12528 results for ""non-traditional+communal+storytelling+approach"+novel+segment+noted+in+critical+commentary"

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• A practical guide for mutational signature analysis in hematological malignancies

  Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, prognosis, and even treatment decisions. However, the field lacks a consensus on analysis and result interpretation. Using whole-genome sequencing of multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and acute myeloid leukemia, we compare the performance of public signature analysis tools. We describe caveats and pitfalls of de novo signature extraction and fitting approaches, reporting on common inaccuracies: erroneous signature assignment, identification of localized hyper-mutational processes, overcalling of signatures. We provide reproducible solutions to solve these issues and use orthogonal approaches to validate our results. We show how a comprehensive mutational signature analysis may provide relevant biological insights, reporting evidence of c-AID activity among unmutated CLL cases or the absence of BRCA1/BRCA2-mediated homologous recombination deficiency in a MM cohort. Finally, we propose a general analysis framework to ensure production of accurate and reproducible mutational signature data.

  Dataset EGAD00001005028

• 10x dataset of an obese human subject

  Biopsies from visceral adipose tissue from the omental depot (OAT) were obtained from an obese individual with participant informed consent obtained after the nature and possible consequences of the studies were explained under protocols approved by the Institutional Review Boards of the Perelman School of Medicine at the University of Pennsylvania, the Children’s Hospital of Philadelphia, or the Tel Aviv Sourasky Medical Center. The obese donor underwent bariatric surgery, the lean donor underwent cholecystectomy. OAT samples were placed in 1 mL of DMEM, and finely minced under sterile conditions before digestion in 50 mL of DMEM with 3 mg/1 mL collagenase IV (Gibco). Samples were incubated at 37°C in a rotating oven for 20-60 min. Adipocyte and stromal vascular fractions (SVF) were separated by centrifugation, and red blood cells (RBCs) were removed from the SVF by histopaque gradient (Sigma). Single-cell RNA-sequencing libraries were prepared using the Chromium platform (10x genomics), and sequenced on the MiSeq 500 or HiSeq 2500 Sequencing System (Illumina).

  Dataset EGAD00001005101

• A non-canonical lymphoblast in refractory childhood T-cell leukaemia

  Refractory cancers may arise either through the acquisition of resistance mechanisms or represent distinct disease states. The origin of childhood T-cell acute lymphoblastic leukaemia (T-ALL) that does not respond to initial treatment, i.e. refractory disease, is unknown. Refractory T-ALL carries a poor prognosis and cannot be predicted at diagnosis. Here, we perform single cell mRNA sequencing of T-ALL from 58 children (84 samples) who did, or did not respond to initial treatment. We identify a transcriptionally distinctive blast population, exhibiting features of innate-like lymphocytes, as the major source of refractory disease. Evidence of such blasts at diagnosis heralds refractory disease across independent datasets and is associated with survival in a large, contemporary trial cohort. Our findings portray refractory T-ALL as a distinct disease with the potential for immediate clinical utility. This dataset contains 56 single-cell RNA sequencing data files with corresponding single-cell T cell receptor sequencing data files. The data here form the validation cohort in our paper.

  Dataset EGAD00001015673

• Single cell transcriptional evolution of myeloid leukaemia of Down syndrome – WGS

  Abstract: Children with Down syndrome have a 150-fold increased risk of developing myeloid leukaemia (ML-DS). Unusually for a childhood leukaemia, ML-DS arises from a preleukaemic state, termed transient abnormal myelopoiesis (TAM), and via a conserved sequence of mutations. Here, we examined the relationship between the genetic and transcriptional evolution of ML-DS from a rich collection of primary patient samples through single cell mRNA sequencing, complemented by phylogenetic analyses in progressive disease. We distilled the transcriptional consequence of each genetic step in the evolution of ML-DS, showing that TAM-defining GATA1 mutations account for most of the ML-DS transcriptome, including those of progressive disease. This transcriptional backbone may thus represent a common vulnerability in ML-DS. We extracted the transcriptional difference between TAM and ML-DS which, unexpectedly, reflected features shared across childhood leukaemia. Our approach delineates the transcriptional evolution of ML-DS and provides an analytical blueprint for distilling consequences of mutations directly from patient samples.

  Dataset EGAD00001015453

• Sebaceous carcinoma tumor/normal exome sequencing and transcriptome sequencing. Transcriptome sequencing of

  Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominated 10/32 samples, while 9 were instead defined by microsatellite instability (MSI) mutations. UV-damage SeC exhibited poorly differentiated, infiltrative histopathologycompared to MSI signature SeC (p = 0.003), features previously associated with dissemination. Strikingly, UV-damage SeC transcriptomes and anatomic distributionclosely resembling those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations/Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquire far fewer mutations without a dominant signature, but show frequent truncating mutations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers.

