Search Results - EGA European Genome-Phenome Archive

whole-genome sequencing of gastric cancer

Gastric cancer is one of the most common cancers. Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer tumorigenesis. Here, we analyzed structural variations and mutational signatures via whole-genome sequencing of 168 gastric cancer samples. Our data demonstrates diverse models of complex structural variations operative in GC, which lead to high-level amplification of oncogenes.

Study EGAS00001003512

Genetic variants of the COL4A3, COL4A4, and COL4A5 genes contribute to thinned glomerular basement membrane lesions in sporadic IgA nephropathy patients

Contribution of pathogenic COL4A3/COL4A4/COL4A5 variants to sporadic IgAN is still unclear. Whole exome sequencing was performed in sporadic IgAN patients with thinned glomerular basement membrane lesions and variations in COL4A3/COL4A4/COL4A5 genes were screened and evaluated. 37 different diagnostic variants in COL4A3/COL4A4/COL4A5 gene in 38 patients (31.1%) were identified.

Study EGAS00001006519

Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells

Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequenced normal cell DNAs from 10 individuals with MAP and study the somatic mutation burden and mutational signatures.

Dataset EGAD00001007958

Targeted_sequencing_of_blood_DNA_from_Human_twins (2019-05-31)

The goals of this study is to investigate the prevalence and heritability of age-related clonal haemopoeisis (ARCH) in healthy elderly individuals.We will use a bespoke bait set to pull down DNA regions of interest in whole blood samples combined with HiSeq at a deep level . By correlating findings from each individual to their respective twin we hope to elucidate whether heritable traits influence the development of ARCH. a. 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/ . This dataset contains all the data available for this study on 2019-05-31.

Dataset EGAD00001005055

Preeclampsia InterPregGen Consortium: Whole Genome Sequencing of 100 unrelated Kazakhs (DNA samples from the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan; Gulnara Svyatova, Principal Investigator

Whole genome sequencing of 100 unrelated Kazakhs in order to impute genotypes into PE cases and controls from Kazakhstan and to provide genetic data and infrastructure for future genetic studies in Kazakhstan and Central Asia more generally and to fill a gap in worldwide information as Central Asia is not adequately represented in available genomic data. This dataset is one component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium collaborators at the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan (Gulnara Svyatova, Principal Investigator)

Dataset EGAD00001005467

ENU-CCK-81 cetuximab pilot project

Cetuximab is a targeted monoclonal antibody against the epidermal growth factor receptor (EGFR) which is used therapeutically for the treatment of KRAS wild-type colorectal cancer (CRC). The Cetuximab sensitive KRAS wild-type CRC cell line NCI-H508 has been treated with a fixed concentration of ENU for 24 hours and then selected with Cetuximab until drug resistant clones were ready to be picked and grown up as sub-clones of the parental cell line. These will have genes causally implicated in cancer sequenced to identify common point mutations in multiple independently derived drug resistant clones as a forward genetic screen for mechanisms of resistance to Cetuximab in CRC.

Dataset EGAD00001001947

Identification of drug resistance genes in melanoma

Our aim is to analyze the genome of human melanoma cell lines and short term culture from human melanoma samples in order to identify genes that confer drug resistance to clinically relevant targeted therapies. We will perform whole-exome sequencing, copy number variation analysis and methylome analysis in a collection of human melanoma cell lines and short term culture that will be then screened for drug sensitivity/resistance through a library of clinically relevant drugs and drug combinations. By the combined analysis of the genomic lesion and the drug sensitivity/resistance profile of different cell lines, we will look for genes whose mutation is associated to the sensitivity or resistance to a specific drug in different samples.

Dataset EGAD00001001124

Multiregion Whole Exome sequencing of pHGG and DIPG

The failure to develop effective therapies for paediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. Analysis of 142 sequenced cases revealed multiple tumour subclones, spatially and temporally co-existing in a stable manner as observed by multiple sampling strategies. This dataset provides multi region sequencing of high grade gliomas and diffuse intrinsic pontine gliomas from 15 patients. DNA was extracted from FFPE sections in 2-13 regions of each tumour and sequenced with Agilent SureSelect whole exome sequencing. Germline DNA was also sequenced in 14 cases. Data was aligned to hg19 with bwa and is provided as 79 separate BAM files.

