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• Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

  Despite recent advances, the dynamics of genome architecture and chromatin function during human cell differentiation and its potential reorganization upon neoplastic transformation remains poorly characterized. Here, we integrate in situ Hi-C and nine additional omic layers to define and biologically characterize the dynamic changes in three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) patients. Beyond conventional active (A) and inactive (B) compartments, an integrative analysis of Hi-C data uncovers a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, we detect that 28% of the compartments change at defined maturation stages and mostly involve the intermediate compartment. The transition from naive to germinal center B cells is associated with widespread chromatin activation, which mostly reverts into the naive state upon further maturation of germinal center cells into memory B cells. The analysis of CLL and MCL neoplastic cells points both to entity and subtype-specific alterations in chromosome organization. Remarkably, we observe that large chromatin blocks containing key disease-specific genes alter their 3D genome organization. These include the inactivation of a 2Mb region containing the EBF1 gene in CLL and the activation of a 6.1Mb region containing the SOX11 gene in clinically aggressive MCL. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture.

  Study EGAS00001004763

• UK10K NEURO ASD SKUSE

  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 of UK origin consists of clinically identified subjects with Autism Spectrum Disorders, mostly without intellectual disability (ie. Verbal IQs >70). The subjects represent children and adults with Autism, Asperger syndrome or Atypical Autism, identified according to standardized research criteria (ADI-algorithm, ADOS). A minority has identified comorbid neurodevelopmental disorders (e.g. ADHD). Family histories are available, with measures of broader phenotype in first-degree relatives.For further information on this cohort please contact David Skuse (d.skuse@ucl.ac.uk).

  Study EGAS00001000114

• Characterization of a human iPSC-derived islet differentiation model

  To explore the contribution of islet development to T2D pathogenesis, we characterised the transcriptomes of 3 human iPSC lines (from independent donors) differentiated along the islet development lineage. Whole transcriptome RNA-seq was performed at 7 developmental stages: definitive endoderm, primitive gut tube, posterior foregut (PF), pancreatic endoderm, endocrine progenitors, endocrine-like cells, and beta-like cells (BLC). Differentially-expressed (ΔExp) genes were assigned to the stage in which they were most upregulated (versus baseline iPSC profile), and used to assess the enrichment of T2D GWAS genes, as well as to predict the upstream transcription factors at each developmental stage.We found 9409 ΔExp genes across all stages, including known markers of islet development (NEUROG3, INS). Genes ΔExp in the most-differentiated (BLC) stage were significantly enriched for genes within the 99% credible sets of T2D GWAS loci. Despite this enrichment in BLC only, over 70% of genes mapping within the credible sets were ΔExp before this stage, highlighting the relevance of key T2D GWAS genes in islet development: e.g. expression of TCF7L2 peaked during the PF stage (log2FC=1.2; q=8.5×10-10). REST and LMNA are also highlighted by the analyses as having a potential function in islet development, considering their pattern of expression and those of the genes they regulate. Transcriptomic signatures derived from this iPSC differentiation model highlight T2D-associated GWAS loci, monogenic diabetes genes and potential master regulators of gene networks with plausible function in islet development. All these provide clues for developmental mechanisms contributing to T2D diabetes pathology.

  Study EGAS00001002721

• Sequencing data for the Genomic Autopsy Study

  The .cram files of the Trio or Quad sequencing data used for generation of the genomic autopsy study. This contains a mix of genome sequencing and exome sequencing data for probands and their parents. A subset of families (n=32) did not provide consent to publicly sharing their data.

  Dataset EGAD00001009737

• Dataset of transcriptomic, whole genome and whole exome sequencing to identify predictive biomarkers in pediatric solid tumors

  This Dataset contains whole genome sequencing data for 148 sample, transcriptome sequencing for 66 samples and exome sequencing for 123 samples from pediatric solid tumors. Sequencing was performed on Illumina NovaSeq 6000 and Illumina HiSeq 4000. The sequencing was paired.

  Dataset EGAD00001015701

• 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

• 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

• 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

• WES of 2 human osteosarcoma and corresponding cell lines

  Progress in the systemic control of osteosarcoma has been limited over the past decades thus indicating the urgent clinical need for the development of novel treatment strategies. Therefore, we have recently developed new preclinical models to study promising novel agents for the treatment of pediatric osteosarcoma. The checkpoint kinase (chk) inhibitor prexasertib (LY2606368) and its salt form (LSN2940930) have recently been shown to be active in adult and pediatric malignancies, including sarcoma. We have now tested the potency of prexasertib in clonogenic survival assays in two new lines of primary patient-derived osteosarcoma cells and in two established osteosarcoma cell lines as a single agent and in combination with cisplatin and the poly ADP-ribose polymerase (PARP) inhibitor talazoparib. Prexasertib alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double-stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations. In combination with cisplatin and talazoparib, prexasertib acts in a synergistic fashion. Chk1 inhibition by prexasertib and its combination with the DNA damaging agent cisplatin and the PARP-inhibitor talazoparib thus emerges as a potential new treatment option for pediatric osteosarcoma which will now have to be tested in preclinical primary patient derived in vivo models and clinical studies.

  Study EGAS00001003923

• Genomic Correlates of Response and Resistance to Immune Checkpoint Blockade in Solid Tumors

  Immune checkpoint inhibitors yield clinical benefit in many cancer types, but molecular predictors of response have not yet been robustly characterized. In this study, we pursued whole exome sequencing (WES) of pre-treatment tumors from patients treated with immune checkpoint therapies - including monoclonal antibodies targeting programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). Using these data, we aim to apply computational pipelines for mutation-calling, neoantigen prediction, and other analyses to validate pre-existing hypotheses regarding response to immune checkpoint therapies and discover new relationships with greater power. Further, by pursuing genomic characterization of tumors from patients with a variety of cancer types, we hope to describe molecular features of intrinsically sensitive or resistant tumors that are both context-specific and shared across cancer types.

  Study phs001565