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• Whole Genome Sequencing Analysis in a Family of Discordant Twins With Non-Syndromic Microtia and Hemifacial Microsomia: Identification of Novel Candidate Genes and Variants

  This research is a non-NIH effort to discover the pathogenesis of non-syndromic microtia and to detect potential candidate genes. Microtia (OMIM 600674, 612290, 251800) is a spectrum of congenital anomalies and facial abnormalities, 90% of the cases followed by hearing loss. Two types of the disease are described in terms of connection to the affected syndromes: anomalies (syndromic) and only clinical manifestation (non-syndromic) associated with other symptoms. Though the exact pathogenesis of microtia remains unknown, pathogenic genes of majority of the microtia syndromic types have been identified. However, the genetic mutation of the non-syndromic microtia has not been confirmed. In this study, whole genome sequencing (WGS) was utilized to screen mutations in monozygotic discordant twins of congenital microtia-atresia and their family members. One of the twins, along with her grandfather, was discordant for microtia-atresia. By bioinformatic analysis of the WGS data from monozygotic twins with microtia and their non-microtia relatives, we proposed that among 28 identified potential genes, 4 of them (CNOT1, ODAD4, TBX15, and GIPC3) could be more responsible for non-syndromic microtia development and phenotypic features. Interested investigators may request to access the DNA genomic sequencing data of the study participants via dbGaP authorized access. In addition to raw genomic sequencing data, datasets of germline mutations and candidate gene mutations may also be available for investigators to request.

  Study phs003216

• Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma

  In IDH-mutant astrocytomas, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain elusive. Here, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2R172K and TP53R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recurrent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2R172K mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 with PDGFRA gain was found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astrocytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. These findings suggest that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma.

  Study JGAS000646

• Raw ONT R9 data: Rapid brain tumor classification from sparse epigenomic data

  This dataset contains 75 Nanopore sequencing experiments using a MinION sequencer and R9 flow cells from 51 patient biopsies. Gzipped tar files containing all fast5 files per sample are provided.

  Dataset EGAD50000000832

• SEF tumor sequencing data

  This dataset contains samples from 8 patients with Sclerosing epithelioid fibrosarcoma. All 8 samples have whole exome tumor data and tumor RNAseq data. 3 samples also have matched normal dna sequence data.

  Dataset EGAD00001011100

• CTCF ChIP-seq of human acute leukemias

  CTCF ChIP-seq of 39 primary samples derived from human acute leukemias, namely AML, T-ALL and mixed myeloid/lymphoid leukemias with CpG Island Methylator Phenotype (CIMP).

  Dataset EGAD00001011059

• Unmapped sequencing reads of EGAD00001007002

  Bam files of unmapped sequencing reads of samples in EGAD00001007002. When utilized in combination with corresponding aligned bam files in dataset EGAD00001007002, they contain all sequencing reads of samples.

  Dataset EGAD00001007647

• Breast cancer sequential sampling study

  This study aims to whole genome sequence DNA derived from breast cancer patients who received neo-adjuvany chemotherapy. All patients had multiple biopsies performed before chemotherapy. Patients who had residual disease after the course of treatment underwent a further biopsy. We aim to characterise the mutations involved.

  Dataset EGAD00001000387

• Exploiting evolutionary steering in cancer therapy

  This dataset contains 9 bam files of exome sequencing for an experiment of evolved resistance. Here a barcoded cell line (HCC827 - POT) has been treated under high concentrations of gefitinib (GEF) and trametinib (TRM) until resistance has evolved, as well as under control conditions (DMSO). The dataset contains exome sequencing of confluent cells for three replicates for each anti-cancer drug as well as two replicates of growth under DMSO conditions. The original barcoded cell line (POT) was also exome sequenced and is included in the cohort. Sequencing was performed on the Illumina NovaSeq platform.

  Dataset EGAD00001005782

• Whole-genome sequencing data of human hematopoietic stem and progenitor cells in post-transplant clonal hematopoiesis

  This dataset contains BAM files of whole-genome sequencing data of single human HSPCs after colony expansion, for three individuals who harbor a DNMT3A mutant clonal hematopoiesis clone in their blood system after hematopoietic cell transplantation. 29 samples are present in this dataset; 10 samples for LTHIT005, 10 samples for LTHIT131, and 9 samples for LTHIT069. In the sample name, samples are annotated for being DNMT3A wildtype (wt) or mutant (mut), except for LTHIT069 (wt samples: F13, H4, K2, L16, N12, mut samples: C8, E10, L9, N5). Whole-genome sequencing was performed after standard Illumina WGS library preparation and sequenced on a Novaseq 6000 using 150 bp paired-end sequencing. The sequencing depth is 15x genome coverage, or 50Gbases per sample.

