, external iliac, common femoral, superficial [now termed "femoral"] femoral, deep femoral [sometimes referred to as "profunda" femoral] and/or popliteal veins. (Note: greater and lesser saphenous veins, or other superficial or perforator veins, were not included as proximal or distal leg DVT). Distal leg DVT (or "isolated calf DVT"), which includes the anterior tibial, posterior tibial and/or peroneal veins. (Note: gastrocnemius, soleal and/or sural [e.g., "deep muscular veins" of the calf] vein thrombosis was not included as distal leg DVT). Arm DVT, which includes the axillary, subclavian and/or innominate (brachiocephalic) veins. (Note: jugular [internal or external], cephalic and brachial vein thrombosis was not included in "arm DVT"). Hepatic, portal, splenic, superior or inferior mesenteric, and/or renal vein thrombosis. (Note: ovarian, testicular, peri-prostatic and/or pelvic vein thrombosis was not included). Cerebral vein thrombosis (includes cerebral or dural sinus or vein, saggital sinus or vein, and/or transverse sinus or vein thrombosis). Inferior vena cava (IVC) thrombosis Superior vena cava (SVC) thrombosis Pulmonary embolism Patients with VTE related to active cancer, antiphospholipid syndrome, inflammatory bowel disease, vasculitis, a rheumatoid or other autoimmune disorder, a vascular anomaly (e.g., Klippel-Trénaunay syndrome, etc.), heparin-induced thrombocytopenia, or a mechanical cause for DVT (e.g., arm DVT or SVC thrombosis related to a central venous catheter or transvenous pacemaker, portal and/or splenic vein thrombosis related to liver cirrhosis, IVC thrombosis related to retroperitoneal fibrosis, etc.), with hemodialysis arteriovenous fistula thrombosis, or with prior liver or bone marrow transplantation were excluded. Controls. A Mayo Clinic outpatient control group was prospectively recruited for this study. Controls were frequency-matched on the age group (18-29, 30-39, 40-49, 50-59, 60-69, 70-79, and 80+ years), sex, myocardial infarction/stroke status, and state of residence distribution of the cases. We selected clinic-based controls using a controls' database of persons undergoing general medical examinations in the Mayo Clinic Departments of General Internal Medicine or Primary Care Internal Medicine. Additionally persons undergoing evaluation at the Mayo Clinic Sports Medicine Center, and the Department of Family Medicine were screened for inclusion as controls. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to venous thrombosis through large-scale genome-wide association studies of 1,300 clinic-based, VTE cases and 1300 clinic-based, unrelated controls. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000289

• A Genome-Wide Association Study in Patients Experiencing Drug-Induced Long-QT Syndrome and/or Torsades de Pointes; A Collaboration Between the NIH Pharmacogenomics Research Network and the RIKEN Yokohama Institute Center for Genomic Medicine

  The goal of this study was to identify genetic risk factors for drug-induced prolongation of the QT interval (diLQT) and the ventricular arrhythmia torsades de pointes (TdP). We conducted a genome-wide association study (GWAS) focusing on subjects with a history of long QT and/or TdP after taking medication. Controls for this study were individuals with a history of cardiac arrhythmias who had begun treatment with potentially QT-prolonging antiarrhythmics. An additional control group of normal volunteers were given ibutilide, a drug with documented proarrhythmic properties. All study participants were recruited and treated/evaluated at Vanderbilt University Medical Center. This study was conducted by the Pharmacogenomics of Arrhythmia Therapy subgroup of the Pharmacogenetics Research Network, a nationwide collaboration of scientists studying the genetic contributions to drug response variability. Genotyping was performed by the RIKEN research institute in Japan using the Illumina 610 Quad Beadchip platform.

  Study phs000331

• A Whole Genome Association Scan for Myopia and Glaucoma Endophenotypes using Twin Studies

  Myopia and glaucoma are highly prevalent ophthalmic disorders worldwide and contribute significantly to ocular morbidity. There is substantial evidence that genetic factors play a significant role in the development of non-syndromic myopia and glaucoma. We propose to perform mapping studies for well-characterized twin populations in the United Kingdom and Australia in order to ultimately identify implicated genes for these disorders and related ocular parameters. This will provide a fundamental molecular understanding of how these disorders develop, and may lead to directed physiologic (i.e. pharmacologic, gene therapy) interventions. Our aim is to dissect the genetic basis of the eye disorders myopia and glaucoma. Instead of limited analyses of the trait/disease in a dichotomous manner, we are using continuous phenotypes of measures of refraction and intermediate phenotypes of glaucoma to analyze quantitative traits in unselected population samples of volunteer twins. Achievement of this goal requires cooperative efforts and large sample sizes. Thus, we have created an international collaboration of large complementary studies.