Dataset EGAD00001004114

ENU-NCI-H508-Cetuximab-SecondRound

Cetuximab is a targeted monoclonal antibody against the epidermal growth factor receptor (EGFR) which is used therapeutically for the treatment of KRAS wild-type colorectal cancer (CRC). The Cetuximab sensitive KRAS wild-type CRC cell line NCI-H508 has been treated with a fixed concentration of ENU for 24 hours and then selected with Cetuximab until drug resistant clones were ready to be picked and grown up as sub-clones of the parental cell line. These will have genes causally implicated in cancer sequenced to identify common point mutations in multiple independently derived drug resistant clones as a forward genetic screen for mechanisms of resistance to Cetuximab in CRC

Dataset EGAD00001002065

ENU-NCI-H508 cetuximab fixed concentration project

Cetuximab is a targeted monoclonal antibody against the epidermal growth factor receptor (EGFR) which is used therapeutically for the treatment of KRAS wild-type colorectal cancer (CRC). The Cetuximab sensitive KRAS wild-type CRC cell line NCI-H508 has been treated with a fixed concentration of ENU for 24 hours and then selected with Cetuximab until drug resistant clones were ready to be picked and grown up as sub-clones of the parental cell line. These will have genes causally implicated in cancer sequenced to identify common point mutations in multiple independently derived drug resistant clones as a forward genetic screen for mechanisms of resistance to Cetuximab in CRC

Dataset EGAD00001001948

Role of Epigenetic Memory in Human Induced Pluripotent Stem Cells Pilot

Fibroblasts have been shown to re-program into induced pluripotent stem (hiPS) cells, through over-expression of pluripotency genes. These hiPS cells show similar characteristics to embryonic stem cells including cell surface markers, epigenetic changes and ability to differentiate into the three germ layers. However it is unclear as to the extent of changes in gene expression through the re-programming process.. 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/

Dataset EGAD00001000828

eMERGE: Northwestern (NUgene) WGS

The NUgene Project is a biorepository with longitudinal medical information from participating patients at Northwestern Medicine affiliated hospitals and outpatient clinics. Participants' DNA samples are coupled with data from a self-reported questionnaire (2 versions were used, 1 before and 1 after February 2006, both are included) and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 3 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated enterprise data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators. The electronic MedicalRecords and Genomics (eMERGE) Network is a consortium of 9 clinical sites with EMR linked DNA biobanks, including Northwestern University and its NUgene biobank, funded by the NHGRI (National Human Genome Research Institute) to investigate the use of electronic medical record systems for genomic research. The goal of eMERGE is to conduct genome-wide association studies in approximately 100,000 individuals using EMR-derived phenotypes and DNA from linked biorepositories. Using electronic phenotyping methods, the consortium has been and is using DNA samples from all participating sites to explore the genetic determinants of approximately 80 phenotypes, including both diseases and traits, for which the electronic phenotyping algorithms have or are being published on PheKB.org. Thus, for the eMERGE network, ~900 NUgene subjects were selected, as described in the study inclusion/exclusion criteria section below, to be genotyped using whole genome sequencing (WGS), for use in the eMERGE network as eMERGE subjects. The criteria used below were selected so that these subjects will likely meet the criteria to be cases and/or controls, of diverse races and/or ethnicities, for at least 1 of the ~80 phenotypes being studied within eMERGE, and could be recontacted for future research if needed.