  Dataset EGAD50000001347

• Efficacy of two different FGFR-inhibitors in a patient with extrahepatic cholangiocarcinoma harboring an FGFR2 mutation

  Cholangiocarcinomas (CCAs) is a type of cancer with few effective systemic therapies. Elucidation of the molecular landscape of the disease from genomic studies based on next generation sequencing (NGS) has contributed to the introduction of new targeted therapies. One of these treatments consists of a class of small molecules that target members of the FGFR family of receptor tyrosine kinases. These drugs are effective and have been approved for cholangiocarcinomas with fusions or rearrangements of FGFR genes. In contrast, the role of these inhibitors in cholangiocarcinomas with mutations in FGFR genes is less well defined. We report here a patient with a cholangiocarcinoma bearing a FGFR2 p.Ser252Trp mutation. The patient was treated with two different FGFR inhibitors, as the first caused ocular toxicity. She obtained clinical benefit from both. This case illustrates the efficacy of FGFR inhibitors on cholangiocarcinoma with specific point mutations. This is the first case to report the clinical benefit of these drugs in FGFR2 p.Ser252Trp mutation. Clinical benefit can be sustained, as seen in our patient. Our case also shows that FGFR inhibitors-induced adverse effects, such as ocular toxicities, may not recur after re-challenge with an alternative drug of the same class.

  Study EGAS50000000015

• Clonal_haematopoiesis_in_patients_with_AAA

  Recent advances in genomics have demonstrated that clonal haemopoiesis driven by leukaemia associated somatic mutations is a relatively common phenomenon that increases in frequency with advancing age. Whilst individuals with clonal haemopoiesis have an increased risk of developing haematological malignancies, they also have an increased mortality from other causes. Additionally, certain mutations are almost exclusively seen in individuals aged 70 years or older, whilst others are seen in individuals with non-haematological cancers including breast and ovarian. Recently, clonal haemopoiesis was found to be associated with a significantly increased risk of atherosclerotic cardiovascular disease. This association is thought to be causative with clonally-derived macrophages showing elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis. Another vascular pathology, abdominal aortic aneurysm (AAA), increases with age and shares risk factors with atherosclerosis (including smoking, male sex, high cholesterol). However, the impact of these risk factors and the overlap between AAA and atherosclerosis is poorly understood. To investigate a possible link between clonal haemopoiesis and AAA, we will study DNA samples from 300 patients with AAA and up to 200 controls for evidence of clonal haemopoiesis. This will be done using target DNA enrichment with biotinylated RNA baits followed by high throughput sequencing.

  Study EGAS00001002873

• Clonal Lineage Tracing of Primary Human Cortical Progenitors, Cell Type Profiles in the Brain Vasculature and Genotyping Data for 22q11DS and Control iPS Lines

  We sought to characterize the cell types produced by individual human cortical progenitors and describe their lineage relationships. We labeled individual human cortical cells with a massively complex lentivirus library encoding a GFP reporter gene and a molecular barcode that could be captured by standard 3' scRNA-seq methodologies. We then cultured the labeled human cells for 6 weeks in either a 1) mouse cortical astrocyte co-culture system or 2) in the mouse cortex as a xenograft. In a separate experiment, we maintained human cortical tissue slices in organotypic slice culture for 12 days. GFP+ cells were then isolated by FACS and then captured on the 10x chromium scRNA-seq platform. An additional sample was labeled by lentivirus and briefly cultured for 3 days prior to being mixed with mouse 3T3 cells in order to perform a cell mixing experiment ("barnyard") to benchmark our methodologies. We found that human individual cortical progenitors gave rise to both excitatory and inhibitory neurons as well as glia.We also sought to characterize the adult brain vasculature in both vascular malformations and non-malformed tissue. We use the 10x chromium scRNA-seq platform across 10 individuals (5 control and 5 arteriovenous malformations). We find broad disregulation across multiple cell types including the immune cells and find a specific monocyte subtype to contribute to a rupture phenotype. We also find a novel population of fibromyocytes in both conditions.Finally, we confirmed the genotype status of iPS lines that were derived from either karyotypically normal control individuals or from DiGeorge Syndrome patients carrying the 22q11.2 deletion using the Illumina Infinium Global Screening Array v3.0.

