Search Results - EGA European Genome-Phenome Archive

Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer (NABUCCO Cohorts 1 and 2)

Study EGAS00001004521

Study of PD-1 negative CD8 effector T-cells in advanced HCC with single-cell sequencing

Study EGAS00001007547

PRECISION WES

WES dataset obtained using Illumina HiSeq 2500, Swift Bioscience library kit, paired reads.

Dataset EGAD00001009639

Biomarker Data Subset

This dataset contains data for CBC counts and absolute protein abundance measurements from ELISA experiments.

Dataset EGAD00001011163

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

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

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

The scRNA dataset for TIGIT in MCL with CART

We collected longitudinal samples from 15 patients with MCL at various clinical time points before and after CAT-T therapy brexucabtagene autoleucel (BA) infusion. The patients were grouped into three categories based on their clinical responses after BA treatment: 1) responsive (n = 9), 2) relapsed (n = 5), and 3) refractory (n = 1). All patients in category #1 and #2 had initially attained a complete response (CR) after BA therapy. The responsive group maintained CR with no relapse at the time of last follow up, while the relapsed group achieved initial CR but eventually relapsed. The 10x Chromium™ Single-Cell 5′ Reagent Kit v2 (PN-1000190, 10x GENOMICS) and Chromium Single-Cell Human TCR amplification Kit (PN-1000252, 10x GENOMICS) were used to perform single-cell separation, cDNA amplification, and library construction for gene expression and TCR repertoire following the manufacturer’s guidelines. Thirty-nine samples passed quality control and underwent single-cell transcriptome profiling with simultaneous single-cell T-cell receptor (TCR) repertoire analysis.

Dataset EGAD00001010180

Durvalumab Plus Tremelimumab Alone or in Combination with Low-Dose or Hypofractionated Radiotherapy in Metastatic Non-Small-Cell Lung Cancer Refractory to Previous PD(L)-1 Therapy: an Open-Label, Multicentre, Randomised, Phase 2 Trial

