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• Mapping genetic variants underlying gene regulation in intestinal cell types to identify novel IBD drug targets

  Biopsies from the terminal ileum and rectum of healthy individuals and terminal ileum and blood from Crohns disease patients are collected and processed single cells and processed for single-cell RNA-sequencing using 10X Genomics 3 v3 and v3.1 and Illumina sequencing. 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 EGAD00001016069

• A Somatic Reference Standard for Cancer Genome Sequencing

  In this study, we separately performed PCR-free whole genome sequencing on the paired tumor/normal melanoma COLO-829 and lymphoblastoid COLO-829BL cell lines across three separate institutions (TGen, Illumina, Genome Sciences Centre at the British Columbia Cancer Agency). We performed a meta-analysis of all data, in combination with the originally reported analysis of these cell lines by Pleasance et al., and report a somatic reference standard based on consensus events. This standard can be used as a reference for tumor/normal whole genome analyses.

  Study phs000932

• Leveraging Extended Families for Cardiovascular Disease Genomic Discovery

  This study characterizes a large early onset atrial fibrillation family and identifies a rare causative mutation (R231H) in the KCNQ1 gene. The age of this mutation is ~5000 years, as estimated using IBD-coalescent methods. The geographic distribution and demographic history of the mutation is described. Induced pluripotent stem cell derived cardiomyocytes carrying the mutation have abbreviated action potential duration, indicating a gain-of-function. This data resource provides exome or whole genome sequencing data for six patients and RNA-seq data from the cardiomyocyte experiments. 

  Study phs002464

• NHLBI's Collection of Datasets for General Research Use (Public Posting of Genomic Summary Results: Not Allowed)

  This collection contains all of NHLBI's authorized individual-level genomic datasets currently in dbGaP that are approved for General Research Use (GRU) and have no further limitations beyond those outlined in the model Data Use Certification Agreement. The public posting of Genomic Summary Results are not allowed. Access to this study collection will include additional authorized individual-level GRU datasets that become available. Renewal of this study collection is required annually. To request access to this study collection, select phs003132 in the dbGaP Authorized Access System.

  Study phs003131

• NHLBI's Collection of Datasets for Health / Medical / Biomedical Research Use (Public Posting of Genomic Summary Results: Allowed)

  This collection contains all of NHLBI's authorized individual-level genomic datasets currently in dbGaP that are approved for Health/Medical/Biomedical (HMB) Research Use and have no further limitations beyond those outlined in the model Data Use Certification Agreement. The public posting of Genomic Summary Results are allowed. Access to this study collection will include additional authorized individual-level HMB datasets that become available. Renewal of this study collection is required annually. To request access to this study collection, select phs003134 in the dbGaP Authorized Access System.

  Study phs003134

• NHLBI's Collection of Datasets for Health / Medical / Biomedical Research Use (Public Posting of Genomic Summary Results: Not Allowed)

  This collection contains all of NHLBI's authorized individual-level genomic datasets currently in dbGaP that are approved for Health/Medical/Biomedical (HMB) and have no further limitations beyond those outlined in the model Data Use Certification Agreement. The public posting of Genomic Summary Results are not allowed. Access to this study collection will include additional authorized individual-level HMB datasets that become available. Renewal of this study collection is required annually. To request access to this study collection, select phs003133 in the dbGaP Authorized Access System.

  Study phs003133

• Intrapatient tumor heterogeneity and clonal evolution in metastatic salivary gland cancer: an autopsy study: access to data

  Funded by the Radboud Oncology Fund and the Dr. C.J. Vaillant Fund, the Salivary Gland Cancer Autopsy research group (Research Group) has sequenced DNA of 17 salivary gland cancer samples of and three healthy control samples from three patients with salivary gland cancer. This research project is led by Carla M.L. van Herpen from Radboud University Medical Centre in Nijmegen, the Netherlands (“Radboudumc”). The DNA sequencing data have been used for an analysis of intrapatient tumor heterogeneity and clonal evolution of metastatic salivary gland cancer. The Research Group is willing to consider applications from third party researchers for access to the DNA sequence data. Access to the data will be granted to qualified researchers for approved use. Access to DNA Sequencing Data is available by application to the Data Access Committee (DAC). Researchers granted access to DNA Sequencing Data must feedback the results of their research to the Research Group, after publication in accordance with the Research Group publication policy set forth in the Data Access Agreement.