  Study phs002624

• Identification and Molecular Characterization of Somatic Mutations in Malformations of Cortical Development

  Genetic mutations causing disease may be inherited, newly acquired in parental gametes and present in the zygote or acquired as somatic events at some point in development after fertilization. The burden and localization of an acquired mutation depend on when the mutation arises. As is the case for inherited genetic variation, there is accumulating evidence that somatic mutations can lead to severe tissue-specific disease. Malformations of cortical development (MCD) represent a group of disorders characterized by a range of morphological and structural abnormalities of the cerebral cortex reflecting errors in embryonic cortical development. MCD are associated with intellectual disability, as well as refractory epilepsy, and may require the surgical removal of the affected tissue. Inherited gene mutations involved in neuronal development explain only a fraction of MCD cases. In this project we sought to evaluate the hypothesis that somatic mutations disrupt embryonic cortical development and are responsible for a substantial fraction of MCD. Using high coverage next generation sequencing of protein-coding regions in DNA extracted from abnormal brain tissue and unaffected tissue (leukocytes) from patients with three forms of MCD, we sought to identify somatic mutations within each patient with MCD. Exome sequence data from study participants are provided to facilitate research into the genetic underpinnings of MCD.

  Study phs002128

• Mapping Systemic Lupus Erythematosus Heterogeneity at the Single Cell Level

  Patients with Systemic Lupus Erythematosus (SLE) display a complex blood transcriptome whose cellular origin is poorly resolved. Using single-cell RNA-seq, we profiled ~276,000 PBMCs from 33 children with SLE (cSLE) with different degrees of disease activity (DA) and 11 matched controls. Increased expression of Interferon-stimulated genes (ISGs) distinguished cSLE from healthy control cells. The high-ISG expression signature (ISGhi) derived from a small number of transcriptionally defined subpopulations within major cell types, including monocytes, CD4+ and CD8+ T cells, NK cells, cDCs, pDCs, B cells and especially plasma cells. Expansion of unique subpopulations enriched in ISGs and/or in monogenic Lupus-associated genes classified patients with the highest DA. Profiling of ~82,000 single PBMCs from adult SLE patients confirmed the expansion of similar subpopulations in patients with the highest DA. This study lays the groundwork for resolving the origin of the SLE transcriptional signatures and the disease heterogeneity towards precision medicine applications. Patient demographics, clinical and laboratory data and treatment are summarized and available. The genomic data for participant aHD2 will not be included in the dataset The study description is reprinted from Nehar-Belaid et. al. Nature Immunology, 2020, with permission from Nature Immunology Group

  Study phs002048

• Childhood Cancer Data Initiative (CCDI): Pediatric In Vivo Testing Program –Sarcoma, Kidney, and Liver Cancers

  The goal was to complete whole exome sequencing (WES) and RNA sequencing (RNA-Seq) on patient derived xenograft samples. Cancer in children is rare with approximately 15,700 new cases diagnosed annually in children 21 years or younger in the U.S. Through use of multimodality therapy (surgery, radiation therapy, and aggressive chemotherapy), 70% of patients will be 'cured' of their disease, and 5-year Event-Free Survival (EFS) exceeds 80%. Consequently, the number of patients that can be enrolled in phase I/II clinical trials is small, and most patients will have been extensively treated, hence drug/radiation resistant. Thus, preclinical studies that accurately translate into effective clinical therapy are an essential component of pediatric drug development. Our group has contributed to studies in the Pediatric Preclinical Testing Program (PPTP) and Pediatric Preclinical Testing Consortium (PPTC) that have led to clinical studies through Children's Oncology Group (COG). Of importance, we have developed and characterized over 330 Patient Derived Xenografts (PDX), developed from tumors both at diagnosis and relapse, that can be used to facilitate pediatric drug development as directed by FDA under the Research to Accelerate Cures and Equity for Children Act (RACE for Children Act).

