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• DETECT-A NGS Data Batch 5

  This batch is a subset of the full DETECT-A dataset, containing 12740 fastq files generated from 3211 subjects. All sequencing was conducted using Illumina HiSeq 4000 and Illumina MiSeq platforms. Note that the division into batches follows no specific criteria and that the sequencing data for each subject has multiple files which may span multiple datasets. Thus, for a comprehensive analysis, it is recommended to request access to all datasets that comprise this study.

  Dataset EGAD00001015426

• Improved Sezary cell detection and novel insights into immunophenotypic and molecular heterogeneity in Sézary syndrome

  We performed a prospective investigation in Sézary syndrome by the application of a standardized multiparameter flow cytometry, FACS-cell sorting, and RNA-sequencing for an in-depth immunophenotypic and transcriptional profiling of Sézary cells.

  Study EGAS00001005229

• Alcohol Dependence: Sequencing from Multiplex Families

  Two multiplex for alcohol dependence family studies were initiated based on the gender of a pair of probands. Ascertainment of a pair of AD probands was used to increase the density of alcohol dependence within the family. Identification of male (Cognitive and Personality Factors in Relatives of Alcoholics Family Study) and female (Biological Risk Factors in Female Alcoholics Family Study) alcohol dependent probands was accomplished by identifying an alcohol dependent proband while in treatment in a substance abuse treatment facility in Pittsburgh and surrounding communities who provided contact information for a sibling whom he/she thought might be interested in participating. The studies had identical ascertainment requirements. DNA was banked for all willing participants.

  Study phs001775

• Genomic Landscape of High-Grade Neuroendocrine Neoplasms

  This project is a multi-omics study of high grade (grade 3) neuroendocrine neoplasms across diverse organs. Genomic analysis using low-pass whole genome sequencing for copy number analysis, whole exome sequencing and whole transcriptomic sequencing using RNAseq were performed. As high grade neuroendocrine neoplasms are highly lethal with a median survival of approximately 7 months, new insights are urgently needed for better prognosis, diagnosis and management. This study focuses on gene and pathway discoveries in this cancer, and includes samples from a diverse set of organs, including the lungs, gastroenteropancreatic tract, breast, prostate, head and neck and bladder. This study was made possible by a generous donation from The Helen B. Rodde Fund.

  Study phs002070

• Sweden-Schizophrenia Population-Based Case-Control Exome Sequencing

  Current findings of the genetic risk of schizophrenia and bipolar disorder emerging from genome wide association studies (GWAS) support a highly polygenic model displaying the full spectrum of causal alleles that includes the extremes of rare, penetrant alleles as well as common alleles of small effect. Lower frequency polymorphism, rare variants and private mutations have eluded measurement by GWAS studies and thus association with disease. In order to create a comprehensive catalogue of low frequency or rare coding variation in individuals with psychiatric disease and to build a foundation for future genetic studies of schizophrenia and bipolar disorder, we have obtained whole exome DNA sequence from a population-based schizophrenia and bipolar disorder Swedish case-control cohort.

  Study phs000473

• Amplicon sequencing of various tumors

  In our previous studies on advanced esophageal, gastric, and colorectal carcinomas, measurement of circulating tumor DNA (ctDNA) in terms of variant allele frequency (VAF) in blood suggested: (1) patients with high VAF have a high chance of relapse; (2) VAF changes in response to treatment; and (3) ctDNA VAF elevation precedes imaging diagnosis of relapse. It is thus necessary to investigate whether these findings can be generalized in a wide cancer spectrum, types of treatment, and relapse phenotypes across cancer types. In the present study, we conduct a non-interventional observational study in a wide cancer spectrum on the basis of technical establishment for ctDNA using our unique digital PCR probe library.

  Study JGAS000366

• Carbamazepine-induced hypersensitivity reactions in Europeans

  An antiepileptic drug carbamazepine is well tolerated by the majority of patients, but can cause severe and potentialy fatal hypersensitivity reactions in a small number of individuals. The aim of this study was to identify genetic predictors of hypersensitivity reactions to carbamazepine. We undertook a genome-wide association study (GWAS) in 22 patients of European ancestry with carbamazepine-induced hypersensitivity syndrome (HSS) and compared our data with genotypes from a healthy population within the WTCCC. We performed imputation of classical HLA alleles according to a recently described method (Science. 2010 Dec 10;330(6010):1551-7. Epub 2010 Nov 4). GWAS statistical analysis was performed using logistic regression with an additive model of inheritance.

  Study EGAS00000000037

• Identification_of_genes_involved_in_congenital_disorders_of_glycosylation_and_3_methylglutaconic_aciduria

  Identification of genes involved in congenital disorders of glycosylation and 3-methylglutaconic aciduria. There are more than 100 genes known for congenital disorders of glycosylation and new disorders are discovered each year. WE included patients with a so far unsolved glycosylation disease. The diagnostic group 3-methyglutaconic aciduria is a heterogenous group of disorders mostly caused by abnormal phospholipid synthesis or in association with mitochondrial dysfunction. We included patients with a so far unsolved disease and 3-methylglutaconic aciduria. 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 EGAS00001002064

• STREP GENE: Genetics and Severe Streptococcal Infections

  This study investigated host genetic susceptibility to invasive group A streptococcal disease in the UK. Cases were either survivors recruited retrospectively through a patient group or identified from the a tissue bank at Imperial College London. Those recruited through the patient group had survived an episode of invasive GAS disease at a UK hospital since 1980 with microbiological confirmation obtained either through Public Health England or from the treating hospital. Those identified from the tissue bank had been diagnosed with invasive GAS disease at the Hammersmith Hospital, London, UK, since 2006. All cases aged less than 65 years without long-term medical conditions genome-wide genotyped using either the Illumina HumanCore or the Global Screening Array platform.

