Search Results - EGA European Genome-Phenome Archive

Investigating Host Genetic Risk Factors for Tuberculosis in Highly Endemic South African Populations

It is apparent from our recent population genetic and admixture mapping work 1–3 that a substantial part of the ancestral input into the South African Coloured (SAC) population is from the San or Khoe groups, which are not well represented in publicly available genetic databases. It is a reasonable assumption that the SAC population in the Western Cape may have derived more genetic input from the present KhoeSan population in the Northern Cape than the San residing in Namibia. It was concluded by our group that it is indeed the southern African KhoeSan group, the ≠Khomani, that best represent the KhoeSan contribution seen in the SAC 4. More recently, it has been shown that there are ancestry related increases in TB susceptibility, especially with increased Bantu-speaking African and KhoeSan ancestry 5. We aim to elucidate the epidemiological and human-host genetic risk factors for TB and the immunological pathways modulating TB infection. The proposed sub-study will enroll people evaluated for TB at Northern Cape community health clinics and their contacts from their households and/or community. We will conduct a demographic interview, collect saliva, which will be used for genetic analysis, and blood to determine latent TB infection status and capture immunological responses to mycobacterial infections at the cellular level and RNA sequencing.

Study EGAS00001007850

A prognostic human brain network for diffuse midline glioma

Diffuse midline glioma (DMG) are near-universally lethal tumours of the paediatric central nervous system. In animal models, DMG form brain-wide, integrated networks through neuron-to-glioma synapses and glioma-to-glioma gap junctional coupling. This extensive connectivity robustly promotes the growth and invasion of DMG and other glial malignancies through paracrine mechanisms and direct neuron-to-glioma synapses. The organisation and clinical implications of these connections in the living human brain, however, remain to be elucidated. Here, we develop tumour network mapping to compute the brain-wide connectivity profile of DMG: defining a conserved brain network across pontine and thalamic DMG associated with patient short-term survival (DMG network). Tumour functional connectivity with the DMG network was independently predictive of patient overall survival across two external validation cohorts. Tumour growth mapped to DMG network-specific trajectories and peak, in-network neurometabolic changes across development spatiotemporally aligned with the peak age incidence of DMG. Single-nucleus RNA-sequencing confirmed diverse synaptic gene enrichment in high-connectivity DMG. Strikingly, incidental surgical resection of high-connectivity thalamic DMG tissue conferred a significant survival advantage. Collectively, these data define a conserved and prognostically important brain network in children with DMG, consistent with the hypothesis that DMG exploit otherwise healthy brain circuits to promote tumour growth.

Study EGAS50000001752

The Cardiogenics study

Cardiogenics is an European collaborative project, it started in January 2007 and was funded by the European Commission through its Sixth Framework Program (reference LSHM -CT-2006-037593) until 2011. It involved several laboratories from France (INSERM UMRS937), Germany (Lübeck University; Regensburg University), United Kingdom (the Welcome Trust Sanger Institute; University of Leicester) and Sweden (Uppsala University Hospital) and was coordinated by a management group composed of scientists from these different institutions. Under the coordination of the management group the laboratories are still developing projects using Cardiogenics data sets. As part of the Cardiogenics project, RNA from monocytes and macrophages of 363 patients with coronary artery disease and 395 healthy individuals was prepared and genome-wide expression was assessed in both cell types using the Illumina HumanRef 8 v3 Beadchip . The DNA of all these individuals was genotyped using the Human 610 Quad custom arrays. Both data sets were used to conduct eQTL analyses. A subsample of subjects included in an allelic-imbalance substudy were also genotyped using the Illumina Human Custom 1.2M array. Detailed description of these datasets can be found in Shah S et al. Circ Cardiovs Genet 2011; Rotival M et al. Plos Genet 2011, Almlöf et al. Plos One 2012 and Garnier S et al. Plos Genet 2013

Study EGAS00001000411

Integrated analysis of relapsed B-cell precursor Acute Lymphoblastic Leukemia identifies subtype-specific cytokine and metabolic signatures