Study phs001191

Effect of Breast Feeding on Immunologic Priming in Young Infants

The mechanisms generating immunoglobulin heavy chain (IgH) biodiversity result in over potentially unique immunoglobulin sequences within an individual. However, over the course of B cell development, B cell receptor (BCR) selection constrains the repertoire significantly. In newborn infants compared to adults, developmental regulation of terminal deoxynucleotidyl transferase (TdT) activity in the bone marrow, selective use of V, D and J gene segments in the IgH locus during fetal life, and immaturity of somatic hypermutation (SHM) and class switch recombination (CSR) mechanisms are likely to contribute to a less diverse IgH repertoire, although the extent of repertoire biodiversity in newborns has not been extensively examined. Furthermore, the fetal IgH repertoire is tightly controlled and for the most part independent of environmental antigenic influences. As a result, the neonatal repertoire, in contrast to older children and adults, is less impacted by the selective pressures of the microbiome, pathogen exposure, and environmental antigens. Evidence for developmental differences in TdT activity is seen in shorter CDR3 lengths and decreased junctional diversity in BCR in both term and preterm newborns. Next Generation Sequencing (NGS) is a sensitive approach to evaluate the neonatal IgH repertoire and assess the relative contribution of each aspect of IgH rearrangement and affinity maturation to overall IgH biodiversity prior to and following isotype class switch. NGS and bioinformatics accurately assess biodiversity by determining the number of unique sequences within the IgH repertoire. Combined with novel analytic tools, NGS provides an approach to compare the extent of somatic hypermutation (SHM), N insertions, V/D/J gene segment usage, and CDR3 length between newborns and adults. Taken together, these measures can be used to assess the earliest events in B cell development using the newborn Ig transcriptome to evaluate the IgM, IgG, and IgA IgH repertoires. The goal of this study was to define the extent of IgH biodiversity in newborns and examine the factors that contribute to the generation of biodiversity during early life. Establishment of the bioinformatics pipeline can be applied to examine the immune deficiency, response to vaccine and infection at molecular population level.

Study phs002073

LCCC1122: Defining the Triple Negative Breast Cancer Kinome Response to GSK1120212

In this study the investigators looked at adaptive reprogramming impact on the kinome when a MEK inhibitor called GSK1120212 (trametinib) was administered in a "window of opportunity" trial. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators gave GSK1120212 for a short period of time (one week) to examine MEK and the other kinase expression in cancer cells both before and after the study drug is given. The investigators gave this drug for research purposes only. The length of time it was given is not intended to treat cancer. Recently researchers at UNC developed a process that can comprehensively profile the majority of the individual kinases in the kinome and examine the impact on kinase expression of kinase inhibitors (Duncan et al, Cell 2012, PMID: 22500798). This can tell us which kinases need to be concurrently blocked to augment responsiveness and prevent acquired resistance so that the investigators can design the best combinations of kinase blocking drugs for triple negative breast cancer. This is especially important for individuals with triple negative breast cancer (TNBC) because there are no targeted drugs available that can block molecules that affect tumor growth. The investigators believe that kinase-blocking drugs have the potential to be a more effective treatment for people with TNBC. In this recently published study (Zawistowski et al, Cancer Discovery 2017, PMID: 28108460), TNBC patients treated with trametinib for 7 days resulted in a transcriptional response characterized by significant reprogramming of the tyrosine kinome, and this adaptive bypass response in human tumors was found to be similar to that seen in preclinical models including TNBC cell lines and mouse xenografts. In this study we also examined whether reprogramming differed between TNBC molecular subtypes, finding that basal-like and claudin-low human TNBC cells and mouse tumor subtypes had different adaptive transcriptional responses to MEK-ERK inhibition. Mechanistically we found that genome-wide enhancer remodeling drove the adaptive transcriptional response, suggesting that epigenetic approaches to reprogramming may be more durable than kinase inhibitor polypharmacology.

Study phs001405

Exceptional Responders Initiative

The Exceptional Responders Initiative is a pilot study to investigate the underlying molecular factors driving exceptional treatment responses of cancer patients to drug therapies. Study researchers will examine molecular profiles of tumors from patients either enrolled in a clinical trial for an investigational drug(s) and who achieved an exceptional response relative to other trial participants, or who achieved an exceptional response to a non-investigational chemotherapy. An exceptional response is defined as achievement of either a complete response or a partial response for at least 6 months duration in a trial or treatment where the overall response rate is < 10%. The hope is to discover underlying molecular features that can be further investigated and may eventually predict benefit from a given drug or class of drugs for a particular patient. This pilot project will successfully characterize approximately 100 cases of tumor tissue and, when available, case-matched germline DNA. All samples will undergo whole exome sequencing, and cases with sufficient nucleic acids will undergo additional analyses (e.g. whole genome sequencing, mRNA-sequencing, mi RNA sequencing, promoter methylation analysis, SNP etc). Each case will be annotated with demographic and clinical information, along with follow-up information minimally sufficient to correlate molecular profiles with response. Both retrospective and prospective collections will be considered. The project will also accept sequencing data and clinical data from patients who have had sequencing performed outside of this project. All data will be de-identified and placed in a controlled access database so other investigators may use them for additional insights. Clinically annotated tissue specimens meeting the criteria will be provided by groups participating in the Exceptional Cases Initiative to a Biospecimen Core Resource (BCR), which will perform quality control on the tissues, and will use a standard operating procedure to isolate nucleic acids. The nucleic acids will be shipped to a sequencing center to perform whole exome sequencing and analysis. These findings will be made available to the broader cancer research community in a controlled access database.