  Study EGAS00001003421

• Next-generation molecular analysis of surgical margins in oral squamous cell carcinoma for assessment of microscopic residual disease and personalized postoperative treatment decision

  Background : Patients operated for an early oral squamous cell carcinoma (OSCC) with clear margins have a 5-year local relapse rate of around 15%. Assessing the microscopic residual disease (MRD) remains a challenge. In a phase II prospective trial, we evaluated the tetranucleotide microsatellite instability markers in the surgical margins in T1-T2 OSCC resected with pathologically clear margins. Goal : Detect MRD in surgical margins and adapt the postoperative decision-making Details : Whole exome sequencing (WES) on early oral squamous cell carcinoma (OSCC) with clear margins, and on resection margins, 86 patients with a median follow-up of 58 months (range 30.4-83 months)

  Study EGAS50000000823

• Splicing signature analysis of RNU2-2 samples

  Dominant pathogenic variants in the snRNA RNU2-2 were recently reported as a cause of neurodevelopmental disorders. In our study we identified additional individuals with dominant variants (n.4G>A and n.35A>G) and we also identified biallelic variants as a novel frequent cause of neurodevelopmental disorder. We obtained blood samples and performed short-term lymhocytes cultures for 19 cases (5 n.4; 5 n.35; 9 biallelic). We generated exome-capture RNA-Seq for these cases that we compared to 49 controls (probands affected from a neurodevelopmental disorder but without RNU2-2 variants). We observed that RNU2-2 variants mainly disturb alternative exon skipping, although affecting different exons.

  Study EGAS50000001410

• 10X whole single cell RNA-seq from pre-frontal cortex biopsy

  The biopsy procedure was performed by a standard operative procedure under general anaesthesia. The placement of burr hole on the frontal lobe, opening of dura and cortex was performed in a routine fashion for VP shunt or VCS surgery. The biopsy was sharp dissected with knife through the leptomeninges, forming a tissue block consisting of cortex and subcortex, and placed in a sterile tube containing CSF. Fresh tissue sample processing was performed within the hours after surgery. The tissue was dissociated followed by red cell and debris removal and counting of the cells to be sequenced with (scRNA-seq; 10x Genomics). After dissociation only non neuronal cells were retrieved.

  Study EGAS50000001058

• ICGC Oesophageal adenocarcinoma - Barrett's samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett’s oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data.

  Study EGAS00001000726

• MPNST - WGS FASTQ

  Understanding the spatial and temporal dynamics of tumour evolution is crucial for determining the drivers of cancer progression. Here, we comprehensively profile a primary malignant peripheral nerve sheath tumour (MPNST) and its recurrence with a multi-omic and spatial approach at single-cell resolution. Leveraging the extensive heterogeneity in copy number aberrations (CNAs) as a native barcoding system, we fully resolve the evolutionary tree of this tumour revealing multi-furcations suggestive of ongoing chromosomal instability. We show gene dosage effects contribute to phenotypic diversity and are predominantly linear. Using laser capture microdissection, we performed spatial lineage tracing in a human tumour, elucidating the relationship between local expansions and interactions between tumour cells and the microenvironment.

  Study EGAS50000001786

• MPNST - LCM WGS FASTQ

  Understanding the spatial and temporal dynamics of tumour evolution is crucial for determining the drivers of cancer progression. Here, we comprehensively profile a primary malignant peripheral nerve sheath tumour (MPNST) and its recurrence with a multi-omic and spatial approach at single-cell resolution. Leveraging the extensive heterogeneity in copy number aberrations (CNAs) as a native barcoding system, we fully resolve the evolutionary tree of this tumour revealing multi-furcations suggestive of ongoing chromosomal instability. We show gene dosage effects contribute to phenotypic diversity and are predominantly linear. Using laser capture microdissection, we performed spatial lineage tracing in a human tumour, elucidating the relationship between local expansions and interactions between tumour cells and the microenvironment.

  Study EGAS50000001789

• RNA-Sequencing of cervical cancers

  Question: Can we identify cervical cancer patients who are at risk for distant metastatic (DM) recurrence following treatment with radiotherapy, concurrent weekly cisplatin and brachytherapy (RTCT). Findings: An immune-based 55 gene risk score was developed using a cohort of 81 patients treated with RTCT that was strongly predictive of DM and cause-specific survival (CSS). The risk score was validated in two independent patient cohorts. A high immune metastatic risk score was associated with a high tumor mutational burden and a ‘cold’, immune-excluded tumor microenvironment at diagnosis. Meaning: The immune gene expression risk score may help to identify patients at risk of DM and potential targets for mitigating this risk.

  Study EGAS50000000087

• Genetic landscape of non-Down syndrome acute megkaryoblastic leukemia

  To define the mutation spectrum in non-Down syndrome acute megkaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL leukemia samples. Our analysis identified a cryptic chromosome 16 inversion [inv(16)(p13.3q24.3)] in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling, and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.

  Study EGAS00001000379

• Alveolar Rhabdomyosarcoma case report

  Rhabdomyosarcoma (RMS) is a mesenchymal malignancy phenocopying muscle and is among the leading causes of death from childhood cancer. Metastatic alveolar rhabdomyosarcoma is the most aggressive subtype with an 8% five-year disease-free survival rate when a chromosomal fusion is present, and 40% five-year disease-free survival rate when negative for a fusion event. The underlying biology of PAX-fusion negative alveolar rhabdomyosarcoma remains largely unexplored and is exceedingly rare in Li-Fraumeni syndrome patients. Here, we present the case of an 11-year old male with fusion-negative alveolar rhabdomyosarcoma studied at end of life with a comprehensive functional genomics characterization, resulting in identification of potential therapeutic targets for broader investigation.

  Study EGAS00001004828

• Next Generation Sequencing platform for targeted Personalized Therapy of Leukemia - Acute myeloid leukemia

  The advent of high-throughput next generation sequencing (NGS) technologies that are revolutionizing genomics and transcriptomics by providing a single base resolution tool for a unified deep analysis of diseases complexity allows a fast and cost-efficient fine-scale assessment of the genetic variability hidden within cohorts of patients affected by the same leukemia. That being so, by potentially highlighting inter-individual differences that may play a role in the differential success of diverse therapeutic interventions, they promise to be crucial for selecting the most appropriate medical treatments. The project aims at the identification of novel prognostic biomarkers for acute myeloid leukemia (AML) and studied the molecular differences between aneuploid and euploid AML.

  Study EGAS00001005464

• Deregulation of DUX4 and ERG in acute lymphoblastic leukemia

  Chromosomal rearrangements deregulating hematopoietic transcription factors are common leukemia-initiating lesions in acute lymphoblastic leukemia (ALL). Here, we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG are hallmarks of a subtype of B-progenitor ALL with a distinct gene expression profile that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression is present in all cases, and is accompanied by profound transcriptional deregulation of ERG, frequent ERG deletion and expression of a truncated ERG isoform, ERGalt. ERGalt utilizes a non-canonical first exon that is bound by DUX4 and induces its expression....