Recent efforts reclassified B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) into more refined subtypes. Nevertheless, outcomes of relapsed BCP-ALL remain unsatisfactory, particularly in adult patients where the molecular basis of relapse is still poorly understood. To elucidate the evolution of relapse in BCP-ALL, we established a comprehensive multi-omics dataset including DNA-sequencing, RNA-sequencing, DNA methylation array and proteome MASS-spec data from matched diagnosis and relapse samples of BCP-ALL patients (n = 50) including the subtypes DUX4, Ph-like and two aneuploid subtypes. Relapse-specific alterations were enriched for chromatin modifiers, nucleotide and steroid metabolism including the novel candidates FPGS, AGBL and ZNF483. The proteome expression analysis unraveled deregulation of metabolic pathways at relapse including the key proteins G6PD, TKT, GPI and PGD. Moreover, we identified a novel relapse-specific gene signature specific for DUX4 BCP-ALL patients highlighting chemotaxis and cytokine environment as a possible driver event at relapse. This study presents novel insights at distinct molecular levels of relapsed BCP-ALL based on a comprehensive multi-omics integrated data set including a valuable proteomics data set. The relapse specific aberrations reveal metabolic signatures on genomic and proteomic levels in BCP-ALL relapse. Furthermore, the chemokine expression signature in DUX4 relapse underscores the distinct status of DUX4-fusion BCP-ALL.

Study EGAS00001002856

Transcriptomic analysis of Acute Myeloid Leukemia stem cells

Acute Myeloid Leukemia (AML) is characterized by the accumulation of clonal myeloid blast cells unable to differentiate into mature leukocytes. Chemotherapy induces remission in the majority of patients, but relapse rates are high and lead to poor clinical outcomes. Since this is primarily caused by chemotherapy-resistant leukemic stem cells (LSCs), it is essential to eradicate LSCs to improve patient survival. LSCs have predominantly been studied at the transcript level, thus lacking information about post-transcriptionally regulated genes and associated networks. Here we extend our previous report on LSC proteomes to healthy age-matched hematopoietic stem and progenitor cells (HSPCs) and correlate the proteomes to the corresponding transcriptomes. By comparing LSCs to leukemic blasts and healthy HSPCs, we validate candidate LSC markers and highlight novel and potentially targetable proteins that are absent or only lowly expressed in HSPCs. In addition, our data provides strong evidence that LSCs harbor a characteristic energy metabolism, adhesion molecule composition, as well as RNA processing properties. Furthermore, correlating proteome and transcript data of the same individual samples highlights the strength of proteome analyses, which are particularly potent in detecting alterations in metabolic pathways. In summary, our study provides a comprehensive proteomic and transcriptomic characterization of functionally validated LSCs, blasts and healthy HSPCs, representing a valuable resource helping to design LSC-directed therapies.