Brief SummaryThis randomized phase II trial studies the side effects of durvalumab and tremelimumab and to see how well they work with or without high or low-dose radiation therapy in treating patients with colorectal or non-small cell lung cancer that has spread to other parts of the body (metastatic). Immunotherapy with durvalumab and tremelimumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving durvalumab and tremelimumab with radiation therapy may work better in treating patients with colorectal or non-small cell lung cancer.Detailed DescriptionPRIMARY OBJECTIVES:I. To assess safety and tolerability of combined checkpoint blockade with MEDI4736 (durvalumab) and tremelimumab alone or with high or low-dose radiation in non-small cell lung cancer (NSCLC). (NSCLC Cohort) II. To compare the overall response (excluding the irradiated lesion[s]) between combined checkpoint blockade with MEDI4736 and tremelimumab alone or combined checkpoint blockade with low or high dose radiation. (NSCLC Cohort) III. To assess safety and tolerability of combined checkpoint blockade with MEDI4736 and tremelimumab with high or low-dose radiation. (Colorectal Cohort) IV. To determine the overall response rate (excluding the irradiated lesion[s]) with combined checkpoint blockade with MEDI4736 and tremelimumab with either low or high dose radiation. (Colorectal Cohort)SECONDARY OBJECTIVES:I. To estimate median progression-free survival and overall survival. (NSCLC Cohort) II. To determine local control within the irradiated field(s) and abscopal response rates. (NSCLC Cohort) III. To evaluate associations between PD-L1 expression as well as levels of infiltrating CD3+, CD8+ T-cells and overall response. (NSCLC Cohort) IV. To explore changes in PD-L1 expression, circulating T-cell populations, T-cell infiltration, ribonucleic acid (RNA) expression, spatial relationship of immune markers, and mutational burden as a result of low or high dose radiation. (NSCLC Cohort) V. To estimate median progression-free survival and overall survival. (Colorectal Cohort) VI. To determine local control within the irradiated field and abscopal response rates. (Colorectal Cohort) VII. To evaluate associations between PD-L1 expression as well as levels of infiltrating CD3+ CD8+ T-cells and overall response. (Colorectal Cohort) VIII. To evaluate changes between PD-L1 expression as well as levels of infiltrating CD3+, CD8+ T-cells induced by targeted low or high dose radiation. (Colorectal Cohort) IX. To explore changes in circulating T-cell populations, T-cell infiltration, RNA expression, spatial relationship of immune markers, and mutational burden as a result of low or high dose radiation. (Colorectal Cohort)OUTLINE: Patients are assigned to 1 of 2 cohorts. NOTE: This Study is only for Cohort 1. Please see phs003294 for Cohort 2COHORT 1: Patients with NSCLC are randomized to 1 of 3 arms.ARM A: Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive high dose radiation therapy once per day (QD) over 10 days for up to 3 fractions.ARM B: Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive low dose radiation therapy every 6 hours twice per day (BID) on weeks 2, 6, 10 and 14.ARM C: Patients receive tremelimumab intravenously (IV) and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses.COHORT 2: Patients with CRC are randomized to 1 of 2 arms.ARM A: Patients receive tremelimumab intravenously (IV) and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses. Beginning at week 2, patients receive high dose radiation therapy once per day (QD) over 10 days for up to 3 fractions.ARM B: Patients receive tremelimumab intravenously (IV) and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses. Beginning at week 2, patients receive low dose radiation therapy every 6 hours twice per day (BID) on weeks 2, 6, 10 and 14.After completion of study treatment, patients are followed for up to 12 weeks.Official TitleA Phase 2 Study of MEDI4736 (Durvalumab) and Tremelimumab Alone or in Combination With High or Low-Dose Radiation in Metastatic Colorectal and NSCLC Conditions Metastatic Colorectal CarcinomaMetastatic Lung Non-Small Cell CarcinomaStage IV Colorectal Cancer AJCC v7Stage IV Lung Non-Small Cell Cancer AJCC v7Stage IVA Colorectal Cancer AJCC v7Stage IVB Colorectal Cancer AJCC v7 Intervention/Treatment Biological: DurvalumabRadiation: Radiation TherapyBiological: Tremelimumab Other Study ID Numbers NCI-2016-01325NCI-2016-01325 ( Registry Identifier ) (REGISTRY: CTRP (Clinical Trial Reporting Program))17-71910021 ( Other Identifier ) (OTHER: Dana-Farber - Harvard Cancer Center LAO)10021 ( Other Identifier ) (OTHER: CTEP) Molecular Technologies / AssaysCyTOFIHCmIFOlinkRNAseqWES

Study phs003295

PREDICT-HD Huntington Disease Study

The purpose of this project is to make clinical measurements from the PREDICT-HD consortium available through the dbGaP mechanism. The phenotype data will first be converted into a community open standard and subsequently exported to dbGaP for archival and open access distribution of the results of the studies. This will permit members of the scientific community to utilize a permanent resource for investigating the interactions of phenotypes upon an international cohort of early Huntington Disease. In version 2 cut of the data we provided HD CAG repeat lengths for both alleles as well as enrollment age of all participants. We have also generated unique identifiers prospectively compatible with the larger initiative GWAS in Huntington's Disease project (also on DbGaP). As such, the version 1 cut of the data was mainly proof of concept and should be deprecated. Going forward, all updates will add-on to version 2 cut of the data. In version 3 cut of the data, we provided baseline or the first usable MRI T1-weighted imaging analysis subcortical and cortical segmentations and cortical parcellations based on a customized Freesurfer 5.2 pipeline developed at The University of Iowa. The customizations to the standard pipeline were mainly to improve bias field correction and image normalization such that segmentation of gray, white, internal csf, dura and surface CSF are optimized for the Freesurfer pipeline. There are 1111 subjects with results in this data release. In version 4 cut of the data, we provided all longitudinal clinical measurements for all subjects (total of 1476) assessmented or enrolled through the end of 2013. Additionally, we are providing measurements on 39 baseline FDG PET images spatially normalized by SPM5 into MNI space, relative regional metabolic values computed in 120 volumes of interest (VOI) defined in the Automated Anatomical Labeling (AAL) Atlas (Tzourio-Mazoyer et al. 2002), and global metabolic values calculated by SPM standard mean voxel value (within per image fullmean/8 mask). This project is a funded ancillary study of PREDICT-HD. In version 5 cut of the data, we provided the first of many forthcoming results from ancilliary studies of PREDICT-HD. In this data cut, we provide individual subject results derived from structural MRI data. The earliest MRI session for each subject was used. The results summarized represent source based morphometry loading coefficients for 23 components (see: "Patterns of Co-Occurring Gray Matter Concentration Loss across the Huntington Disease Prodrome", Ciarochi et al., 2016, Front Neurol. 2016; 7: 147, Published online 2016 Sep 21. doi: 10.3389/fneur.2016.00147]. In this version 6 cut of the data, we provide a full set of derived data, more than 10,000 raw MRI images, and ancillary study data sets. For sample information please link to: PREDICT-HD Biospecimen Resources