  Study EGAS00001001923

• Reliable assessment of telomere maintenance mechanisms in neuroblastoma

  Telomere maintenance mechanisms (TMM) are a hallmark of high-risk neuroblastoma, and are conferred by activation of telomerase or alternative lengthening of telomeres (ALT). However, detection of TMM is not yet part of the clinical routine, and consensus on TMM detection, especially on ALT assessment, remains to be achieved. We here propose a workflow to reliably detect TMM in neuroblastoma. We show that unambiguous classification is feasible following a stepwise approach that determines both, activation of telomerase and ALT. The workflow proposed in this study can be used in clinical routine and provides a framework to systematically and reliably determine telomere maintenance mechanisms for risk stratification and treatment allocation of neuroblastoma patients.

  Study EGAS00001006510

• ICGC Oesophageal adenocarcinoma - pilot samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett's oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data.

  Study EGAS00001000559

• Developmental Mechanisms of Human Congenital Heart Disease in Subjects with 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome)

  The study is designed to identify genetic modifiers of cardiovascular defects in subjects with 22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome or velo-cardio-facial syndrome. Affymetrix 6.0 arrays were processed on 1,480 subjects with known cardiovascular anomalies or with normal structures, all with 22q11.2DS. One sample is a duplicate so it was removed. There are 1,472 samples total of unrelated, de-identified, probands. Over 90% have the same sized 3 million base pair deletion flanked by low copy repeats (LCR22) A and D, while approximately 6% have nested A to B deletions. The rest have other nested deletions, that include a deletion in the vicinity of TBX1 (between LCR22 A and B). A subset of the data was used to identify copy number variations serving as modifiers. Some data were previously published by Dr. Emanuel's team at Children's Hospital of Philadelphia in PA, USA (PMID:26742502; PMID:4896312; PMID:25892112; PMID:4570279). The de-identified DNA data from unrelated subjects come from multiple research sites in the US and Europe as part of the International 22q11.2 Consortium and the International 22q11.2 Brain and Behavior Consortium.

  Study phs001339

• Method to Assess Lung Water Accumulation During Exercise

  The goal of this non-significant risk medical device study is to test the initial technical feasibility of a 0.55T MRI in healthy volunteers by technical optimization of scanner protocols, and to test accuracy of standard MR measurements in adult patients with known stable disease. Exercise-induced lung water is a key feature in heart failure. Dynamic quantitative lung water imaging during exercise stress is therefore of interest to unmask latent heart failure. We developed a novel magnetic resonance imaging (MRI) method using a proton density weighted ultrashort echo time MRI sequence along with a time-resolved and respiratory motion compensated image reconstruction for exercise lung water imaging. We validated our method in a porcine model of dynamic lung water accumulation (n=5), and tested its feasibility for use in humans using 12 healthy subjects, 1 patient with heart failure with preserved ejection fraction, and 1 patient with heart failure with reduced ejection fraction. Data suggest the novel imaging method is capable of dynamically imaging lung water accumulation during exercise stress. Reference 1 (PMID: 37288601) contains the main results for this study.

  Study phs003346

• NHLBI Recipient Epidemiology Donor Evaluation Study (REDS)-III - Brazil Sickle Cell Disease Cohort (REDS-BSCDC)

  The Recipient Epidemiology and Donor Evaluation Study (REDS)-III program established a Brazilian Sickle Cell Disease (SCD) Cohort to identify molecular determinants of response to transfusions, alloimmunization and risk factors associated with HIV infection. The Brazil population presents a complex admixture of African, European, Asian and Indigenous heritage and will provide insights into genetic, demographic, social, and healthcare system determinates of SCD outcomes. The REDS-III Brazil SCD cohort began in the Fall of 2013 and aimed to: Establish a cohort of SCD patients with a comprehensive centralized electronic database of detailed clinical, laboratory and transfusion information, as well as establish a repository of blood samples to support biological studies relevant to SCD pathogenesis and transfusion complications; Characterize changes in markers of inflammation in response to transfusion by analyzing chemokine/cytokine panels in serial post transfusion specimens; Identify single nucleotide polymorphisms (SNPs) that contribute to the risk of red blood cell alloimmunization in SCD by performing a genome-wide association (GWA) study in transfused SCD patients; Characterize risk of HIV and HIV outcomes in the Brazilian SCD population and compare SCD outcomes among HIV sero-positive and sero-negative SCD patients.

  Study phs001972

• Nanobody-Tethered Transposition Allows for Multifactorial Chromatin Profiling at Single-Cell Resolution

  Chromatin states are functionally defined by a complex combination of histone modifications, transcription factor binding, DNA accessibility, and other factors. However, most current single-cell-resolution methods are unable to measure more than one aspect of chromatin state in a single experiment, limiting our ability to accurately measure chromatin states. Here we introduce nanobody-tethered transposition followed by sequencing (NTT-seq), a new assay capable of measuring the genome-wide presence of multiple histone modifications and protein-DNA binding sites at single-cell resolution. NTT-seq utilizes recombinant Tn5 transposase fused to a set of secondary nanobodies (nb). Each nb-Tn5 fusion protein specifically binds to different immunoglobulin-G antibodies, enabling a mixture of primary antibodies binding different epitopes to be used in a single experiment. We apply bulk- and single-cell NTT-seq to generate high-resolution multimodal maps of chromatin states in cell culture and cells of the human immune system, demonstrating the high accuracy and sensitivity of the method. We further extend NTT-seq to enable simultaneous profiling of cell-surface protein expression alongside multimodal chromatin states to study cells of the immune system.