  Dataset EGAD00001004016

• The mutational landscape of normal human endometrial epithelium

  All normal somatic cells are thought to acquire mutations. However, characterisation of the patterns and consequences of somatic mutation in normal tissues is limited. Uterine endometrium is a dynamic tissue undergoing cyclical shedding and reconstitution lined by a gland-forming epithelium. Whole genome sequencing of normal endometrial glands showed that most are clonal cell populations derived from a recent common ancestor, with mutation burdens differing from other normal cell types and many fold lower than endometrial cancers. Mutational signatures found ubiquitously account for most mutations. Many, in some women all, endometrial glands are colonised by cell clones carrying driver mutations in cancer genes, often with multiple drivers. Total and driver mutation burdens increase with age, but are also influenced by other factors, including body mass index and parity, and clones with drivers often originate during early decades of life. The somatic mutational landscapes of normal cells differ between cell types and are revealing the procession of neoplastic change leading to cancer.

  Dataset EGAD00001004547

• Validation of a Haloplex platform for targeted re-sequencing of the exons of 25 genes

  We recently used the Agilent SureSelect platform to re-sequence a set of genes known to be mutated in human AML. The results from 10 AML DNA samples were very satisfactory, but the effort required was significant. Thus, we decided to re-sequence the same genes using the Haloplax system for target enrichment in 48 AML samples. We planned to do this using MiSeq and have data from a pilot of 3 samples. The data is promising but coverage appears pathcy so far. However, in order to get a better understanding of the data we will need deeper sequencing. We will need two lanes of HiSeq to get the same degree coverage as Sureselect. his 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/