Study EGAS00001004402

Projects

Projects Jointly managed by the European Bioinformatics Institute (EMBL-EBI) in Cambridge (UK) and the Centre for Genomic Regulation (CRG) in Barcelona, the EGA provides an invaluable service to the worldwide biomedical research community. The teams leading the EGA are involved in several international partnerships and consortia in numerous scientific fields, where they contribute to ambitious projects. In addition to the project listed below, the EGA is in a long-standing partnership with the Global Alliance for Genomics and Health (GA4GH), as described on the dedicated page. On-going projects Project Duration Domain Funder Tags CANDLE | CANDLE project aims to conceptualise and advance the development of National Cancer Data Nodes (NCDNs) in European countries. These NCDNs will boost the reuse of cancer data for research, innovation and policy making, in order to improve diagnostics and treatment for cancer patients, as well as prevention and early detection. 2025-2028 Cancer Horizon Europe DOCUMENTATION EASIGEN-DS | The EASIGEN-DS project aims to conduct a design study to establish a new European Research Infrastructure on Advanced Genomics Technologies, EASIGEN. To develop an excellent scientific, technological and operational design, we will conduct landscape studies, stakeholder consultations, and community surveying. 2025-2028 Genomic and health data Horizon Europe DATA MANAGEMENT DOCUMENTATION INFRASTRUCTURE Go-IMPaCT | Go-IMPaCT will contribute sequenced genomes and provide infrastructure as part of IMPaCT-Cohort, one of the three fundamental pillars of the Precision Medicine Infrastructure associated with Science and Technology (IMPaCT) program in Spain. Along with the Genome of Europe (GoE) project, around 18.000 people will have their genomes sequenced, also contributing to Spain's commitments in 1+MG. Go-IMPaCT will fund the development of an EGA node to manage and share this genomic and phenoclinic data, laying the foundations for regional and ethnic genomic variability in Spain to be available for research purposes. The IMPaCT cohort is created with the spirit of being an open research tool, compatible with the rest of the health research ecosystem, and other international initiatives. 2025-2027 Large-scale genomics and health data; personalised medicine Instituto de Salud Carlos III ACCESS DISCOVERY INFRASTRUCTURE METADATA STANDARDS FAIR-FEGA | This project seeks to accelerate data depositions into FEGA, significantly increasing the data flow in and from FEGA nodes. It will build capacity within the FEGA nodes and increase awareness in a wide range of stakeholders, thus altogether achieving the ultimate goal of enhancing data reuse. The project will be carried out by a strategic consortium comprising seven ELIXIR nodes and two ELIXIR communities. 2025-2026 Not applicable ELIXIR ACCESS DISCOVERY DOCUMENTATION INFRASTRUCTURE METADATA STANDARDS FEGA-Connect | A consortium of six ELIXIR nodes plus the Polish FEGA node (in-kind contribution) joining forces to build a solid base to develop solutions for effective multi-omic sensitive data integration between FEGA nodes and other infrastructures and specialised Data repositories. We aim to promote a more coherent data deposition, discoverability and retrieval of multi-omics datasets, providing FAIRer data and consequently accelerating research. 2025-2026 Multi-omics data ELIXIR ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE METADATA STANDARDS IMPaCT-Data 2 | IMPaCT-Data 2 will develop a digital platform for the integration and modelling of biomedical data associated with IMPaCT (Precision Medicine Infrastructure associated with Science and Technology) projects in Spain. It will deploy a sustainable infrastructure that facilitates the integration, standardisation, interoperability and analysis of clinical, genomic, molecular and medical imaging data. This platform will be aligned with European projects such as Genome of Europe (GoE), the first project to make use of the European Genomic Data Infrastructure (GDI), and EUCAIM. IMPaCT-Data 2 will benefit from advanced Artificial Intelligence and High Computing Capacity Systems capabilities, offering robust and accessible tools for researchers from the National Health System in Spain. 2025-2026 Large-scale genomics and health data; personalised medicine Instituto de Salud Carlos III ACCESS DISCOVERY INFRASTRUCTURE METADATA STANDARDS SenSec | This project aims to establish a mechanism for orchestrating secure access to sensitive data hosted by the EGA, whether in Central EGA or any Federated Node, from Galaxy, a popular open-source, community-driven VRE (Virtual Research Environment) for bioinformatics analysis. Building on a previous prototype that enabled Galaxy users within Trusted Research Environments (TREs) to decrypt sensitive data for workflow execution without sharing private encryption keys, SenSec will expand this prototype into a comprehensive solution for secure data analysis in Galaxy, facilitating encrypted data access and transfer from FEGA/EGA repositories to designated TREs. 2025-2026 Genomic and health data; trusted research environment ELIXIR ACCESS DATA ANALYSIS ERDERA | The European Rare Disease Research Alliance (ERDERA) takes over EJPRD to deliver concrete health benefits to rare disease patients in the next decade by advancing prevention, diagnosis and treatment research. To leave no one behind, over 170 organisations championed by the European Union and member states are working hand in hand to make Europe a world leader in rare diseases research and innovation. 2024-2034 Rare diseases Horizon Europe; "La Caixa" Foundation cofunds CRG's contribution ACCESS DATA ANALYSIS DISCOVERY INFRASTRUCTURE SYNTHIA | The aim of SYNTHIA is to deliver validated, reliable tools and methods for synthetic data generation (SDG). The tools will cover multiple data types including lab results, clinical notes, genomics, imaging and m-health data. SYNTHIA also hopes to make possible the generation of longitudinal data. 2024-2029 Genomic and health data; multi-omics; AI solutions Innovative Health Initiative (IHI) DATA ANALYSIS DATA MANAGEMENT INFRASTRUCTURE GoE | The Genome of Europe initiative aims to build a European network of national genomic reference cohorts of at least 500.000 citizens. These reference cohorts will be selected to be representative of the European population. 