  Study phs003068

• Resistance Development in Basal Cell Nevus Syndrome through the Basal to Squamous Transition

  While basal cell carcinomas (BCCs) arise from ectopic hedgehog pathway activation and can be treated with pathway inhibitors, sporadic BCCs display high resistance rates, while tumors arising in Gorlin syndrome patients with germline Patched (PTCH1) mutations are uniformly suppressed by inhibitor therapy. In rare cases, Gorlin syndrome patients on long-term inhibitor therapy will develop individual resistant tumor clones that rapidly progress, but the basis of this resistance remains unstudied. Here we report a case of a Smoothened inhibitor (SMOi)-resistant tumor arising in a Gorlin patient on suppressive SMOi for nearly a decade. Using a combination of multi-omics and spatial transcriptomics, we define the tumor populations at the cellular and tissue level to conclude that Gorlin tumors can develop resistance to SMOi through the previously described basal to squamous cell carcinoma transition (BST). Intriguingly, through spatial whole exome genomic analysis, we nominate PCYT2, ETNK1, and the phosphatidylethanolamine biosynthetic pathway as novel genetic suppressors of BST resistance. These observations provide a general framework for studying tumor evolution and provide important clinical insight into mechanisms of resistance to SMOi for not only Gorlin syndrome but sporadic BCCs as well.

  Study phs003415

• Defining Cutaneous Gene Expression Signatures in Juvenile Dermatomyositis

  Skin inflammation in juvenile dermatomyositis (JDM) can signal disease onset or flare up and prevent complete disease remission. Our objective was to evaluate JDM cutaneous expression signatures through tape stripping in both lesional and non-lesional skin and as compared to paired blood. A total of 28 JDM and 20 control (CTL) patients participated in the study. All patients had tape strip sampling of non-lesional (NL) skin at enrollment visit. Within our JDM cohort, paired lesional (L) skin was additionally sampled if rash was present. 16/28 of JDM patients had at least one additional skin sample associated with a follow-up (FU) visit (total number of follow-up samples included = 26 NL and 4 L). We identified a common innate immune signature in both lesional and non-lesional JDM skin. Using unsupervised hierarchical clustering of skin expression data, we distinguished a JDM molecular subgroup characterized by a mitochondrial dysfunction signature. In comparison to blood expression data, we determined that skin may more effectively highlight the JDM subgroup characterized by a mitochondrial dysfunction expression signature. Data available include bulk RNA-sequencing data from tape strips and blood of the JDM and control patients from this study.

  Study phs003884

• NHLBI TOPMed: Trans-Omics Analysis for Congestive Heart Failure (TOPCHeF)

  Heart failure (HF) is a serious, common, morbid condition that has a huge public health impact. In 2012 alone, there were >1M hospital discharges and >1.7M outpatient visits where HF was the principal diagnosis. HF is the most common hospital discharge diagnosis of the elderly and led to costs in excess of $30B in 2012. Unfortunately, HF therapies have not impacted the 50% 5-year mortality over the past two decades. Our laboratory focuses on cardiomyopathies (CMs) and HF. Dilated cardiomyopathy (DCM) has been a main focus of our laboratory and is the first and third most frequent cause of heart transplantation and HF, respectively. Attention is shifting from the mere identification and cataloging of CM/HF genes and mutations to understanding the molecular and functional cellular processes that drive HF. In this study, we will utilize whole genome sequencing (WGS) and transcriptome analysis of left ventricle samples from adult and pediatric samples from heart banks at the University of Colorado Anschutz Medical Campus and the Children's Hospital Colorado to develop a complete understanding of left ventricular biology and a partial understanding of HF inferred through the lens of a single-chamber perspective.

  Study phs002038

• 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

• Onco-exaptation of an Endogenous Retroviral LTR Drives IRF5 Expression in Hodgkin Lymphoma

  The transcription factor interferon regulatory factor 5 (IRF5) is upregulated in Hodgkin lymphoma (HL) and a key regulator of the aberrant transcriptome characteristic of this disease. Here we show that IRF5 upregulation in HL is driven by transcriptional activation of a normally dormant endogenous retroviral LOR1a long terminal repeat (LTR) upstream of IRF5. Specifically, through screening of RNA-seq libraries, we detected LTR-IRF5 chimeric transcripts in multiple HL cell lines but not in normal B-cell controls. In HL, the LTR was in an open and hypomethylated epigenetic state and we further show the LTR is the site of transcriptional initiation. Among HL cell lines, usage of the LTR promoter strongly correlates with overall levels of IRF5 mRNA and protein, indicating that LTR transcriptional awakening is a major contributor to IRF5 upregulation in HL. Taken together, oncogenic IRF5 overexpression in HL is the result of a specific LTR transcriptional activation. We propose that such LTR derepression is a distinct mechanism of oncogene activation (“onco-exaptation”) and that such a mechanism warrants further investigation in molecular and cancer research.

  Study EGAS00001001205

• Dissection of the molecular complexity of colorectal cancer in pre-clinical models identifies predictive signatures of sensitivity to EGFR inhibitors

  Colorectal carcinoma (CRC) is a heterogeneous tumour entity, with only a fraction of the tumours responding to currently available therapies. A detailed understanding of the biology and genetics of CRC is a prerequisite for precision medicine. To address this challenge in clinical oncology, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed an integrated pre-clinical platform analysing drug sensitivity in the established matched patient-derived in vivo and in vitro models, 46 three-dimensional cell cultures and 59 xenografts, recapitulating many of the molecular features of the donor tumours. We generated extensive omics information on patient tumours and their derived models used to generate a compendium of drug sensitivity data. We could distinguish tumour molecular sub-groups responding differently to therapy and identified a novel independent predictor of sensitivity to the EGFR inhibitor cetuximab. The findings reported here will advance our understanding of CRC and its response to therapy.

  Study EGAS00001001752

• Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients

  The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include the maximisation of response and use of maintenance therapy. We used whole exome sequencing to study the genetics of paired presentation and relapse samples from 56 newly diagnosed patients, following induction therapy, randomised to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patients included were considered high risk, relapsing within 30 months of maintenance randomisation. Patients achieving a complete response had predominantly branching evolutionary patterns leading to relapse, characterised by a greater mutational burden, an altered mutational profile, bi-allelic inactivation of tumour suppressor genes, and acquired structural aberrations. Conversely, in patients achieving a partial response the evolutionary features were predominantly stable with a similar mutational and structural profile. There were no significant differences between patients relapsing after maintenance lenalidomide vs observation. This study shows that the depth of response is a key determinant of the evolutionary patterns seen at relapse.