Study phs000222

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

EGAD00000000048

Sequencing data from oestrogen-receptor-alpha-positive metastatic lobular breast cancer sample

Dataset EGAD00000000048

EGAD00010000722

Pilot experiment on functional genomics in osteoarthritis (coreex)

Dataset EGAD00010000722

Transcriptome of (peripheral blood), from donor Sample A, replicate 2 Freezing replicates

Freezing replicates

Dataset EGAD00001010085

Transcriptome of (peripheral blood), from donor Sample A, replicate 2 Technical replicates

Technical replicates

Dataset EGAD00001010083

chr1_allsamples_imputated

Chromosome 1 imputed genotypes of samples genotyped on the Axiom Human Genotyping SARS-CoV-2 array (GRCh38)

Dataset EGAD00010002525

LOPEZ_2019.vcf.gz

Genotype data for new samples in Lopez et al 2021

Dataset EGAD00010002100

Mutation and Microsatellite Burden Predict Response to PD-1 Inhibition in Children with Germline DNA Replication Repair Deficiency: An Observational Registry Study

Study EGAS00001005579

Ovarian subtypes tumor methylation data

This dataset contains ovarian endometriod and ovarian, stomach, pancreatic and colorectal mucinous tumor tissue samples

Dataset EGAD00010002773

Metadata file

"Master" file of patient clinical characteristics and outcomes, samples, and the results of certain analyses, including immunohistochemistry.

Dataset EGAD00001008792

Oxford Nanopore sequencing for APL

Raw fast5 file of Oxford Nanopore sequencing for an APL patient sample

Dataset EGAD00001008151

Reference epigenome OB56_N_PreA_WGBS data generated from KEP study

A OB56_N_PreA_WGBS paired end data for Preadipocytes(fat)

Dataset EGAD00001003479

RPPA analysis + clinical data

RPPA analysis from FAIRLANE Trial of Neoadjuvant Ipatasertib Plus Paclitaxel for Triple-Negative Breast Cancer.

Dataset EGAD00001008507

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

Karyotype Evolution in Response to Chemoradiotherapy and Upon Recurrence of Esophageal Adenocarcinomas

The genome of esophageal adenocarcinoma (EAC) is highly unstable and might evolve over time. Here, we track karyotype evolution in EACs in response to treatment and upon recurrence through multi-region and longitudinal analysis. To this end, we introduce L-PAC, a bio-informatics technique that allows inference of absolute copy number aberrations (CNA) of low-purity samples by leveraging information of high-purity samples from the same cancer. Quantitative analysis of matched absolute CNAs reveals that the amount of karyotype evolution induced by chemoradiotherapy (CRT) is predictive for early recurrence and depends on the initial level of karyotype intra-tumor heterogeneity. We observe that CNAs acquired in response to CRT are partially reversed back to the initial state upon recurrence. CRT hence alters the fitness landscape to which tumors can adjust by adapting their karyotype. Together, our results indicate that karyotype plasticity contributes to therapy resistance of EACs.