2024-2028 Large-scale genomic and health data Horizon Europe ACCESS DISCOVERY INFRASTRUCTURE METADATA STANDARDS HEREDITARY | HEREDITARY aims to transform the way we approach disease detection, prepare treatment response, and explore medical knowledge by building a robust, interoperable, trustworthy, and secure framework that integrates multimodal health data (including genetic data) while ensuring compliance with cross-national privacy-preserving policies. 2024-2027 Neurodegenerative disorders, gut-brain interplay Horizon Europe DATA MANAGEMENT DATA ANALYSIS EOSC-ENTRUST | The mission of EOSC-ENTRUST is to create a European network of trusted research environments for sensitive data and to drive European interoperability by joint development of a common blueprint for federated data access and analysis. 2024-2026 Trusted Research Environment Horizon Europe INFRASTRUCTURE EBV-MS | "Targeting Epstein-Barr Virus Infection for Treatment and Prevention of Multiple Sclerosis". The ambitious goals of the project are to answer the questions why only a few EBV infected persons develop MS, and define the underlying mechanism of this process, as well as clarify if targeting the EBV infection can prevent MS or improve the disease course. 2023-2028 Viral-host genetics; immune response; disease modelling; disease prevention; AI/ML solutions Horizon Europe DATA MANAGEMENT DATA ANALYSIS WISDOM | WELL-BEING IMPROVEMENT THROUGH THE INTEGRATION OF HEALTHCARE AND RESEARCH DATA AND MODELS WITHOUT BORDER FOR CHRONIC IMMUNE-MEDIATED DISEASES aims to deploy novel approaches for data processing, harmonisation, management, and secure data sharing and federated access for diseases like multiple sclerosis. Using an end-user guided approach, it will facilitate responsible and critical assessment of the use of AI in healthcare. 2023-2028 Chronic immune-mediated diseases Horizon Europe DATA MANAGEMENT INFRASTRUCTURE EUCAIM | EUropean Federation for CAncer IMages is a project that will build a highly secure, federated and large-scale European cancer imaging platform, with capabilities that will greatly enhance the potential of Artificial Intelligence in oncology. 2023-2027 Cancer Digital Europe Programme (DIGITAL) DISCOVERY CONTAGIO | CONTAGIO (COhorts Network To be Activated Globally In Outbreaks) aims to create coordination mechanisms to rapidly react to infectious disease (re-)emergence in low- and middle-income countries (LMICs). 2023-2026 Infectious Diseases European Commission - Horizon Europe ACCESS DATA MANAGEMENT DISCOVERY Youth-GEMs | Youth-GEMS (Gene Environment Interactions in Mental Health TrajectorieS of Youth) will conduct research into the genetic and environmental factors of mental health in young European people. 2022-2027 Mental health European Commission - Horizon Europe DATA MANAGEMENT DISCOVERY GDI | The European Genomics Data Infrastructure project is enabling access to genomic and related phenotypic and clinical data across Europe. It is doing this by establishing a federated, sustainable and secure infrastructure to access the data. 2022-2026 Genomic and health data European Commission - Horizon Europe; "La Caixa" Foundation cofunds CRG's contribution DISCOVERY DOCUMENTATION INFRASTRUCTURE IMPaCT-T2D | The IMPaCT-T2D project aims at studying the complete genomes of a large cohort of patients with Type 2 Diabetes mellitus (T2D), using modern sequencing technologies and artificial intelligence (AI) in order to improve the stratification and pharmacological treatment in the context of precision medicine. 2022-2025 Cardiovascular and Complex Diseases Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE Completed projects Project Duration Domain Funder Tags EOSC4Cancer | EOSC4Cancer builds on existing projects, research outcomes and established community solutions to create the federated FAIR data, analysis and services infrastructure needed for European Cancer research programmes. 2022-2025 Cancer European Commission - Horizon Europe DISCOVERY EuCanImage | A European Cancer Image Platform Linked to Biological and Health Data for Next-Generation Artificial Intelligence and Precision Medicine in Oncology. 2020-2025 AI Solutions in Oncology European Commission - H2020 Programme; "La Caixa" Foundation cofunds CRG's contribution DATA MANAGEMENT METADATA STANDARDS GenoMed4ALL | A consortium built to empower personalised medicine in the field of haematological diseases through the use of AI and the pooling of genomic and clinical data. 2020-2025 Hematological diseases European Commission - H2020 Programme DISCOVERY METADATA STANDARDS BY-COVID | The BeYond-COVID project aims to make COVID-19 data accessible to scientists in laboratories but also to anyone who can use it, such as medical staff in hospitals or government officials. Going beyond SARS-CoV-2 data, the project will provide a framework for making data from other infectious diseases open and accessible to everyone. 2021-2024 Infectious diseases European Commission - H2020 Programme ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE IMPaCT-Data | IMPaCT-Data aims to create the infrastructure for secondary use of data from Spanish healthcare systems - electronic health records, medical imaging and genomic repositories - and contribute with the knowledge and methodology produced to the healthcare system. 2021-2024 Large-scale genomics and health dataSpanish Ministry of Science and Innovation; Instituto de Salud Carlos III ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE LaMarato | It is a project aimed at creating and developing a catalan interhospitalary network to interrogate genetic variants from thousands of genetic tests carried out in patients with rare diseases from the main catalan hospitals. 2021-2024 Genomic and health data Fundacio La Marato de TV3 (catalan foundation) DISCOVERY HealthyCloud | This consortium will contribute a Strategic Agenda towards the European Health Research and Innovation Cloud. The project will work in collaboration with a broad range of stakeholders to ensure that all voices are included and that the results are technically and ethically sound. 2021-2023 Not Applicable European Commission - H2020 Programme DOCUMENTATION B1MG | Beyond 1 Million Genomes aims to create a network of genetic and clinical data across Europe. The project provides coordination and support to the 1+ Million Genomes Initiative (1+MG). This initiative is a commitment of 24 EU countries, the UK and Norway to give cross-border access to one million sequenced genomes by 2022. 