  Study EGAS00001003539

• Pipeline Olympics: Continuous benchmarking of computational workflows for DNA methylation sequencing data

  DNA methylation is a widely studied epigenetic mark and a powerful biomarker of cell type, age, environmental exposure, and disease. Genome-wide DNA methylation profiling is usually performed using whole-genome sequencing following selective conversion of unmethylated cytosines into thymines via bisulfite treatment or enzymatic methods. Numerous software tools facilitate processing of raw sequencing data for DNA methylation profiling, but a comprehensive benchmarking has been lacking. In this study, we systematically compared methods and tools for processing DNA methylation sequencing data. We established a dedicated benchmarking dataset comprising genome-wide DNA methylation profiling data for four reference samples using five experimental protocols each. The results of data processing were compared to highly quantitative locus-specific DNA methylation measurements available for 46 genomic loci. Based on this gold-standard reference dataset, we identified workflows that consistently demonstrated high performance. We present our results in an interactive application that provides a “living benchmark” ready for continuous updating as new workflows are proposed and require benchmarking against existing methods. In summary, our study provides guidance for any laboratory studying DNA methylation on a genome-wide scale.

  Study EGAS50000000541

• Whole Genome Sequencing of Neuroblastoma

  Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour1. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%)2-5. Here we present a whole genome sequence analysis of 87 neuroblastoma of all stages. Only few recurrent amino-acid changing mutations were found. In contrast, analysis of structural defects identified in 18% of high stage neuroblastoma a local shredding of chromosomes, known as chromothripsis6. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization7-9. In addition, ATRX, TIAM1 and a series of regulators of the Rac Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumors with defects in these genes were aggressive high stage neuroblastoma, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromotripsis and neuritogenesis gene alterations, which frequently occur in high risk tumors.

  Study EGAS00001000222

• 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

• Whole genome sequence and RNA-seq data from paired tumour and germline samples from mesothelioma patients.

  Malignant pleural mesothelioma (MPM) has a poor overall survival with few treatment options. Whole genome sequencing (WGS) combined with RNA sequencing (RNA-seq) analysis of the immune features of MPM offers the prospect of identifying changes that could inform future clinical trials. We analysed somatic mutation and RNA-seq data from 229 MPM samples, including 58 MPM samples that had undergone WGS from our own institutions, together with other published data. This combined analysis identified somatic driver genes, including newly identified candidate genes. Whole genome doubling was a frequent event that correlated with shorter survival. Mutational signature analysis revealed dominant signatures and showed that defects in homologous recombination repair were infrequent in our cohort. Within the tumour immune environment we identified high M2 macrophage infiltrate linked with MMP2, MMP14, TGFB1 and CCL2 expression, representing an immunosuppressive environment. A small subset of samples had a higher proportion of CD8 T cells and a high cytolytic score, suggesting a ‘hot’ immune environment which is independent of the somatic mutations. We propose that our findings on genomic changes and subtypes of immune microenvironments may influence therapeutic planning in the future.

  Study EGAS00001005196

• Allele-specific expression of GATA2 due to epigenetic dysregulation in double mutated CEBPA AML

  Transcriptional deregulation is a central event in the development of acute myeloid leukemia (AML). To identify potential disturbances in gene regulation, we conducted an unbiased screen of allele-specific expression (ASE) in 209 AML cases. The gene encoding GATA binding protein 2 (GATA2) displayed ASE more often than any other myeloid or cancer-related gene. GATA2 ASE was strongly associated with CEBPA double mutations (CEBPA DM), with 95% of cases presenting GATA2 ASE. In CEBPA DM AML with GATA2 mutations, the mutated allele was preferentially expressed. We found that GATA2 ASE is a somatic event lost in complete remission, supporting the notion that it plays a role in CEBPA DM AML. Acquisition of GATA2 ASE involved silencing of one allele via promoter methylation, compensated by overactivation of the other allele, thereby preserving expression levels. Notably, promoter methylation was also lost in remission together with GATA2 ASE. In summary, we propose that GATA2 ASE is acquired by epigenetic mechanisms and is a prerequisite for the development of AML with CEBPA DM. This finding constitutes a novel example of an epigenetic hit cooperating with a genetic hit in the pathogenesis of AML.

  Study EGAS00001004684

• Genomics-based personalized oncology in cancer of unknown primary (CUP, project H021)

  To perform a comprehensive genomic characterization of 70 patients suffering from cancer of unknown primary (CUP) we used whole-exome, whole-genome, transcriptome and methylome analysis. We detected a substantial mutational heterogeneity with genes most commonly affected by SNVs, indels and fusions being TP53, TTN, MUC16, ABCA13, COL6A3, KRAS, LRP1B, XIRP2 and CSMD3. The most common fusion involved FGFR2, the most common focal deletion affected CDKN2A. A molecular tumor board recommended genomics-based therapies in 56/70 (80%) patients which were applied in 20/56 (35.7%) cases. Entity predictions based on transcriptome and methylome data could be made in up to 62/70 (88.6%) cases but were conclusive in only 16/48 (33.3%) cases. Germline analysis revealed 6 (likely) pathogenic mutations in 5 patients. Recommended therapies translated into a mean PFS2/1 ratio of 3.61 (median=2.25) with a median PFS1 of 89 days (n=17) compared to a median PFS2 of 182.5 days (n=20). Our data emphasize the clinical benefit of comprehensive genetic approaches in diagnostic and therapeutic management and underline the need for innovative, mechanism-based clinical trials in this heterogeneous group of diseases.

  Study EGAS00001004786

• An Atlas of Cells in the Human Tonsil

  Palatine tonsils are secondary lymphoid organs representing the first line of immunological defense against inhaled or ingested pathogens. Here, we provide a comprehensive census of cell types forming the human tonsil by applying single cell transcriptome, epigenome, proteome and adaptive immune repertoire as well as spatial transcriptomics, resulting in an atlas of >350,000 cells. We provide a glossary of over one hundred annotated cell types and states, and disentangle gene regulatory mechanisms that drive cells through specialized lineage trajectories. Exemplarily, we stratify multiple tonsil-resident myeloid slancyte subtypes, establish a distant BCL6 superenhancer as locally active in both follicle-associated T and B cells, and describe SIX5 as a potentially novel transcriptional regulator of plasma cell maturation. Further, our atlas is a reference map to understand alterations observed in disease, here we discover immune-phenotype plasticity in tumoral cells and microenvironment shifts of mantle cell lymphomas (MCL). To facilitate such reference-based analysis, we develop HCATonsilData and SLOcatoR, a computational framework that provides programmatic and modular access to our dataset; and allows the straightforward annotation of future single-cell profiles from secondary lymphoid organs.