Study EGAS00001007711

Multiomic spatial landscape of innate immune cells at central nervous system borders

The innate immune compartment of the human central nervous system (CNS) is highly diverseand includes several immune cell populations such as macrophages that are frequent in the brain parenchyma (microglia) and less numerous at the brain interfaces as CNS-associated macrophages (CAMs).Due to their scantiness and particular location, little is known about the presence of temporally and spatially restricted CAM subclasses during development, health and perturbation. Here, we combined single-cell RNA-sequencing, time-of-flight mass cytometry and single-cell spatial transcriptomics with fate mapping and advanced immunohistochemistry to comprehensively characterize the immune system at human CNS interfaces. We also provide a comprehensive analysis of resident and engrafted myeloid cells in the brains of 15 individuals with peripheral blood stem cell transplantation, revealing compartment-specific engraftment rates across different CNS interfaces... Our results highlight myeloid diversity at the interfaces of the human CNS with the periphery and provide insights into the complexities of the human brain’s immune system.

Study EGAS50000000030

Human Brain Small Extracellular Vesicles Contain Selectively-Packaged, Full-Length mRNA

Brain cells release and take up small extracellular vesicles (sEVs) containing bioactive nucleic acids. sEV exchange is hypothesized to contribute to stereotyped spread of neuropathological changes in the diseased brain. We assessed mRNA from sEVs of non-diseased (ND) and Alzheimer’s disease (AD) human postmortem brain, using short- and long-read sequencing. sEV transcriptomes were distinct from bulk tissue, showing enrichment for multiple genes including mRNAs encoding ribosomal proteins and L1Hs transposable elements. AD versus ND sEVs showed enrichment of inflammation-related and depletion of synaptic signaling mRNAs. sEV mRNA from cultured murine primary neurons, astrocytes, or microglia showed similarities with human brain sEVs and revealed cell-type specific packaging. Nearly 80% of human brain sEV transcripts sequenced using long-read sequencing were full-length. Motif analyses of sEV-enriched full-length isoforms revealed RNA-binding proteins that may be associated with sEV loading. Collectively, we show that mRNA in brain sEVs is selectively-packaged and altered by disease state.

Study EGAS50000000029

Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo

Oncogenic alterations in EGFR frequently co-occur with additional genetic alterations in EGFR-driven lung adenocarcinoma (LUAD), but how specific combinations of mutations affect tumor phenotypes and responses to targeted therapy is yet unknown. We leveraged a genetically engineered mouse model of EGFR mutant/Trp53-deficient LUAD to study the consequences of inactivating 10 different tumor suppressor genes on the fitness and tyorosine kinase inhibitor (TKI) sensitivity of these tumors. We found that loss of Keap1 is associated with a reduced response to therapy. In patients, we found that mutations in the KEAP1/NFE2L2/CUL3 pathway are associated with a significantly shorter time to treatment failure for EGFR TKI therapy compared to matched patients with wild-type KEAP1/NFE2L2/CUL3 tumors. We also analyzed whole exome sequencing data from tumor specimens before TKI treatment and at the time of treatment resistance for mutations in the KEAP1 pathway and these data are being submitted here.  

Study phs002334

Clonal Evolution of Pre-Leukemic Hematopoietic Stem Cells Precedes Human Acute Myeloid Leukemia

Acute myeloid leukemia is an aggressive clonal malignancy of the bone marrow that is the direct result of sequential acquisition of mutations in a single lineage of cells. In this study, we investigate a model in which this mutational acquisition occurs serially in long-lived self-renewing hematopoietic stem cells eventually resulting in frank acute myeloid leukemia. Coding mutations in multiple AML patients were identified using exome sequencing followed by sanger sequencing validation. The level of these mutations was then assessed in residual hematopoietic stem cells from each patient using targeted deep sequencing. These population-level estimates of mutant allele burden were then validated in single cell assays targeted to the identified mutations. This allowed for determination of the order of acquisition of the mutations that preceded the development of the leukemia. The results of this study identify pre-leukemic hematopoietic stem cell clones that could contribute to patient relapse and outcome.