2020-2023 Not applicable European Commission - Horizon Europe DATA MANAGEMENT INFRASTRUCTURE METADATA STANDARDS ELIXIR-CONVERGE | An alliance with the goal of Connecting and aligning ELIXIR Nodes to deliver sustainable FAIR life-science data management services. 2020-2023 Data Management and Infectious Diseases European Commission - H2020 Programme DATA MANAGEMENT INFRASTRUCTURE METADATA STANDARDS IHCC | The International HundredK+ Cohorts Consortium aims to create a global platform for translational research ? informing the biological and genetic basis for disease and improving clinical care and population health. 2020-2022 Translational research NIH; The Wellcome Trust; CZI INFRASTRUCTURE METADATA STANDARDS PPCG | The Pan Prostate Cancer Group aims to harmonise and interrogate Whole Genome DNA Sequence data generated around the world from over 2000 men with prostate cancer, with associated transcriptome and methylome data to include men from different clinical categories, and ethnicities. This project is about providing breakthrough advances through analysis of a very large series of Whole Genome DNA data from prostate cancer contributed by many of the leading scientists and clinicians working in prostate cancer genomics. 2019-2024 Cancer Cancer Research UK DATA MANAGEMENT CINECA | Consortium providing a Federated solution enabling population-scale genomic and biomolecular data accessible across international borders accelerating research and improving the health of individuals resident across continents. 2019-2023 Large-scale Genomics and Health Data European Commission - H2020 Programme ACCESS DATA MANAGEMENT DISCOVERY INFRASTRUCTURE EASI-Genomics | A project designed to provide easy access to cutting-edge DNA sequencing technologies to researchers from academia and industry, within a framework that ensures compliance with ethical and legal requirements, as well as FAIR and secure data management. 2019-2023 Next Generation Sequencing European Commission - H2020 Programme ACCESS EJP-RD | An European consortium built to create a comprehensive, sustainable ecosystem allowing a virtuous circle between research, care, and medical innovation. 2019-2023 Rare diseases European Commission - H2020 Programme ACCESS DATA MANAGEMENT DOCUMENTATION METADATA STANDARDS EOSC-Life | EOSC-Life brings together the 13 Life Science research infrastructures (LS RIs) to create an open, digital and collaborative space for biological and medical research. The project will publish 'FAIR' data and a catalogue of services provided by participating RIs for the management, storage and reuse of data in the European Open Science Cloud (EOSC). 2019-2023 Not applicable European Commission - H2020 Programme DOCUMENTATION EUCANCan | A federated network aiming at implementing a cultural, technological and legal integrated framework across Europe and Canada, to enable and facilitate the efficient sharing of cancer genomic data. 2019-2023 Cancer European Commission - H2020 Programme DATA MANAGEMENT METADATA STANDARDS The Federated EGA framework: supporting sensitive data management across the ELIXIR Nodes | This project is a direct continuation of the FHD IS with the goal to position the FEGA framework as the core infrastructure driver to support human data sharing for research. 2019-2023 Human genomic data ELIXIR INFRASTRUCTURE UK Biobank | UK Biobank is a large-scale biomedical database and research resource, containing in-depth genetic and health information from half a million UK participants. This project is to archive whole genome sequencing and other genetic data for UK Biobank participants. 2019-2023 Large-scale Genomics and Health Data The Wellcome Trust; UKRI; Amgen; AstraZeneca; GSK; Johnson & Johnson DATA MANAGEMENT INFRASTRUCTURE VEIS | The core mission of VEIS is to create an open ecosystem of technologies that will address and adapt to the requirements of the systems used to analyse and interpret -omics and clinical data in research and application environments in biomedicine. The aim of the project is to leverage the value of the EGA for both industry and society. 2019-2022 Oncology and Rare diseases Generalitat de Catalunya and European Regional Development Fund (ERDF) ACCESS DISCOVERY ELIXIR BEACON IS | This study follows on from a number of earlier activities that have established the ELIXIR Beacon Project. The main aim is to extend the Beacon protocol, developed at EGA, to become the reference ELIXIR Data Discovery product 2019-2021 Not applicable ELIXIR DISCOVERY ELIXIR FHD IS | This project coordinates the delivery of FAIR compliant metadata standards, interfaces, and reference implementation to support the federated ELIXIR network of human data resources. 2019-2021 Human genomic data ELIXIR INFRASTRUCTURE ELIXIR Rare Disease | The Rare Disease Community extends and generalises the system of access authorisation and high volume secure data transfer developed within the EGA. The goal of the Community is to create a federated infrastructure that will enable researchers to discover, access and analyse different rare disease repositories across Europe. It is doing this in partnership with other European infrastructure projects, namely RD-CONNECT, BBMRI-ERIC and E-Rare.2019-2021 Rare diseases ELIXIR INFRASTRUCTURE Solve-RD | Solve-RD - solving the unsolved rare diseases - is a research project funded by the European Commission. It echoes the ambitious goals set out by the International Rare Diseases Research Consortium (IRDiRC) to deliver diagnostic tests for most rare diseases by 2020. The current diagnostic and subsequent therapeutic management of rare diseases is still highly unsatisfactory for a large proportion of rare disease patients - the unsolved RD cases. For these unsolved rare diseases, we are unable to explain the etiology responsible for the disease phenotype, predict the individual disease risk and/or rate of disease progression, and/or quantitate the risk of relatives to develop the same disorder. 2018-2024 Rare diseases European Commission - H2020 Programme ACCESS DATA MANAGEMENT METADATA STANDARDS EuCanShare | An EU-Canada joint infrastructure for next-generation multi-Study Heart research. 2018-2022 Cardiovascular Diseases European Commission - H2020 Programme ACCESS METADATA STANDARDS