  Study phs003160

• Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy

  Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In murine models, hematopoietic Tet2 mutation enhanced the immune checkpoint blockade (ICB) response via the combined presence of phagocytes, CD4 and CD8 T cells. This effect was lost with myeloid- or T-cell restricted Tet2 inactivation, or in mice with 20% Tet2-mutant hematopoiesis. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially restricted cell states linked to tumor progression while inducing anti-tumor states. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, alongside decreased exhaustion and regulatory phenotypes. This murine data was clinically relevant, since tumors from colorectal cancer and melanoma patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, inflammation, and T cell activation. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, we demonstrate that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

  Study EGAS50000001191

• METABRIC: Data from Batra et al (2021); DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation

  DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, RRBS-based profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, the study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.

  Study EGAS00001004327

• Whole-exome sequencing data of patients with T follicular helper cell lymphomas

  This dataset contains WES data analyzed using the Genomon2 pipeline (v.2.6.2, https://github.com/Genomon-Project) from 14 patients with T follicular helper cell lymphomas (TFHLs). A list of somatic mutations called by the Genomon2 pipeline for each sample is provided as a txt file.

  Dataset EGAD50000000401

• BAM files from capture-based targeted sequencing of 12 agressive B-cell lymphoma tumour samples (IG-MCL-panel)

  This dataset contains BAM files from capture-based targeted sequencing of 12 agressive B-cell lymphoma tumour samples for cases 1 to 6 and 8 to 13. The sequencing panel used is a MCL-oriented panel containing 159 genes.

  Dataset EGAD50000000801

• Dataset of Recurrent resistance mutations to lirafugratinib delineate treatment sequences for FGFR2-driven tumors

  This dataset is made of 23 pairs of RNAseq and 36 pairs of Exome-seq, both sequenced from Illumina Novaseq. This includes 47 samples, composed of 25 tumors, 13 healthy and 9 xenograft

  Dataset EGAD50000001981

• Flexible and rapid validation of structural variants using adaptive sampling

  This is the DAC that oversees the application and approval process for access to the Oxford Nanopore fastq files associated with the study, "Flexible and rapid validation of structural variants using adaptive sampling". The DAC members include Dr. Stephen W. Scherer (swscherer@sickkids.ca) and Dr. Lars Feuk (lars.feuk@igp.uu.se).

  Dac EGAC50000000748

• Untargeted serum metabolomics profiled by Metabolon Inc.

  Raw untargeted metabolomics profiled by Metabolon Inc. for 540 samples from healthy individuals. Files include sample names and run details which can be matched to their metagenomic sequencing samples from PRJEB11532 and PRJEB17643. Information regarding metabolite metadata is also available, including

  Dataset EGAD00001006247

• CYPTAM - PacBio SMRT sequencing

  Dataset contains CYP2D6 sequencing data of 566 individuals who used tamoxifen as adjuvant breast cancer therapy. Phenotype data consists of the ratio between the metabolites endoxifen and desmethyltamoxifen (Metabolic ratio (MR)) as a proxy for CYP2D6 enzyme activity. Each sample is linked to one bam-file containing the CYP2D6 sequence.

  Dataset EGAD00001005972

• Somatic copy-number alterations in plasma circulating tumor DNA from advanced EGFR-mutated lung adenocarcinoma patients

  This is the raw data obtained from shallow whole-genome sequencing of plasma DNA (plasma-seq) for calling of somatic copy number alterations as well as focal amplifications from patients with lung cancer.

  Dataset EGAD00001007505

• Genetic and epigenetic characterization of adenoid cystic carcinoma

  Whole genome sequences of ACC primagrafts, Histone modification maps and transcription factor binding maps for ACC primagrafts and primary tumors. Processed ChIP-seq data is available on GEO under accession number GSE76465.

  Dataset EGAD00001001662

• POISED (Peanut Oral Immunotherapy: Safety, Efficacy, and Discovery)

  Phase 2 POISED (Peanut Oral Immunotherapy: Safety, Efficacy, Discovery) Study In this randomized, double-blind, placebo-controlled (DBPC) clinical trial, blinded placebo group received oat flour, whereas in active participants, dosage was built-up for over ~ 52 weeks and subsequently maintained on 4000 mg peanut protein, daily for next 52 weeks. 80 (98.77%) per-protocol active participants passed the food challenge at week 104. Subsequently, for 12 weeks, peanut ingestion was avoided in a randomized group of 51 blinded active participants (i.e., peanut avoidance group). 21 (41.2%) participants in the peanut avoidance group passed the 4000 mg double-blind, placebo-controlled food challenge (DBPCFC) without any allergic reaction at week 117, thus demonstrating sustained unresponsiveness. These 21 participants continued oral immunotherapy (OIT) for every three months and afterwards were allowed to continue peanut OIT discontinuation if they passed. 8 participants passed the DBPCFCs, 12 months after peanut discontinuation (week 156), i.e. they achieved long-term sustained unresponsiveness with no allergic reaction in response to food challenge. For detailed description, please refer to Chinthrajah et al., PMID: 31522849.