Study phs000549

The Finland-United States Investigation of NIDDM Genetics (FUSION) Study

The Finland-United States Investigation of NIDDM Genetics (FUSION) study is a long-term effort to identify genetic variants that predispose to type 2 diabetes (T2D) or that impact the variability of T2D-related quantitative traits. The initial effort involved linkage analysis of affected-sibling-pair (ASP) families based on over 5,000 individuals living in Finland, and association fine mapping based on these family members and additional T2D cases and controls. We completed a genome-wide association scan on 1161 T2D cases and 1174 normal glucose tolerant (NGT) controls. Individual-level data is available for the 919 T2D cases and 787 NGT controls who reconsented to the use of their data or are deceased (phs000100). In addition, we selected these 919 T2D cases and a matched set of 919 NGT controls (774 overlapping with GWAS) for targeted sequencing of 78 genes associated with glucose, insulin, and/or lipids. 400 of these T2D cases were also chosen for whole-exome sequencing (phs000702).

Study phs000867

Prospective Analysis of Genotypes in Adults Undergoing Therapy for Lung Cancer (Paclitaxel Cohort)

Lung cancer is frequently treated with paclitaxel in combination with several other agents; however, paclitaxel treatment is often ineffective or limited by treatment-related toxicities. Heritable variants in genes associated with absorption, distribution, metabolism, and elimination may predict paclitaxel clinical outcome and toxicity. We designed a prospective multi-institutional study that recruited 546 patients receiving therapy with a 5-year follow up. All patients were genotyped using the Drug Metabolizing Enzymes and Transporters (DMET) platform, which ascertains 1931 genotypes in 235 genes. Genotypes were compared to the progression-free survival of paclitaxel therapy and clinically-significant paclitaxel toxicities. Seven genetic variants were associated with paclitaxel PFS (in ABCB11, ABCC3, ABCG1, CYP8B1, NR3C1, FMO6P, and GSTM3), whereas four genetic variants (in VKORC1, SLC22A14, GSTA2, and DCK) were associated with paclitaxel toxicities. The present SNPs have limited clinical utility but suggest that certain genes are related to important paclitaxel pathways in lung cancer.

Study phs001660

Neuropsychiatric Genetics of African Populations - Psychosis (NeuroGAP-Psychosis)

The NeuroGAP-Psychosis study was conducted in South Africa, Kenya, Uganda and Ethiopia as a response to the lack of genetic diversity in large genomic studies of psychiatric disorders. The study aims to expand knowledge of the genetic and environmental risk factors for neuropsychiatric disorders in Africa through large-scale sample collection and analysis. The initial design is a case-control study in which cases are individuals with schizophrenia or bipolar disorder and controls are age, sex and ancestry matched with individuals from the same geographic location. Cases are patients who are recruited from clinical facilities, both inpatient and outpatient. Controls are people who present for treatment for general medical conditions at health facilities. Data on phenotype, mental disorders, history of physical health problems, substance use and history of past traumatic events was collected from all participants. Additionally, a sample of saliva is collected for DNA extraction. DNA samples were sent to the Broad Institute for genotyping using Illumina Infinium Global Screening Array.  

Study phs002528

A Genome-wide Association Study (GWAS) of Risk for Osteosarcoma

This is a genome-wide association study (GWAS) of osteosarcoma, the most common primary bone malignancy. Osteosarcoma typically occurs in adolescents and young adults. It occurs at increased frequency in several inherited cancer predisposition syndromes but the genetic contribution to sporadic osteosarcoma is largely unexplored. The objective of this study was to identify genetic risk factors for osteosarcoma by conducting a genome-wide association study. We developed collaborations with multiple institutions in order to attain the necessary sample size required to discover novel loci in the genome associated with osteosarcoma using the GWAS approach. Genomic DNA (either blood or buccal in source) derived from osteosarcoma cases was obtained from each participating institution or research group. De-identified blood or buccal cell DNA samples from osteosarcoma cases were derived from existing biobanks at the collaborative institutions. Control subjects were derived from existing NCI cohorts and matched by gender and ethnicity.