  Study phs000142

• 1000 Genomes Used for Cloud Testing

  WARNING: This is a test data set. The phenotype data was not checked to match 1000 Genomes project. Use with caution.This study provides public access to a demonstration subset of 1000 genomes sequence data in dbGaP. It is intended to be used by software developers who design, implement and validate pipelines for dbGaP data. While this project distributes only public data, it uses dbGaP security mechanisms which include a project-specific security key and a decryption password. Since the data are public, the key and password for this project will be included by SRA into public demonstration packages that permit users to test and validate the security of their computational pipelines. Note that all public users of this data will be logged under the same project and account ID. The datasets attached to this project must be restricted to 1000 Genomes data identical to the project's public FTP site. To access these test data using SRA toolkit use prj_phs710EA_test.ngc.

  Study phs000710

• Risk-Stratified Therapy for Acute Myeloid Leukemia in Down Syndrome

  Study ID: Children's Oncology Group (COG) - AAML1531NCT Number: NCT02521493Trial Title: Risk-Stratified Therapy for Acute Myeloid Leukemia in Down SyndromeSubmitted in collaboration with the NCTN/NCORP Data ArchiveData presented in the following publication(s): 34320162 Disease type(s): Hematopoietic Neoplasm/Leukemia - Acute Myeloid Leukemia; Hematopoietic Neoplasm/Leukemia - Myelodysplastic SyndromeDataset(s) included:NCT02521493-D1: There are 2 datasets associated with PMID 34320162, NCT02521493-D1 through NCT02521493-D2. The NCT02521493-D1 dataset is a patient level dataset (single row per patient) containing patient characteristics, laboratory findings, and outcome for eligible myeloid leukemia in children with Down syndrome (ML-DS) enrolled on the AAML1531 clinical trial.NCT02521493-D2: There are 2 datasets associated with PMID 34320162, NCT02521493-D1 through NCT02521493-D2. The NCT02521493-D2 dataset is an adverse event level dataset (single row per adverse event, period, and patient) containing information of the micro-organisms associated with adverse events by period in the AAML1531 clinical trial.

  Study phs004081

• Single cell RNA sequencing of human embryonic forebrain after slice culturing for between four weeks and one month

  With the aim of verifying normal tissue development in our Organotypic Timelapse recording with Transcriptomic Readout (OTTR) live tissue imaging method, we performed single cell RNA sequencing in organotypic slice cultures containing labelled cells from virally delivered ubiquitous Enhanced yellow fluorescent protein (EYFP)-expression. Human fetal cortices of PCW 7.5-10.5 were cut into strips along the dorso-ventral axis and directly placed en face, ventricular side down, on PTFE culturing membranes. To assess tissue health with our culturing method, we performed single cell RNA-seq analysis of the cortical explants (using adjacent slices from the same samples subjected to timelapse imaging). We cultured these control slices for four days in vitro (mimicking the start of a live imaging experiment after lentiviral infection and expression of EYFP), 11 days in vitro (corresponding to the end of one week of live imaging), and for two weeks and one month in vitro.

  Study EGAS50000001185

• Cell-type eQTLs for single-cell Mendelian Randomisation

  The following study mapped eQTLs in the post-mortem human brain from snRNA-seq generated on 391 individuals. Following eQTL discovery and identification of state-specific eQTLs (dynamic associations interacting with disease), colocalisation and MR was performed integrating GWAS from 42 traits, for the identification of putatively causal genes with cell-type specific context. This study contains raw sequencing data and genotype for two datasets used in this work; - The MRC 60 dataset, which contains snRNA-seq generated on post-mortem brain from 60 control individuals (104 samples total, split across prefrontal cortex and hippocampus). Samples were pooled into 27 distinct pools, each of which was split across 4 lanes. Following sequencing and mapping using cellranger, demultiplexing was done using Demuxlet using the pool-specific genotype data (which contain sample IDs). - The Roche PD dataset, which is 10X multiome data generated on on 70 PD and 22 control individuals.