Study phs001145

NHLBI GO-ESP: Lung Cohorts Exome Sequencing Project (Pulmonary Arterial Hypertension)

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The syndrome of pulmonary hypertension (PH) is a pulmonary disease that carries very high morbidity and mortality. Pulmonary arterial hypertension (PAH) is a category of PH (WHO Group 1) that includes several entities (idiopathic or heritable PAH, and PAH associated with other diseases such as connective tissue diseases including scleroderma-associated PAH) and carries a dismal prognosis, in particular when it relates to scleroderma-associated PAH (median survival of about 4 years). It is believed that the severity of structural changes involving the pulmonary vasculature and right ventricular failure are genetically determined. The 'Genomics and Genetics of Pulmonary Arterial Hypertension' study at Johns Hopkins University aims to identify genetic determinants associated with risk of PAH in a cohort of European American and African American participants with and without PAH. The study also focuses on patients with scleroderma, who are further stratified according to those who have or do not have PAH. The broad goals of the Lung GO/ESP-GO falls into two general categories: (i) discovery of all variants (i.e., common and rare) in all protein-coding regions of the human genome (i.e., the exome) conferring risk to complex pulmonary diseases including PAH. The Johns Hopkins University PAH cohort offers a unique opportunity to elucidate genetic variants that cause PAH.

Study phs000290

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

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

Study phs002514

Security Overview

Security Overview The European Genome-phenome Archive (EGA) houses consented human data under controlled access. Access decisions are handled by the relevant Data Access Committee (DAC), which autonomously manages requests through the DAC Portal. This document provides an overview of EGA’s practices in ensuring the security of data stored at EGA. As security is a prime concern of the EGA, the EGA is a member of the Global Alliance for Genomics and Health (GA4GH) Data Security work stream. The EGA contributes and helps develop the recommendations outlined the GA4GH Security Technology Infrastructure document, which defines guidelines, best practices, and standards for building and operating an infrastructure that promotes responsible data sharing in accordance with the GA4GH Privacy and Security Policy. Explore the EGA dataflow to gain deeper insights! Accessing data in the EGA involves several steps. First, users need to create an EGA account. Once logged in, they can request access to data controlled by a DAC through the EGA website (see documentation). The DAC oversees these requests through the DAC Portal, and if approved, grants the necessary permissions to the user's EGA account, allowing them to access and download all relevant data and metadata for the requested dataset(s). The key points of EGA security strategy are: 1 Regular Risk Assessment The EGA regularly identifies and assesses risk related to the following: Breach of confidentiality,Breach of privacy or autonomy,Malicious or accidental corruption or destruction of data archived at EGA,Disruption of services provided by the EGA. 2 Risk mitigation The EGA implements and maintains safeguards to minimise the risks identified above in accordance with the 6 control objectives listed in Appendix 1 and outlined in the GA4GH Security and Infrastructure document.If a breach is discovered, the EGA applies a defined protocol to minimise damage. 3 Identity and authorisation management The EGA authenticates the identity of individuals or software accessing controlled access data held at the EGA.The EGA ensures an appropriate level of assurance (LoA) is applied to the identity consistent with the risk associated with that individual, such as multi-factor authentication for DACs.The EGA provides the minimum access rights and privileges consistent with the user’s identity, allowing access consistent with the GA4GH Privacy and Security Policy, as determined by the appropriate DAC. 4 Audit Logs The EGA maintains a set of logs recording: Changes to user access rights,Data access requests,Resource usage. 5 Cryptography, communication security, and data integrity The EGA ensures data transmission integrity using a hash function.All data transmitted to or from the EGA is end-to-end encrypted.All data at EGA is stored using strong encryption.Encryption keys are not stored in the same system as the encrypted data.All data archived at EGA must be accompanied by a signed submission statement ensuring appropriate consent or ethical approval has been obtained, and is in accordance with all applicable laws and regulations. The EGA has a defined protocol defining the response in the event of a security breach, and is continuing to work with the GA4GH Data Security Work Stream to help define best practice and associated standards for breach responses. Appendix 1 GA4GH Control Objectives Control Objective 1: Implement technology safeguards to minimise the risk of unauthorised access, use, or disclosure of confidential and private data.Control Objective 2: Implement technology safeguards to minimise the risk of discovery, access, and use of individuals’ clinical and genomic data, and individual identities, other than as authorised by applicable jurisdictional law, institutional policy, and individual consents.Control Objective 3: Implement technology safeguards to minimise the risk of accidental or malicious corruption or destruction of data.Control Objective 4: Implement technology safeguards to minimise the risk of disruption, degradation, and interruption of services enabling access to data.Control Objective 5: Implement technology safeguards to minimise the risk of potential security attacks and misuse of authorised accesses and privileges.Control Objective 6: Implement technology safeguards to promptly detect the failure to attain the above control objectives and to respond with proper countermeasures.Appendix 2Refer to the document below to learn more about EGA long-term data preservation policy and procedures at EMBL-EBI.Long-term data preservation