Study phs000734

The Microbial Ecology of Bacterial Vaginosis: A Fine Scale Resolution Metagenomic Analysis

Archived self-collected vaginal swabs were utilized from a pilot study of vaginal douching cessation (NIH/NIAID R03-AI061131). Thirty-nine non-pregnant, reproductive-age women who reported the use of vaginal douche products in the two months prior to screening were enrolled. Thirty-three of these successfully completed the 16-week longitudinal study. Participants self-collected vaginal swabs and smears twice weekly. We report sequences based on the analysis of 16S rRNA gene sequences amplified from whole genomic DNA isolated from the swabs. Bacterial vaginosis (BV) is defined by Gram's stain of vaginal fluid (Nugent's score =7). The large body of information generated will facilitate understanding of vaginal microbial community dynamics, the etiology of BV, and drive the development of better diagnostic tools for BV. Furthermore, it is hoped that the information will enable a more personalized treatment of BV and ultimately, prevent adverse sequelae associated with BV.

Study phs000261

Genetic Study of Vascular Anomalies

Vascular anomalies are malformations or tumors of the vasculature that can result in significant morbidity and mortality. Vascular anomalies are caused by germline or post-zygotic pathogenic variants in genes that regulate cell growth and vascular development. Complex or extensive vascular anomalies are often intractable despite interventions such as sclerotherapy, embolization, or surgery. In recent years, targeted therapy has played an increasingly crucial role in the management of these diseases. Identification of the molecular causes of vascular anomalies is essential to provide efficacious therapy; however, genetic profiling is often limited by difficulty obtaining affected tissues and limited sequencing depth. The lack of this information limits treatment options and the precision of targeted therapy, especially for primary complex lymphatic anomalies. To address these limitations, we have applied novel techniques, including analysis of unconventional samples such as endothelial cells isolated from lymphatic fluid and cell-free DNA, deep coverage exome sequencing, and unique molecular identifier ultra-deep targeted sequencing, in the molecular profiling of these diseases.

Study phs003197

RNA-Seq of PBMC's from rUTI Patients and Healthy Controls

Recurrent urinary tract infections (rUTIs) are a major health burden worldwide, with history of infection being a significant risk factor. While the gut is a known reservoir for uropathogenic bacteria, the role of the microbiota in rUTI remains unclear. We conducted a year-long study of women with and without history of rUTIs, from whom we collected urine, blood and monthly fecal samples for multi-omic interrogation. The rUTI gut microbiome was significantly depleted in microbial richness and butyrate-producing bacteria compared to controls, reminiscent of other inflammatory conditions, though Escherichia coli gut and bladder dynamics were comparable between cohorts. Blood samples revealed signals of differential systemic immunity, leading us to hypothesize that rUTI susceptibility is in part mediated through a syndrome involving the gut-bladder axis, comprising gut dysbiosis and differential immune response to bacterial bladder colonization, manifesting in symptoms. This work highlights the potential for microbiome therapeutics to prevent and treat rUTIs.  (Reprinted from medrxiv.org ) 

Study phs002728

Single-cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation

GABAergic interneurons are essential for neural circuit function and their loss or dysfunction is implicated in human neuropsychiatric disease. In vitro methods for interneuron generation hold promise for studying human cellular and functional properties and ultimately therapeutic cell replacement. We used a protocol for generating cortical interneurons from hESCs and analyzed the properties and maturation timecourse of cell types using single-cell RNAseq (data available at GEO under: GSE93802 on March 10 2017). Transcriptomic profiles of the hESC-derived interneurons were compared to several different populations of cells from mid-gestation human neocortex that showed differing levels of PAX6 and SOX2 expression. For this study, 104 samples of 100 human neocortical cells each, have been sorted based on SOX2 and PAX6 expression, mRNA recovered from the fixed cells by FRISCR, and transcriptomic profiles generated by SmartSeq2. The RNA-seq data from the 104 100-cell samples is included in this dbGaP study.