  Study EGAS50000000687

• 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

• ROCHE PD 92 Multiome dataset

  This dataset contains 10X Multiome data generated on post-mortem brain from 92 individuals (70 PD, 22 controls). For the Roche_PD dataset, nuclei were isolated using Nuclei Pure Prep Nuclei Isolation Kit (Sigma Aldrich) with the following modifications. The tissue was lysed in Nuclei Pure Lysis Solution with 0.1% Triton X, 1mM DTT and 0.4U/ul SUPERase-In™ RNase Inhibitor (ThermoFisher Scientific) freshly added before use and homogenized with the help first of a 23G and then of a 29G syringe. Cold 1.8M Sucrose Cushion Solution, prepared immediately before use with the addition of1mM DTT and 0.4U/ul RNase Inhibitor, was added to the suspensions before they were filtered through a 30μm strainer. The lysates were then carefully and slowly layered on top of 1.8M Sucrose Cushion Solution previously added in new Eppendorf tubes. Samples were centrifuged for 45 minutes at 16000xg at 4°C. Pellets were re-suspended in Nuclei Storage Buffer with RNase Inhibitor, transferred in new Eppendorf tubes and centrifuged twice for 5 minutes at 500xg at 4°C. Finally purified nuclei were re-suspended in Nuclei Storage Buffer with RNase Inhibitor, stained with trypan blue and counted using Countess II (Life technology). After count, nuclei permeabilization was carried out following the demonstrated protocol for single cell multiome ATAC + Gene Expression sequencing from 10x Genomics. A total of 12,000 estimated nuclei from each sample was used for the transposition step and then loaded on the Chromium Next GEM Single Cell Chip J. ATAC library and gene expression library construction was performed using the Chromium Next GEM Single Cell Multiome ATAC + Gene Expression kit according to the manufacturer’s instructions. Libraries were sequenced using Illumina NovaSeq 6000 System and NovaSeq 6000 S2 Reagent Kit v1.5 (100 cycles), aiming at a minimum sequencing depth of 30K reads/nucleus. Genotype was generated as previously described (Bryois et al, Nature Neuroscience, 2022).

  Dataset EGAD50000000964

• Searching for variants associated with endometriosis

  We explored regulatory mechanism of a SNP on chromosome 9p21 associated with endometriosis by leveraging “allele-specific” functional genomic approaches. By re-sequencing 1.29 Mb of 9p21 region and scrutinizing DNase-seq data from the ENCODE project, we prioritized rs17761446 as a candidate functional variant that was in perfect linkage disequilibrium with the original GWAS SNP (rs10965235) and located on DNase I hypersensitive site. Chromosome conformation capture followed by high-throughput sequencing revealed that the protective G allele of rs17761446 exerted stronger chromatin interaction with ANRIL promoter. We demonstrated that the protective allele exhibited preferential binding affinities to TCF7L2 and EP300 by bioinformatics and chromatin immunoprecipitation (ChIP) analyses. ChIP assays for histone H3 lysine 27 acetylation and RNA polymerase II reinforced the enhancer activity of the SNP site. The allele specific expression analysis for eutopic endometrial tissues and endometrial carcinoma cell lines showed that rs17761446 was a cis-regulatory variant where G allele was associated with increased ANRIL expression.

  Study EGAS00001001741

• Single cell RNA sequencing and Whole Genome Sequencing on different cells from the same sample for a triple negative patient derived xenograft and ovarian cancer cell lines.

  Measuring gene expression of genomically defined tumour clones at single cell resolution would associate functional consequences to somatic alterations, as a prelude to elucidating pathways driving cell population growth, resistance and relapse. In the absence of scalable methods to simultaneously assay DNA and RNA from the same single cell, independent sampling of cell populations for parallel measurement of single cell DNA and single cell RNA must be computationally mapped for genome-transcriptome association. Here we present clonealign, a robust statistical framework to assign gene expression states to cancer clones using single-cell RNA-seq and DNA-seq independently sampled from an heterogeneous cancer cell population. We apply clonealign to triple-negative breast cancer patient derived xenografts and high-grade serous ovarian cancer cell lines and discover clone-specific dysregulated biological pathways not visible using either DNA-Seq or RNA-Seq alone.

  Study EGAS00001003387

• Trans-ethnic genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

  We carried out a trans-ethnic genome-wide association and replication study of blood pressure phenotypes amongst up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 novel loci to be associated with blood pressure (P=3.9x10-11 to P=5.0x10-21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that at some of the loci identified DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 novel loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7, TBX2) function. The novel and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, cardiovascular and all-cause mortality (P=0.04 to 8.6x10-6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

  Study EGAS00001001427

• We describe a method to culture organoids from adult human kidney tissue and describe applications for the culture system.