  Study phs003071

• Deep whole genome ctDNA chronology of treatment-resistant prostate cancer

  Circulating tumor DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring. We performed deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and demonstrate that ctDNA harbors multiple dominant populations whose evolutionary histories frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally-expanded cancer driver alterations, each individual metastasis contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent androgen receptor (AR) pathway inhibitors, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment-resistance. Finally we leverage nucleosome footprints in ctDNA to infer mRNA abundance in synchronously biopsied metastases, including treatment-induced changes in AR pathway transcriptional activity.

  Dataset EGAD00001008460

• HV31 - Read identifier list for local CCS, CLR, ONT and MGI reads

  This file contains read identifiers for local CCS, CLR, ONT and MGI reads for each of the eight selected genomic regions (HLA, KIR, IGH, IGK, IGL, TRA, TRD, andTRG). We extracted these reads by aligning whole-genome sequencing data to a draft whole-genome de novo assembly, and selecting reads that map to contigs representing each region. These reads were involved in the polishing and validation of the HV31 assembly. Please refer to the relevant manuscript (https://doi.org/10.1101/2021.02.03.429586) for additional details. Read identifiers are stored in JSON format. Along with the full FASTQ files, this file enables convenient re-analysis of the HV31 sequencing data in the eight selected regions.

  Dataset EGAD00001007761

• Chromatin immunoprecipitation linked to next-generation whole genome sequencing (ChIP-Seq) for H3K36me3 in paediatric high grade glioma cell lines KKNS4 and SF188 with and without a G34V mutation in H3F3A

  Glioblastomas of children and young adults have a median survival of only 12-15months and are clinically and biologically distinct from histologically similar cancers in older adults1. They are defined by highly specific mutations in the gene encoding the histone H3.3 variant H3F3A2, occurring either at or close to key residues marked by methylation for regulation of transcription – K27 and G34. We performed chromatin immunoprecipitation linked to next-generation whole genome sequencing (ChIP-Seq) for H3K36me3 in order to test the hypothesis that, rather than total H3K36me3, the G34V mutation may instead result in differential binding of the trimethyl mark throughout the genome. Compared with H3F3A wild-type SF188 paediatric GBM cells, H3K36me3 was found to be significantly differentially bound in KNS42 cells at 5130 distinct regions of the genome corresponding to 156 genes. Concurrent whole genome DNA sequencing demonstrated that this was not confounded by copy number alterations. The cerebral hemispheric-specific G34 mutation drives a distinct expression signature through differential genomic binding of the K36 trimethylation mark (H3K36me3). The transcriptional program induced recapitulates that of the developing forebrain, and involves numerous markers of stem cell maintenance, cell fate decisions and self-renewal. Critically, H3F3A G34 mutations cause profound upregulation of MYCN, a potent oncogene which is causative of glioblastomas when expressed in the correct developmental context. This driving aberration is selectively targetable in this patient population by inhibiting kinases responsible for stabilisation of the protein.

  Study EGAS00001001437

• 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

• 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

• MorphoITH: A Framework for Deconvolving Intra-Tumor Heterogeneity Using Tissue Morphology

  The ccRCC-ITH study WES dataset is derived from a morphology guided multi-regional sequencing dataset used to study the relationship between morphology and genetic evolution. It contains whole exome sequencing data of 18 tumor and 2 adjacent normal samples from 2 UTSW patients, who have consented to depositing their genomic data to public repository. Tumor samples come from different tumor sites, including primary tumor, thrombus and metastases. WES was performed using 75bp paired-end fragments at an average read depth > 50x on a NovaSeq 6000 platform (Illumina, San Diego, CA, USA). The raw data is in fastq format.