Study phs001276

A Whole Genome Association Scan for Myopia and Glaucoma Endophenotypes using Twin Studies

Myopia and glaucoma are highly prevalent ophthalmic disorders worldwide and contribute significantly to ocular morbidity. There is substantial evidence that genetic factors play a significant role in the development of non-syndromic myopia and glaucoma. We propose to perform mapping studies for well-characterized twin populations in the United Kingdom and Australia in order to ultimately identify implicated genes for these disorders and related ocular parameters. This will provide a fundamental molecular understanding of how these disorders develop, and may lead to directed physiologic (i.e. pharmacologic, gene therapy) interventions. Our aim is to dissect the genetic basis of the eye disorders myopia and glaucoma. Instead of limited analyses of the trait/disease in a dichotomous manner, we are using continuous phenotypes of measures of refraction and intermediate phenotypes of glaucoma to analyze quantitative traits in unselected population samples of volunteer twins. Achievement of this goal requires cooperative efforts and large sample sizes. Thus, we have created an international collaboration of large complementary studies.

Study phs000142

Hi-C Profiling of Solid Tumor Samples

Structural variants, such as translocations, inversions, duplications, and deletions, have long been recognized as mutations that can contribute to the initiation and progression of cancer. This can occur through a variety of mechanisms, including changes in gene dosage and the generation of fusion genes. In recent years, it is becoming increasingly clear that these events also can alter how genomes are organized in 3D space in the nucleus and contribute to changes in enhancer-promoter regulation. However, it remains poorly understand how often 3D genome structural changes occur in cancers, what genes are affected by these events, and in which tumor types. This study is part of ongoing work to better characterize 3D genome structural changes across a variety of tumor types to better understand where and when 3D genome structure changes as the result of structural variation in cancer genomes and to characterize the genes and tumor types affected.

Study phs003227

National Institute of Environmental Health (NIEHS) Sciences Study of Somatic Mutation Load in Clones of Single Human Cells

Accumulation of genetic changes with time and proliferation of cells is inevitable. We report here the genome-wide magnitude and spectra of mutations accrued in skin fibroblasts over the lifetime of healthy humans. We found that every cell contains at least one somatic chromosomal rearrangement and 600 - 13,000 base substitutions, similar to the median mutation load in human cancers. The mutation spectra and correlation of changes with epigenomic features also resemble many human cancers. Interestingly, the magnitude of ultraviolet light-characteristic mutations, representative of environmental mutagenesis, in sun-exposed skin was comparable to the number of mutations attributed to endogenous DNA damage estimated in unexposed cells. Our methodology allows delineating the precise contributions of environmental and endogenous factors to the accrual of genetic changes in the human body. This is fundamental to understanding the etiology, and improving the prognosis and prevention of cancers and other genetic diseases.

Study phs001182

Wisconsin Longitudinal Study on Aging

The Wisconsin Longitudinal Study (WLS) is a long-term study of a random sample of men and women, who graduated from Wisconsin high schools in 1957, and their siblings. The WLS panel started out with a panel of 10,317 members from the class of 1957. Over time a second panel of 8,734 randomly selected siblings of the original graduate panel were recruited for the study. Of these combined panel members, 9,027 survived and contributed saliva for genetic analysis. Survey data were collected from the original respondents or their parents in 1957, 1964, 1975, 1992, 2004, and 2011, and from a selected sibling in 1977, 1994, 2005, and 2011. WLS data provide a detailed record of educational, social, psychological, economic, mental and physical health characteristics of a relatively homogeneous population that is almost entirely of Northern and Western European ancestry. Saliva was first collected in 2007-2008 by mail. Additional samples were collected in the course of home interviews that began in March 2010.