Documentation about/security

Upcycling and merging data to challenge the dogma and identify new therapeutic targets for Glioblastoma

Glioblastoma is the most common brain tumour. Characterised by a poor prognosis and its recurrence after multimodal treatments, the search for preventable risk factors has been mainly inconclusive up to date. Recently, the data merge from datasetsdeposited at the EGA allowed Aaron Diaz’s team to discover that the glioblastoma cells shift toward a mesenchymal phenotype when the tumour is recurring. Challenges in glioblastoma research As for virtually all cancer types, many efforts have been made to unveil the molecular features responsible of the disease, and several cellular pathways have indeed been identified as being frequently mutated in glioblastoma. Nonetheless, targeted therapies based on identified genes have so far failed to improve outcome, thus survival mostly relies on a standard treatment unchanged since 2005. This is a frustrating situation for both the scientific and medical communities, and above all for the patients, still facing a dreadful path. Some researchers hypothesised that this may be due to the inability to efficiently target cancer stem cells, the originators of the other cell types, thus inducing cancer relapse. In 2019 Charles P. Couturier and colleagues sequenced RNA from single cells of freshly excised glioblastomas of 16 patients, and demonstrated that glioblastoma cells replicate normal brain cell development with a conserved neural cancer cell hierarchy centered around glial progenitor-like cells. In this way, they helped identify the possible target cells to improve efficacy and durability of treatment. Data upcycling at the EGA: the glioblastoma case study Single cell RNA sequencing is generated with a laborious and expensive protocol. The quality of the starting material is crucial (cells sample freshly extracted from the patients) and often several attempts are needed before producing reliable quality sequencing results. Collecting big numbers of patients is also challenging. The sequencing data produced by Kevin Petrecca’s group in Montreal, Canada and deposited at the EGA (EGAS00001004422) was recently upcycled by Lin Wang in San Francisco, California and pooled with their freshly produced ones, and then deposited at the EGA as Dataset EGAS00001004909 The data merge allowed Aaron Diaz’s team to discover that the glioblastoma cells shift toward a mesenchymal phenotype when the tumour is recurring. They profiled 86 primary-recurrent patient-matched paired glioblastoma samples with single-nucleus RNA, among other techniques. These very comprehensive results lead the team to challenge the findings from several other cancer fields where chemotherapy standard chemo-radiation therapy selection pressure at the level of genomic alterations; this is indeed not the case for glioblastoma, where the pressure results in phenotypic transition between cellular states. Several technical controls were made to ensure that the merge of the data was not introducing a bias in the results, and an Inter-table analysis demonstrated nearly equal contribution to overall variance from each of the studies included, indicating that the findings were not due to inter-laboratory technical effect. A novel principal-component analysis showed that the largest contribution to variation in primary glioblastoma neoplastic cells was an axis between MES (mesenchymal) and proneural expression programs. In summary, treating glioblastoma often makes a MES, as commented by Lucy Stead about this remarkable work. Check Aaron Diaz’s team Nature Cancer paper, with strong technical tools, state of the art analysis and data from different sources converging to the same outcomes that made possible a significant step toward a better handling of a frightful cancer. References Couturier, C.P., Ayyadhury, S., Le, P.U. et al. Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy. Nat Commun 11, 3406 (2020). Stead, L.F. Treating glioblastoma often makes a MES. Nat Cancer 3, 1446–1448 (2022). Wang, L., Jung, J., Babikir, H. et al. A single-cell atlas of glioblastoma evolution under therapy reveals cell-intrinsic and cell-extrinsic therapeutic targets. Nat Cancer 3, 1534–1552 (2022). Related links: Kevin Petrecca’s group dataset deposited at the EGA: EGAS00001004422 Lin Wang dataset deposited at the EGA: EGAS00001004909