Documentation about/projects-and-funders/projects

National Cancer Institute Clinical and Laboratory Analysis of Familial Cancer

The purpose of this study is to continue the analysis begun on 09C0079 which was focused on identification of the genetic mutation associated with a new gastric polyposis syndrome, Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS). GAPPS, first described in 2012, is an autosomal dominant gastric polyposis syndrome that confers a substantial risk for gastric adenocarcinoma. The GAPPS phenotype consists of a carpeting of greater than 100 fundic gland polyps (FGPs) in the oxyntic mucosa of the gastric body and fundus, with antral sparing with some FGPs displaying high-grade dysplasia. This is in contrast to sporadic FGPs that are benign, most often are not associated with high-grade dysplasia though low-grade dysplasia has been reported, and are fewer in number. Gastric FGPs have been found to be associated with Familial Adenomatous Polyposis (FAP) and attenuated FAP, which is an autosomal dominant condition associated with germ line mutations in APC which confers a phenotype consisting of multiple (>100) adenomatous polyps in the colon and rectum developing after the first decade of life. FGPs are reported to occur in 12-84% of patients with FAP, whereas sporadic FGPs are identified in ~5% of patients undergoing upper gastrointestinal endoscopy. Gastric adenocarcinoma arising from FGPs in individuals with FAP have been reported. Other manifestations of FAP and AFAP include polyps in the upper gastrointestinal tract, congenital hypertrophy of retinal pigment epithelium, osteomas and epidermoid cysts, supernumerary teeth, desmoid formation, and other malignancies such as thyroid, small bowel cancer, hepatoblastoma, and medulloblastoma. Thus far there are no reports in GAPPS of polyposis arising in the esophagus, gastric antrum, pylorus, small intestine, or colon.