Study phs001157

DNA Methylation Studies in CREW Cohorts (URECA and COAST)

Children's Respiratory Environment Workgroup (CREW) is an NIH-funded project consisting of 12 individual U.S. cohorts and three scientific centers working together to identify phenotypes and causes of childhood asthma. CREW includes data from a large number of children and their families, with broad diversity in terms of ethnicity, family characteristics, neighborhoods and geographic locations. In this study, we identified differentially methylated regions from whole-genome bisulfite sequencing (WGBS) in nasal epithelial cells from 39 children of European or African ancestries, and with or without allergic asthma. Study participants were from two of the CREW cohorts: the Urban Environment and Childhood Asthma (URECA) cohort and the Childhood Origins of Asthma (COAST) cohort.The URECA children are also participants of a larger genetic study, in which DNA samples are derived from blood. That data is presented in the "Whole Genome Sequencing in the Inner City Asthma Consortium (ICAC) Cohorts - phs002921" study.

Study phs003321

NHLBI TOPMed: MWCCS: Sex Differences in the Role of Multi-Omics in HIV-Associated Carotid Artery Atherosclerosis

The MACS-WIHS Combined Cohort Study (MWCCS) is a multicenter prospective cohort study of men and women in the U.S. that aims to understand and reduce the impact of chronic health conditions, including heart, lung, blood, and sleep (HLBS) disorders that affect people living with HIV. MWCCS, which currently has over 5000 active study participants, is designed to investigate a spectrum of questions relating to the basic science, clinical science, and epidemiology of HIV infection in the U.S., with a focus on comorbidities among men and women living with HIV. The current substudy, nested within the MWCCS, integrates detailed metabolomics and proteomics data, among other "omics" measures, to improve the understanding of the etiology of atherosclerosis and cardiovascular disease in women and men with HIV, guide mechanistic studies, and provide insights to more efficient intervention strategies. Data on 374 men are included in the current substudy.

Study phs003651

KDM6A Loss Triggers an Epigenetic Switch that Disrupts Urothelial Identity and Drives Cell Proliferation in Bladder Cancer

Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. How mutations of this chromatin modifier impact the epigenetic landscape to promote carcinogenesis is poorly understood. Here, we demonstrate that KDM6A loss triggers an epigenomic switch that disrupts urothelial identity and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 binds KDM6A at enhancers to activate genes instructing urothelial differentiation. In KDM6A-deficient cells, we observed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn represses FOXA1 target genes and activates cell-cycle progression genes. Importantly, ATF3 depletion reverses the cell proliferation phenotype. These data establish that KDM6A loss creates an epigenetic state that drives tumor growth in an ATF3-dependent manner, forging a molecular vulnerability that can be targeted by novel therapeutic strategies.

Study phs002801

Spatial atlas of human atherosclerosis highlights role of the microvasculature in disease

Atherosclerosis is a pervasive contributor to ischemic heart disease and stroke. Despite the advance of lipid lowering-therapies and antihypertensive agents, the residual risk of an atherosclerotic event remains high and developing therapeutic strategies has proven challenging. This is due to the complexity of atherosclerosis with a spatial interplay of multiple cell types within the vascular wall. Here we generate an integrative high-resolution map of human atherosclerotic plaques combining single-cell RNA-seq from multiple studies and spatial transcriptomics data from 12 human specimens, with different stages of atherosclerosis. We show cell-type and atherosclerosis-specific expression changes and spatially constrained alterations in cell-cell communication. We highlight the possible recruitment of lymphocytes via ACKR1 endothelial cells of the vasa vasorum, the migration of vascular smooth muscle cells towards the lumen by transforming into fibromyocytes, and cell-cell communication in the plaque region, indicating an intricate cellular interplay within the adventitia and the subendothelial space in human atherosclerosis.

Study EGAS50000000660

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