  Dataset EGAD50000001550

• Reference Panel for Imputation Analysis Based on Whole Genome Sequencing Data of 3,256 Japanese Individuals(BioBank Japan genotype data)

  This reference panel was constructed using whole genome sequencing data from 3,256 Japanese individuals and the 1000 Genomes Project. It provides high accuracy and utility in analyzing genetic polymorphisms, while also reflecting the genetic diversity specific to the Japanese population. This dataset is expected to contribute to the advancement of genetic research and personalized medicine.

  Study JGAS000746

• Evidence for Enhancer Activity in Intron 1 of TNFRSF1A Using CRISPR/Cas9 in Human Induced Pluripotent Stem Cell-derived Macrophages

  Use of CRISPR/Cas9 technology to study the TNFRSF1A gene, which plays a key role in autoimmune diseases such as ankylosing spondylitis, multiple sclerosis, and inflammatory bowel disease. By editing a specific regulatory element within the TNFRSF1A locus, we have identified the role of an enhancer element that is not well understood.

  Study EGAS50000000703

• PARADIGM: Combined ctDNA and serum PSA for dynamic monitoring of metastatic prostate cancer starting first-line treatment

  The prognosis of newly-diagnosed metastatic prostate cancer is highly variable. The PARADIGM prospective cohort study evaluated predictors of survival in blood collected at the start of each of the first six treatment cycles from 114 high-volume metastatic patients starting androgen deprivation therapy combined with docetaxel or an androgen receptor pathway inhibitor.

  Study EGAS50000001357

• Cancer genomics for elucidation of molecular mechanisms of carcinogenecis and progression in lung cancer

  The objective of this project is to analyze genomic aberrations and gene expression changes such as mutations, deletions, amplifications, and hypermethylation in human lung cancer cells at the somatic cell level, and to contrast these with clinicopathological information to elucidate the molecular mechanisms and characteristics of lung cancer development and progression at the genetic level.

  Study JGAS000756

• 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

• 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

• MediMer: A versatile do-it-yourself peptide-receptive MHC class I multimer platform for tumor neoantigen-specific T cell detection

  Peptide-loaded MHC class I (pMHC-I) multimers have revolutionized our capabilities to monitor disease-associated T cell responses with high sensitivity and specificity. To improve the discovery of T cell receptors (TCR) targeting neoantigens of individual tumor patients with recombinant MHC molecules, we developed a peptide-loadable MHC class I platform termed MediMer. MediMers are based on soluble disulfide-stabilized β2-microglobulin/heavy chain ectodomain single-chain dimers (dsSCD) that can be easily produced in large quantities in eukaryotic cells and tailored to individual patients’ HLA allotypes with only little hands-on time. Upon transient expression in CHO-S cells together with ER-targeted BirA biotin ligase, biotinylated dsSCD are purified from the cell supernatant and are ready to use. We show that CHO-produced dsSCD are free of endogenous peptide ligands. Empty dsSCD from more than 30 different HLA-A,B,C allotypes, that were produced and validated so far, can be loaded with synthetic peptides matching the known binding criteria of the respective allotypes, and stored at low temperature without loss of binding activity. We demonstrate the usability of peptide-loaded dsSCD multimers for the detection of human antigen-specific T cells with comparable sensitivities as multimers generated with peptide-tethered β2m-HLA heavy chain single-chain trimers (SCT) and wild-type peptide-MHC-I complexes prior formed in small-scale refolding reactions. Using allotype-specific, fluorophore-labeled competitor peptides, we present a novel dsSCD-based peptide binding assay capable of interrogating large libraries of in silico predicted neoepitope peptides by flow cytometry in a high-throughput and rapid format. We discovered rare T cell populations with specificity for tumor neoepitopes and epitopes from shared tumor-associated antigens in peripheral blood of a melanoma patient including a so far unreported HLA-C*08:02-restricted NY-ESO-1-specific CD8+ T cell population. Two representative TCR of this T cell population, which could be of potential value for a broader spectrum of patients, were identified by dsSCD-guided single-cell sequencing and were validated by cognate pMHC-I multimer staining and functional responses to autologous peptide-pulsed antigen presenting cells. By deploying the novel CHO producer cell-based dsSCD MHC-I MediMer platform, we hope to significantly improve success rates for the discovery of personalized neoepitope- specific TCR in the future by being able to also cover rare HLA allotypes.

  Study EGAS50000000065

• Set_of_human_mesenchymal_CSA

  51 DNA methylation arrays of human samples initially diagnosed as mesenchymal chondrosarcoma. Microdissection of the cartilage and/or the small round cell component from the same sample may have occurred. As mentioned in the sample descriptions, the diagnoses of four samples have been revised. Additional molecular investigations were conducted for a subset of samples as described in the related publication.