  Dataset EGAD00001000603

• Implementation of the GDPR

  Data Protection 1 About the EGA The European Genome-phenome Archive (EGA) was formally launched in 2008 at the European Bioinformatics Institute (EMBL-EBI), an outstation of the European Molecular Biology Laboratory (EMBL), to address an identified need for archiving and sharing the results of genome-wide association studies from the Wellcome Trust Case Control Consortium. In late 2012, with the signing of a memorandum of understanding (and subsequent formal agreement in 2016) between EMBL-EBI and the Centre for Genomic Regulation (CRG), the EGA formally became a joint project of the two institutes. The two institutes work together to support the EGA services, including supporting submissions, web site, strategic leadership, and data infrastructure developments. 2 EMBL-EBI & GDPR The EGA is co-managed by EMBL-EBI and CRG. EMBL-EBI is an international organisation established by treaty and has certain privileges and immunities (e.g. exemptions from the application of national law) and also may self-regulate its activities (e.g. establish its own institutional legal framework) within the framework of its founding act of 1973. The General Data Protection Regulation (GDPR) is a European Union (EU) regulation that legislates how organisations can share and process personal data of EU citizens. EMBL places great value in maintaining collaboration with researchers who are subject to GDPR. For that reason, it is of utmost importance for EMBL to handle data received from those collaborators in a secure and responsible manner. Mindful of its public mandate and the sensitivity of the data it handles, EMBL has always ensured a high level of data protection in its activities. Since the introduction of GDPR in May 2018, EMBL has established its internal policy on General Data Protection (IP68), exercising its right to self-regulate its operations,., IP 68 establishes a robust personal data protection framework that provides for data protection principles, enforceable data subject rights and oversight and redress mechanisms offering a level of protection comparable with GDPR. 3 CRG & GDPR The Centre for Genomic Regulation (CRG) is an international biomedical research institute of excellence, created in July 2000 and mainly participated by the Catalan Government. It is a non-profit foundation and its mission is to discover and advance knowledge for the benefit of society, public health and economic prosperity. The CRG is a CERCA center. CERCA is the collective organisation for all research centres of excellence in Catalonia. CERCA ensures these centres develop successfully by promoting synergies and strategic cooperation improving their visibility and the impact of their research and promoting the dialogue amongst both public and private stakeholders. As a legal entity based in Spain and operating within the EU, the CRG ensures the compliance with the GDPR and the legal regulations on personal data protection applicable at the national level, as well as any other legislation that may replace, modify or supplement the above-mentioned in terms of personal data protection. 4 EGA & GDPR EGA GDPR Schema 4.1 Genetic and phenotypic data Within GDPR, there are two main actors: data controllers and data processors. Data controllers are persons or entities which determine the purposes and means that the personal data may be processed, e.g. companies, researchers, or universities. For EGA, the data controller is ultimately the data producer and the submitter(s) who submit the data to EGA. The data controller also creates a Data Access Committee (DAC) who will decide on data access permissions at EGA. Data processors are the persons or entities which process the data on behalf of a data controller. With regard to GDPR, EGA is a data processor as it processes data as instructed by the data controller. GDPR applies to any organisation which accesses personal data from an individual within the EU. Under GDPR, personal data is defined as any data that is identifiable, including names and email addresses as well as health-related and genetic data. EGA does not accept personally identifiable data except genetic and phenotypic data, so all other data submitted to EGA, such as names and addresses, must be pseudonymised. GDPR requires that data controllers implement data protection principles, such as data minimisation, to minimise the risk of data leakage, and protect the rights of the data subjects. As a data processor, EGA has a set of security policies that are followed to minimise the risk of unauthorised data access or data loss. In its role as a data processor, EGA requires all submitters to sign a Data Processing Agreement (DPA) when the submission account is first created. This agreement is only required to be signed once per submitter, and will remain valid for future submissions to EGA. 4.2 Other personal data The EGA also collects personal data as part of our interactions with submitters, data access committees, and researchers accessing data distributed by EGA. The below privacy notices explain what personal data is collected by the specific service you are requesting, for what purposes, how it is processed, and how we keep it secure. Privacy Notices for EGA Title Version Last Updated EGA Data Access Committee Account Privacy Notice for EGA Data Access Committee Account 1.0 February 6, 2019 EGA User Account Privacy Notice for EGA User Account 1.0 February 6, 2019 EGA Helpdesk Service Privacy Notice for EGA Helpdesk Service 1.0 February 6, 2019 EGA Website Service Privacy Notice for EGA Website Service 1.0 February 6, 2019 Documentation Title Version Description EGA Security Overview Security Document 1.1 The EGA Security Document provides an overview of EGA’s practices in ensuring the security of data stored at EGA. EGA Data Processing Agreement Data Processing Agreement 1.5 The Data Processing Agreement must be completed and returned as part of the submission process. Please note that this document is non-negotiable. Authorised Submitters Authorised Submitters Formulary 1.0 The Authorised Submitters Form must be completed and returned as part of the submission process. Please list all those that should have access to the submission account in order to submit to the EGA should be detailed here. Dispute Resolution Any controversy or claim arising out of, or relating to, the DPA (including the enforceability or breach thereof, any question regarding its existence, validity or termination) or relating to the EGA Service shall be resolved using the internal dispute resolution mechanisms of EGA including those related to Data Protection. The EGA’s internal dispute resolution mechanism has the following procedure: EGA OPERATIONAL PHASE: Meetings between EGA staff and the Data Controller.LEGAL MANAGEMENT PHASE: Meetings between legal teams of EMBL, CRG and the Data Controller. DIRECTION MANAGEMENT PHASE: Negotiation between the legal representatives of EMBL, the CRG and the Data Controller. If the internal dispute resolution mechanism doesn’t resolve the controversy or claim the next phase is:ARBITRATION PHASE: Resolution by arbitration under the WIPO Expedited Arbitration Rules (“Rules”).

  Documentation about/privacy-notice

• A New High-Throughput Sequencing-Based Technology to Study Heterochromatin Structure

  In this study we report epigenomic and transcriptomics datasets for normal control fibroblasts. The following cell lines were obtained from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research: AG08498, AG07095, originally collected as part of the NIA Aging Cell Repository study. We applied a high-throughput sequencing-based technique, named Sequential Analysis of MacroMolecules accessibilitY (SAMMY-seq), for the genome-wide mapping of chromatin regions separated by differential accessibility. The method is based on the sequential extraction of multiple chromatin fractions, corresponding to increasingly compacted and less accessible chromatin regions, which are mapped along the genome using high-throughput sequencing. Additionally we carried out ChIP-seq for the H3K9me3 and H3K27me3 histone modifications and RNA-seq for the characterization of transcriptome in control fibroblasts.

  Study phs002202

• Genetic Epidemiology of Chronic Lymphocytic Leukemia

  Chronic lymphocytic leukemia (CLL) is a subtype of B-cell lymphoproliferative disorders (LPD), and is the most common form of adult leukemia in Caucasians in the United States. Small lymphocytic lymphoma (SLL) is also a B-cell LPD and is typically considered to be the same disease as CLL, based on pathology. We consider CLL and SLL as the same disease entity, and hereafter refer to both simply as "CLL". Using genealogical databases and cancer records, the familial clustering for CLL is one of the strongest for all cancer sites, strongly implicating germline genetic risk. We ascertained CLL cases and controls for a genomewide association study (GWAS) that was undertaken as part of the International Lymphoma Epidemiology (InterLymph) consortium GWAS. Some CLL cases are also part of extended high-risk CLLpedigrees.

  Study phs001568