  Study EGAS00001006375

• Cross-Sectional Characterization of Idiopathic Bronchiectasis

  This GDMCC protocol will study adult patients with non-CF, idiopathic bronchiectasis, whose genetic etiologies are not known. Idiopathic bronchiectasis is reportedly more common in females with certain tall, thin body types and associated with environmental organisms, such as nontuberculous mycobacterium (NTM). The other susceptibility factors predisposing to bronchiectasis or acquisition of NTM are unclear. The study will attempt to broaden the understanding of this disease by comparing gender-associated factors and NTM status. A relatively equal number of both females/males and NTM/non-NTM infected subjects will be enrolled. Approximately 300 people may be screened to find 260 eligible subjects, since a small number (e.g., 40 patients) may be diagnosed with PCD, vCF, or other known etiology as an explanation for the bronchiectasis. This single-visit protocol will use a systematic approach to characterize the physical features, radiographic patterns, and associated lower airway microbial flora. There is no natural history of disease course follow-up component to this protocol. Participants will have one outpatient clinic visit for evaluation with a physical examination including detailed body size measurements, medical history, collection of blood samples for routine lab tests and genetic analyses, and a chest X-ray if no recent one is available. Participants will also have tests of lung function, and measurement of a gas called nitric oxide in the nose. Participants whose initial tests show abnormal results may also be asked to have a nasal scrape to collect cell samples and/or a skin sweat test to measure salt concentrations. Participants will also have a sputum specimen collected during the visit and will be asked to collect two additional early morning sputum samples and a mouth rinse at home within 2 weeks of the clinic visit, and mail the sample collection materials to the research team. Careful evaluation and characterization of the physical and clinical characteristics will guide the genetic characterization of idiopathic bronchiectasis, and likely lead to an improved diagnostic approach. Identification of disease causing genes may provide new therapeutic targets.

  Study phs001279

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): Identification of VUR genes by exome sequencing

  Primary vesicoureteric reflux (PVUR), or non-syndromic VUR, is the most common type of congenital anomaly of the kidney and the urinary tract (CAKUT). PVUR is the single most important risk factor for pyelonephritis and renal parenchymal scarring in the pediatric age group. Renal parenchymal scarring due to PVUR is referred to as reflux nephropathy and is a major cause of end stage kidney disease requiring dialysis and kidney transplantation in children. PVUR shows familial aggregation; however, the specific genetic cause(s) of PVUR is unknown despite a number of linkage studies. Reasons for this include: variable expression of the disease, difficulty with case ascertainment, genetic heterogeneity and lack of large pedigrees that can facilitate locus identification. We have ascertained a large 97 member PVUR kindred spanning five generations. We performed a genome-wide linkage study (GWLS) on this family and obtained a significant genome-wide LOD score of 3.3 on chromosome 6p. We performed exome sequencing on affected individuals in the family and identified mutations in tenascin XB (TNXB) as a cause of familial VUR. The proposed studies have the following specific objectives: a) to define the role of tenascin genes in the etiology of PVUR, and b) to identify new PVUR causative genes. Our specific aims are (1) To perform mutation analysis in TNXB and other tenascins in a cohort of 200 individuals with familial and sporadic PVUR and define genotype/phenotype correlations. (2) To perform sequential genome wide linkage studies (GWLS) and whole exome/targeted sequencing in families with PVUR. Impact on public health: Identification of PVUR genes may provide a novel non-invasive diagnostic tool for a subset of children with PVUR. Furthermore, this research will provide insights into the pathogenesis of PVUR and further elucidate the pathways involved in the development of the kidney and genitourinary tract. Future studies will define the role of the genes in the etiology of other malformations of the kidney and urinary tract and also seek to unravel the mechanisms by which the identified gene causes PVUR and other malformations of the kidney and the urinary tract.

  Study phs000778

• GENEVA Genes and Environment Initiatives in Type 2 Diabetes (Nurses' Health Study/Health Professionals Follow-up Study)

  Type 2 diabetes mellitus (T2D) affects approximately 21 million individuals in the U.S., or almost 10% of the U.S. adult population. Because diabetes is determined by both genetic and environmental factors, a better understanding of the etiology of diabetes requires a careful investigation of gene-environment interactions. The Nurses' Health Study (NHS) and Health Professionals' Follow-up Study (HPFS) are well-characterized cohort studies of women and men for whom stored blood and DNA samples are available as well as detailed information on dietary and lifestyle variables. The major goals of the project include: 1. To conduct a GWA analysis among 3,000 cases of T2D and 3,000 healthy controls in NHS/HPFS cohorts. 2. To use information on the joint effects of genes and a list of carefully selected environmental exposures at the initial screening stage to test gene-environment interactions. This approach optimizes our power to detect variants that have a sizeable marginal effect and those with a small marginal effect but a sizeable effect in a stratum defined by an environmental exposure. For this analysis, we have developed a joint test of genetic marginal effect and gene-environment interaction. This flexible two-degree-of-freedom test generally provides greater power than standard methods and has the potential to uncover both marginal genetic effects and stratum-specific effects. The Version 1 (v1) dbGaP release of data from the GENEVA Diabetes Study (NHS/HPFS) includes data from the NHS only. The Version 2 (v2) dbGaP release includes data from both the NHS and HPFS. 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 type 2 diabetes mellitus through large-scale genome-wide association studies of well-characterized cohorts of nurses and health professionals. Genotyping was performed at the Broad Institute of MIT and Harvard, a GENEVA genotyping center. Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000091

• FEGA FAQs: a summary of the Q+A session from the FEGA workshop at ELIXIR AHM 2024