Study phs001935

1 Intratumoral genetic heterogeneity and clonal evolution following neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal tumors.

Purpose: Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment forpatients with locally advanced rectal cancer. However, little is known about the effect of nCRT in the mutational landscape and intratumoral genetic heterogeneity (ITGH) of rectal tumors. Moreover, response to nCRT vary substantially among patients and the genetic determinants of treatment response are not fully understood. Here, we sought to determine the impact of nCRT in the mutational landscape and ITGH of rectal tumors and to identify putative drivers of therapeutic resistance. Patients and Methods: We analyzed whole-exome sequencing (WES) and clinical data from 79 primary non-treated rectal cancers obtained from The Cancer Genome Atlas (TCGA). We also compared the mutational landscape of a matched set of peripheral blood cells, irradiated tumor-adjacent colonic mucosa and pre and post-treatment tumor samples to determine the iatrogenic effects of nCRT and its impact in tissue genetic heterogeneity. Finally, we performed WES of 7 matched pre and post-treatment tumor samples to examine how nCRT affects the clonal architecture of rectal tumors. Results: We show that rectal tumors exhibit remarkable ITGH, which increases with disease progression. We also show that nCRT, per se, does not introduce novel somatic mutations, nor alters the clonal architecture of the irradiated colonic mucosa. Instead, we show that it acts as a potent selective pressure, favoring the expansion of tumor cell subpopulations more prone to resist therapy and increasing ITGH in the residual tumor. Conclusion: Our results reveal the highly heterogeneous and dynamic clonal architecture of rectal tumors undergoing nCRT. Our results also uncover putative genetic determinants of response to nCRT and a possible role for ITGH in predicting treatment outcome.

Study EGAS00001003250

Evolutionary dynamics of residual disease in human glioblastoma

Glioblastoma is the most common and aggressive adult brain malignancy against which conventional surgery and chemoradiation provide limited benefit. Even when a good treatment response is obtained, recurrence inevitably occurs either locally (c.80%) or distally (c.20%), driven by cancer clones that are often genomically distinct from those in the primary tumour. Glioblastoma cells display a characteristic infiltrative phenotype, invading the surrounding tissue and often spreading across the whole brain. We hypothesised that cancer cells responsible for relapse reside in two compartments of residual disease that are left behind after treatment: the infiltrated normal brain parenchyma, and the sub-ventricular zone (SVZ). In this model, residual disease subclones diverge early during glioblastoma evolution, may remain dormant in the normal parenchyma and are responsible for recurrence. To test our hypothesis, we performed whole-exome sequencing of 69 multi- region samples collected using fluorescence-guided resection from 11 patients, including the infiltrating tumour margin (M) and the SVZ for each patient, as well as matched blood. We used a phylogenomic approach to dissect the spatio-temporal evolution of each tumour and unveil the relation between residual disease and the main tumour mass. We also analysed two patients with paired primary-recurrence samples with matched residual disease. Our results suggest that the infiltrative phenotype is an early evolutionary trait of glioblastoma, giving rise to the tumour mass detected at surgery. After treatment, the same infiltrative clone may seed the growth of a recurrent tumour, thus representing the ‘missing link’ between the primary tumour and recurrent disease. These results are consistent with recognised clinical phenotypic behaviour and suggest that more specific therapeutic targeting of cells in the infiltrated brain parenchyma may improve patient’s outcome.

Study EGAS00001003043

BLUEPRINT EpiVar ChIP-seq in lineage specifying transcription factors

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

Dataset EGAD00001004571

12312 results for "cancer rna-seq"

in 21.68 milliseconds.