  Dataset EGAD00010002515

• BIOMIROX

  This dataset regroups RNAseq of paired primary colorectal cancers and liver metastases extracted from 113 patients In Paris and Besançon University Hospitals. 216 FASTQ files from single-end 3' PolyA (QuantSeq 3′mRNA-Seq Kit FWD for Illumina (Lexogen)) RNAseq samples were generated On NOVASEQ 6000 (ILLUMINA).

  Dataset EGAD50000000443

• WES for CNV-verified CTCs from 2 patients with metastatic prostate cancer

  This dataset contains 4 paired fastq files sequenced by illumina Novoseq 6000. WES analysis (illumina platform, PE150, 100x coverage) was performed on a pool of CNV-verified CTCs that were enriched using high-throughout microfluidic device from entire leukopak from patients with metastatic prostate cancer (GU-1 and GU-2).

  Dataset EGAD50000001005

• Saliva_Fulani_Database

  In total, 90 DNA samples were genotyped on the Illumina Infinium H3Africa Consortium array (designed for 2,271,503 SNPs; using BeadChip type: H3Africa_2019_20037295_B1). Genotyping was performed at the SNP&SEQ Technology Platform (NGI/SciLifeLab Genomics, Sweden). Saliva Fulani dataset includes individuals from the following populations: 30 individuals from Senegal_FulaniLinguere, 30 individuals from Mauritania_FulaniAssaba, and 30 individuals from Mali_FulaniInnerDelta.

  Dataset EGAD50000000653

• Single-Cell Profiling of the Human Endometrium in Polycystic Ovary Syndrome: Uncovering Disease Signatures and Treatment Responses

  Single-nuclei map of human endometrial biopsies from women with and without PCOS to identify cell-type-specific disease signatures, compositional variations, and transcriptomic reversibility after a 16-week intervention with metformin or lifestyle. Single nuclei were extracted from 27 frozen endometrial biopsies for snRNA-seq using the 10X Genomics protocol.

  Dac EGAC50000000468

• HIV-phyloTSI: PANGEA (veSEQ-HIV)

  This dataset includes sample numbers TSI_0001 to TSI_0202 and TSI_0316 to TSI_0425 for the PANGEA (veSEQ-HIV) cohort of the study. Samples were sequenced using the Illumina NovaSeq system and the veSEQ-HIV method (see Bonsall, Golubchik et al 2020, DOI: 10.1128/JCM.00382-20). Each sample has a BAM file, and its associated reference file.

  Dataset EGAD50000001309

• HIV-phyloTSI: PANGEA (PCR amplicon)

  This dataset includes sample numbers TSI_0426 to TSI_0527 for the PANGEA (PCR amplicon) cohort of the study. Samples were generated by pooling four overlapping PCR amplicons (see Gall et al 2012, DOI: 10.1128/JCM.01516-12). The sequencing was conducted using the Illumina NovaSeq system. Each sample has a BAM file, and its associated reference file.

  Dataset EGAD50000001308

• WGS of thymic epithelial tumors and paired normal

  Among the 20 newly sequenced cases, we conducted additional whole-genome sequencing (WGS) on five out of eight CN-type thymomas, excluding three with low tumor cell fractions (< 0.1). Libraries for WGS were prepared using the TrueSeq DNA PCR-free Prep Kit following standard Illumina protocols.

  Dataset EGAD50000001160

• Dataset for melanoma-WHOLE_GENOME

  Rare cancer sequencing data of 22 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008889

• RNA-seq on neuroblastoma PDX model COG-N-519 treated with control miR-1283 and test miR-99b-5p mimics

  RNA-sequencing on neuroblastoma PDX model COG-N-519 treated with control miR-1283 and test miR-99b-5p mimics. Three samples from each of the treatment condition were analysed. Next-Seq platform was used for sequencing.

  Dataset EGAD00001007754

• Spatial transcriptomics of 1 untreated prostate cancer.

  Two sections of cryopreserved prostate cancer tissue from one untreated prostate cancer patient were profiled for spatial transcriptomics using the Visium Spatial library preparation protocol from 10x Genomics. The GRCh38 aligned sequencing reads from the two prostate cancer tissue sections are provided as BAM files.

  Dataset EGAD00001007921