  The ELIXIR All Hands Meeting (AHM) was held in Uppsala, Sweden this June. We at EGA always look forward to this meeting as a chance to see many of our partners and colleagues face-to-face. The Federated EGA (FEGA) is one initiative that always benefits from the AHM, and this year FEGA was in the spotlight, with several questions related to the advances we've made recently. We held this year's FEGA workshop a little differently, with most time for discussions on various “hot topics”. Organised in different breakouts, over 2 rounds, participants could choose which session they wanted to attend. One breakout was a general Q+A about FEGA and the path to join. We had a diverse range of participants, including experts from Central EGA (CEGA) and FEGA inaugural nodes, people from up and coming nodes at various stages of readiness, as well as participants not directly a part of FEGA but curious to learn more. It made for a great discussion! In this blog post, we highlight some of the questions for those who didn’t have a chance to be there. What is the FEGA Collaboration Agreement? It is a legal agreement between the node and Central EGA (CEGA) where both parties agree to certain responsibilities, like what services will be provided, sharing of public metadata with CEGA, interoperable technologies and more. The agreement is for 4 years, with the expectation of long-term sustainability. If a node is made up of multiple institutes, one institute must be the signatory. This could require a legal agreement within the node. CEGA is composed of CRG and EMBL-EBI (EGA itself has its own legal agreement between these institutes) Check the FEGA Collaboration Agreement What about purely medical data? Is this accepted in FEGA? CEGA only accepts data approved for secondary research use. We do accept medical data collected in this context, as do some nodes. Nodes are able to accept any data they like, as long as it is sensitive, thus in need of controlled access. What about other data types other than genomics? Like proteomics or images? They can be accepted, although CEGA is currently not designed with those formats in mind, so they might not fit with precision in the data model. The FEGA nodes are welcome to accept any data they want. Proteomic studies generating sensitive data are increasing, and specific work will likely be developed in the near future to adress this need. Does CEGA require a certain amount or type of data to be shared by the node? No, we do not and it's up to each node to decide what specific data types they accept and in what format. Nonetheless, a FEGA node has the duty to be open to data submission from any institution of their country, and can't be limited by design to a single or limited data source. Does CEGA and FEGA require a certain amount or type of details and description on the data to be submitted to the node? Data description (technical and biological), usually called metadata in this field, is crucial for the findability of the submitted data. Thus, we highly recommend including as much information as available to maximise the discoverability of the data. Specifical minimal metadata is defined in the submission schema, and thresholds are specified by the nodes. We are currently working towards a unified FEGA metadata model. What are the geographical borders of FEGA? FEGA should make the E for Everyone, because any institute worldwide could join and we indeed do have countries and use-cases worldwide. Some of them are very close to officially joining the federation. What are the main differences between FEGA and GDI? The two networks have a lot in common and also some critical differences. You can read all about this in one of our latest blog post. If you have more questions, please consider having a look at the FEGA onboarding webpage and, of course, don't miss our workshop at the ELIXIR AHM next year!

  Blog fega-faqs-elixir-ahm-2024

• Systolic Blood Pressure Intervention Trial (SPRINT-BioLINCC)

  Available DataThe available data include all elements of the previously released SPRINT Primary Outcome Paper (SPRINT-POP) data, the full SPRINT clinical data including the MRI and MIND data, and select ancillary study data (Ambulatory Blood Pressure Monitoring, APOL1, Acute Kidney Injury, ASK, Heart, FAST, PWV, Renal Resistance, Biomarkers, Plasma AD).ObjectiveThe Systolic Blood Pressure Trial (SPRINT) was conducted to test the hypothesis that treating systolic blood pressure to a target of less than 120 mm Hg, as compared to a target of less than 140 mm Hg, would reduce the incidence of cardiovascular disease.BackgroundHypertension is a highly prevalent condition among adults and is a leading risk factor for myocardial infarction and stroke. Further, isolated systolic hypertension is the most common form of hypertension in adults over 50 years of age. Observational studies have shown a monotonic increase in cardiovascular risk with systolic blood pressures above 115 mm Hg; however, general population clinical trials have only documented the benefits of lowering systolic blood pressure to a target of 150 mm Hg. A 2007 expert panel sponsored by the National Heart, Lung, and Blood Institute designated the hypothesis that lowering the systolic blood pressure goal to a level SubjectsA total of 9361 participants were enrolled, with 4,678 randomized to the intensive-treatment group and 4,683 randomized to the standard-treatment group.DesignSPRINT was a randomized, single blinded (outcome adjudicators were blinded to treatment assignment) treatment trial with participants randomized to a systolic blood-pressure target of either less than 140 mm Hg (the standard-treatment group) or less than 120 mm Hg (the intensive-treatment group). Following randomization, baseline hypertensive regimens were adjusted in accordance with study treatment algorithms established for each group. The study formulary included all major classes of antihypertensive agents. Investigators could prescribe other antihypertensive medications, but the use of drug classes with the strongest evidence for reduction in cardiovascular outcomes was encouraged. This included thiazide-type diuretics as the first-line agent, loop diuretics for participants with advanced chronic kidney disease, and beta-adrenergic blockers for participants with coronary artery disease. Medications for participants in the intensive-treatment group were adjusted on a monthly basis to target a systolic blood pressure of less than 120 mm Hg. Medications for participants in the standard-treatment group were adjusted to target a systolic blood pressure of 135 to 139 mm Hg, and the dose was reduced if systolic blood pressure was less than 130 mm Hg on a single visit or less than 135 mm Hg on two consecutive visits. Lifestyle modification was encouraged as part of the management strategy.Participants were seen monthly for the first 3 months and every 3 months thereafter. Demographic data were collected at baseline. Clinical and laboratory data were obtained at baseline and every 3 months thereafter. A structured interview was used in both groups every 3 months to obtain self-reported cardiovascular disease outcomes. Medical records and electrocardiograms were obtained for documentation of events. Incidences of hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia that were evaluated in an emergency department were included in adverse event reporting. Occurrences of acute kidney injury or acute renal failure requiring hospitalization were also monitored. The primary outcome was a composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.ConclusionsThe blood pressure intervention was stopped in August of 2015 (median follow-up of 3.26 years) after the cardiovascular outcome results exceeded the boundary for efficacy at two consecutive time points. Compared with a systolic blood pressure target of less than 140 mm Hg, an intensive systolic blood pressure target of 120 mm Hg resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause. Significantly higher rates of some adverse events were observed in the intensive-treatment group.