  Adult Stem Cell (ASC)-derived organoids are 3D epithelial structures that recapitulate essential aspects of their organ of origin. We have developed conditions for the long-term growth of primary kidney epithelial organoids. Cultures can be established from mouse and human kidney tissue, as well as from urine and can be expanded for at least 20 passages (> 6 months). Chromosome numbers remain normal. Human organoids represent proximal as well as distal nephron segments, as evidenced by gene expression, immunofluorescence and tubular functional analyses. BK virus infection of organoids recapitulates in vivo phenomena. Organoids can be established from Wilms nephroblastoma. Kidney organoids from Cystic Fibrosis (CF) patient’s urine allowed ex vivo assessment of treatment efficacy. Finally, organoids cultured on microfluidic organ-on-a-chip plates adopt a tubular conformation and display active transport function. Adult kidney-derived organoids allow studies of hereditary, infectious and malignant kidney disease in a personalized fashion.

  Study EGAS00001002729

• RNA-seq profiling of NKX6.1 reporter iPSC lines for isolation and analysis of functionally relevant neuronal and pancreas populations

  We generated human induced pluripotent stem cell (iPSC) lines with a GFP reporter inserted in the endogenous NKX6.1 locus. Characterisation of the reporter lines demonstrated faithful GFP labelling of NKX6.1 expression during pancreas and motor neuron differentiation. We performed three independent in vitro differentiations towards the pancreatic endocrine lineage. We FACS-purified GFP positive and negative cells from stage 7 cultures, and generated Smart-Seq2 RNA-sequencing libraries for the pre-sorted cells, as well as the two GFP-sorted cell populations. Gene expression profiling by RNA-sequencing reveals that the NKX6.1-positive population closely resembles mature human beta cells and the functional evaluation of purified populations shows that the glucose-responsive beta-like cells are enriched within the NKX6.1-positive population. These reporter lines provide a valuable resource to the scientific community for the derivation of functional relevant pancreas and neuronal cell subtypes.

  Study EGAS00001002802

• Multimodal Epigenetic Sequencing Analysis (MESA) of Cell-free DNA for Non-invasive Cancer Detection

  Multimodal characterization of cell-free DNA (cfDNA) in the blood can enable the sensitive and non-invasive detection of human cancers but remains technically challenging and costly. Here, we developed Multimodal Epigenetic Sequencing Analysis (MESA), a flexible and sensitive method of capturing and integrating multimodal epigenetic information of cfDNA using a single experimental assay, i.e., non-disruptive bisulfite-free methylation sequencing, such as Enzymatic Methyl-seq (EM-seq) and TET-assisted pyridine borane sequencing (TAPS). MESA can simultaneously infer cfDNA methylation, nucleosome occupancy, nucleosome fuzziness, and fragmentation profile for regions surrounding the promoters and polyadenylation sites (PASs). MESA’s integrated analysis of multimodal epigenetic features significantly improved the performance of cancer detection models compared to the usage of any single modality alone. MESA captures additional and highly complementary epigenetic information from cfDNA without additional experimental assays, highlighting the importance and clinical prospect of using multimodal epigenetic features for non-invasive cancer detection

  Study EGAS00001006462

• Single molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer

  Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing (WGS) data from 2,511 individuals in the Pan-Cancer Analysis of Whole Genomes (PCAWG) study as well as 489 individuals from four prospective cohorts and found distinct regional and mutation type specific frequencies in tissue and cell-free DNA (cfDNA) of cancer patients that were associated with replication timing and other chromatin features. A machine learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected >90% of lung cancer patients, including those with stage I and II disease. The fixed model was validated in an independent cohort, detected patients with cancer earlier than standard approaches, and could be used to monitor response to therapy. This approach lays the groundwork for non-invasive cancer detection using genome-wide mutation features that may facilitate cancer screening and monitoring.

  Study EGAS00001007248

• Adult human kidney organoids originate from CD24+ cells and represent an advanced model for adult polycystic kidney disease

  Adult kidney organoids have been described as strictly tubular epithelial and termed tubuloids. While the cellular origin of tubuloids has remained elusive, here we report that they originate from a distinct CD24+ epithelial subpopulation. Long-term-cultured CD24+-derived tubuloids represent a functional human kidney tubule. We show that kidney tubuloids can be used to model the most common inherited kidney disease, namely autosomal dominant polycystic kidney disease (ADPKD), reconstituting the phenotypic hallmark of this disease with cyst formation. Single-cell RNA sequencing of CRISPR/Cas9 gene-edited PKD1 and PKD2 knockout tubuloids and human ADPKD and control tissue show similarities in upregulation of disease-driving genes. Furthermore, in a proof of concept, we demonstrate that tolvaptan, the only approved drug for ADPKD, shows a significant effect on cyst size in tubuloids but no effect in a pluripotent-stem-cell-derived model. Thus, tubuloids derive from a tubular epithelial subpopulation and represent an advanced model for ADPKD disease modeling.

  Study EGAS00001006551