Blog upcycling-and-merging-data-to-challenge-glioblastoma

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

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

Study EGAS00001007115

HCA_Thymus_Disease_DiGeorge_Transplant_RNA

Single cell transcriptomics study of thymic transplant biopsies Allogeneic thymus transplantation is the only curative therapy for complete DiGeorge Syndrome (cDGS), a rare severe primary immunodeficiency characterised by athymia. GOSH is one of only two centres worldwide to offer this treatment. Despite a lack of major histocompatibility complex (MHC)-matching between donor and host, transplanted thymus becomes repopulated by recipient bone marrow derived precursor cells and supports development of functional T-cells. The mechanisms underlying thymopoiesis in this context are poorly understood, but over time we observe reconstitution of T-cell immunity, with the ability to produce host naïve T-cells showing a broad T-cell receptor (TCR) repertoire and to generate MHC-restricted T-cell proliferative responses. Although lifesaving, the achieved immunological reconstitution is typically not complete with circulating T-cell numbers usually remaining below the age related normal ranges. Additionally, we observe persistence of donor-derived T-cells of unknown clinical significance. To gain more insight into the mechanisms by which MHC-mismatched transplanted thymus supports T-cell development with self-tolerance, as well as into the basis of suboptimal T-cell immunity, we now aim to investigate immune reconstitution after thymus transplantation in further detail by using single-cell transcriptomics, applied to thymic transplant biopsies and peripheral blood samples collected during standard post-transplant patient care. By identifying which lineages of host- derived cells repopulate the thymic tissue after transplantation, we will be able to address the role of MHC in positive and negative T-cell selection during T-cell differentiation. We will also be able to clarify the exact ontogeny of the persistent donor T-cells, as well as their possible role. Understanding the mechanisms of action of HLA-mismatched transplanted thymus will contribute to treatment optimisation. Additionally, our research provides a unique opportunity to further investigate key immunological concepts, such as tolerance and autoimmunity, challenging existing paradigms in thymus immunology. 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 EGAS00001004025

MM GWAS dataset

This is a meta-analysis of myeloma datasets, both with and without the UK Biobank cohort included.

Dataset EGAD50000000422

DAC for Studies of "Genetics and Genomics of Cardiovascular Diseases" Group at MDC Berlin, Germany

DAC for Studies of "Genetics and Genomics of Cardiovascular Diseases" Group at MDC Berlin This is an umbrella DAC.

Dac EGAC50000000481

An aggregated vcf file

Germline variants calls were defined using the sequenced reads derived from 230 patients with hepatocellular carcinoma. This dataset is comprised of one aggregated vcf file.

Dataset EGAD00001009410

A small cell lung cancer genome reports complex tobacco exposure signatures

Cancer is driven by mutation. Worldwide, tobacco smoking is the major lifestyle exposure that causes cancer, exerting carcinogenicity through 60 chemicals that bind and mutate DNA. Using massively parallel sequencing technology, we sequenced a small cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. 22,910 somatic substitutions were identified, including 132 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general expression-linked repair pathway were evident. We identified a tandem duplication that duplicates exons 3-8 of CHD7 in-frame, and another two lines carrying PVT1-CHD7 fusion genes, suggesting that CHD7 may be recurrently rearranged in this disease. These findings illustrate the potential for next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.

Study EGAS00000000051

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