  Study phs003483

• Systolic Blood Pressure Intervention Trial (SPRINT-Imaging)

  Available DataSystolic Blood Pressure Intervention Trial, SPRINT-Imaging, provides access to ECG signals data from the SPRINT clinical trial. The clinical phenotyping and outcomes data from the trial are associated with SPRINT-BioLINCC, phs003483.ObjectiveThe Systolic Blood Pressure Trial (SPRINT) was conducted to test the hypothesis that treating systolic blood pressure to a target of less than 120 mm Hg, as compared to a target of less than 140 mm Hg, would reduce the incidence of cardiovascular disease. BackgroundHypertension is a highly prevalent condition among adults and is a leading risk factor for myocardial infarction and stroke. Further, isolated systolic hypertension is the most common form of hypertension in adults over 50 years of age. Observational studies have shown a monotonic increase in cardiovascular risk with systolic blood pressures above 115 mm Hg; however, general population clinical trials have only documented the benefits of lowering systolic blood pressure to a target of 150 mm Hg. A 2007 expert panel sponsored by the National Heart, Lung, and Blood Institute designated the hypothesis that lowering the systolic blood pressure goal to a level SubjectsA total of 9361 participants were enrolled, with 4,678 randomized to the intensive-treatment group and 4,683 randomized to the standard-treatment group. DesignSPRINT was a randomized, single blinded (outcome adjudicators were blinded to treatment assignment) treatment trial with participants randomized to a systolic blood-pressure target of either less than 140 mm Hg (the standard-treatment group) or less than 120 mm Hg (the intensive-treatment group). Following randomization, baseline hypertensive regimens were adjusted in accordance with study treatment algorithms established for each group. The study formulary included all major classes of antihypertensive agents. Investigators could prescribe other antihypertensive medications, but the use of drug classes with the strongest evidence for reduction in cardiovascular outcomes was encouraged. This included thiazide-type diuretics as the first-line agent, loop diuretics for participants with advanced chronic kidney disease, and beta-adrenergic blockers for participants with coronary artery disease. Medications for participants in the intensive-treatment group were adjusted on a monthly basis to target a systolic blood pressure of less than 120 mm Hg. Medications for participants in the standard-treatment group were adjusted to target a systolic blood pressure of 135 to 139 mm Hg, and the dose was reduced if systolic blood pressure was less than 130 mm Hg on a single visit or less than 135 mm Hg on two consecutive visits. Lifestyle modification was encouraged as part of the management strategy. Participants were seen monthly for the first 3 months and every 3 months thereafter. Demographic data were collected at baseline. Clinical and laboratory data were obtained at baseline and every 3 months thereafter. A structured interview was used in both groups every 3 months to obtain self-reported cardiovascular disease outcomes. Medical records and electrocardiograms were obtained for documentation of events. Incidences of hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia that were evaluated in an emergency department were included in adverse event reporting. Occurrences of acute kidney injury or acute renal failure requiring hospitalization were also monitored. The primary outcome was a composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. ConclusionsThe blood pressure intervention was stopped in August of 2015 (median follow-up of 3.26 years) after the cardiovascular outcome results exceeded the boundary for efficacy at two consecutive time points. Compared with a systolic blood pressure target of less than 140 mm Hg, an intensive systolic blood pressure target of 120 mm Hg resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause. Significantly higher rates of some adverse events were observed in the intensive-treatment group.

  Study phs003566

• Cohort A germline exome sequencing

  Cohort A includes glioma tumors of varied grading and pathology from male and female individuals. Germline DNA was isolated from whole blood.

  Study EGAS50000000952

• WGS of a Li-Fraumeni patient's HSPCs

  WGS data of clonally expanded HSPCs from a Li-Fraumeni patient at the time of second cancer (Burkitt lymphoma and <5% t-MN) after primary osteosarcoma diagnosis and a reference MSC bulk.

  Dataset EGAD00001011257

• A Pilot Trial of Complement Inhibition Using Eculizumab to Overcome Platelet Transfusion Refractoriness in HLA Allo-Immunized Patients

  Platelet transfusion can be a life-saving procedure in preventing or treating serious bleeding in patients who have low and/or dysfunctional platelets. Heavily transfused patients frequently develop human leukocyte antigen (HLA) allo-immunization resulting in platelet transfusion refractoriness and a high risk for life-threatening thrombocytopenia. Data suggest complement activation leading to the destruction of platelets bound by HLA allo-antibodies may play a pathophysiologic role in platelet refractoriness. We conducted a pilot trial to investigate the use of eculizumab to treat platelet transfusion refractoriness in allo-immunized patients with severe thrombocytopenia. We hypothesized that when we treated patients having platelet refractoriness with eculizumab, platelet counts would increase to higher numbers after platelet transfusions, decreasing the risk of bleeding complications associated with having a low platelet count. The response of the treatment was assessed by the corrected platelet count increment (CCI) 10 - 60 min and 18 - 24 h post transfusion, and any requirement for subsequent platelet transfusions following eculizumab. Reference 1 (PMID: 32086819) contains the main results for this trial.

  Study phs003212

• Introducing Federated EGA Affiliates: a newly defined tier in the Federated EGA Network

  We're happy to announce that we are now accepting Affiliates in the Federated EGA Network! Federated EGA is a global network of repositories enabling secure discovery and access to sensitive human data. Currently, Federated EGA consists of Central EGA (CEGA), which serves the global community, and nine national Nodes that serve respective jurisdictions. Did you know that the Federated EGA (FEGA) has always envisioned a third tier within the network? This brings us to FEGA Affiliates, recently defined in the newly approved "Federated EGA Structure and Organisation" document. This new tier broadens the range of institutions or organisations that can become part of FEGA. Thus begins a new era for the network. What is a FEGA Affiliate? A FEGA Affiliate archives and serves controlled-access data within its own governance scope, while still participating in federated discovery through the EGA catalogue. Affiliates can be individual organisations or institutions, healthcare genomics initiatives, consortia of institutions, as well as project-specific consortia (national or international). In practical terms, a FEGA Affiliate: Hosts and safeguards the data it archives. Submits non-personal metadata to CEGA so studies are discoverable and can receive EGA accessions. Manages permissions and data access workflows for its datasets. Provides data access and/or distribution, along with support, to authorised users. Key takeaways about FEGA Affiliates FEGA is now organised into three tiers: CEGA, FEGA Nodes, and FEGA Affiliates. Affiliates archive data from their own organisation and/or selected partner institutions (for example, an international consortium). Affiliates make studies discoverable through the EGA catalogue by submitting non-personal metadata for accessioning. Access decisions and conditions are managed locally by the Affiliate (e.g. distribution or access in a trusted research environment). Are you considering whether your institution or project might be a good fit as a FEGA Affiliate? Would you like to learn more about this tier? We have published a blog post that addresses potential common questions, providing answers on this topic. You can read it here.

  Blog fega-affiliates