  Dac EGAC50000000792

• Sequencing data for Clinical Trial

  This study is a tri-institutional Phase 1/randomized Phase 2 trial, bevacizumab-naïve rHGA patients were randomized to either LITT (laser interstitial thermal therapy) plus pembrolizumab (LITT+PEM) or non-LITT surgery plus pembrolizumab (NLS+PEM). Randomization ceased after 21 patients when emerging data showed limited adjuvant ICI (immune checkpoint inhibitors) benefit, and the next 24 patients all received LITT+PEM. The goal of the trial is to use LITT, a minimally invasive cytoreductive approach, to prime these “cold” tumors for enhanced ICI response. rHGA= high-grade astrocytoma

  Study EGAS50000001144

• Whole-genome sequencing of cell-free DNA from pancreatic and breast cancer cohorts for fragmentomic and tumor fraction analysis

  This project provides whole-genome sequencing data from cell-free DNA collected from patients with pancreatic ductal adenocarcinoma and breast cancer, alongside healthy and benign controls. The study aims to identify novel liquid biopsy biomarkers by exploring the relationship between per-base quality scores and fragmentomic signals like end-motifs and fragment length. Furthermore, the data supports the development of Bayesian deep learning frameworks for the uncertainty-aware estimation of tumor fraction and ploidy in low-concentration clinical samples.

  Study EGAS50000001620

• ChIP sequencing for β-catenin and histone modifications in HCC cell lines and organoids with CTNNB1 mutations

  CTNNB1 mutation is a major driver of HCC, particularly in metabolic-associated subtype. This study utilized patient-derived tumour organoids and cell lines harbouring various endogenous CTNNB1 mutations to comprehensively map the transcriptional repertoire regulated by mutant β-catenin through ChIP-seq under normal and fatty conditions. Genome-wide binding patterns of β-catenin were integrated with ChIP-seq data for histone modifications H3K27ac and H3K27me3 to assess active and repressive chromatin states. Oleic acid treatment was used to model fatty conditions.

  Study EGAS50000001274

• Molecular counting enables accurate and precise quantification of methylated ctDNA for tumor-naive cancer therapy response monitoring

  Personalized cancer treatment can significantly extend survival and improve quality of life for many patients, but accurate and real-time therapy response monitoring remains challenging. To overcome logistical and technical challenges associated with therapy response monitoring via imaging scans or assays that track the variant allele fraction (VAF) of somatic mutations in circulating tumor DNA (ctDNA), we developed a tumor-naive liquid biopsy assay that leverages Quantitative Counting Template (QCT) technology to accurately and precisely quantify methylated ctDNA (Northstar ResponseTM).

  Study EGAS50000000734

• Molecular correlates for HPV-negative head and neck cancer engraftment prognosticate patient outcomes

  Head and neck squamous cell carcinoma (HNSCC) tumors were sampled from 88 patients. Samples were implanted subcutaenously into the flank of NOD/SCID/IL2R-/- mice. Mice were then monitored weekly for tumor growth and the time of initial palpation was recorded. Mice were euthanized when tumors reached 15 mm in diameter or after 6 months. If no tumor formed by 6 months, the patient tumor was defined as Non-engrafter (N). RNA-seq was performed on all primary tumor samples and successfully engrafted patient-derived xenograft (PDX) samples.

  Study EGAS50000000714

• Y90 radioembolization followed by intravenous Nivolumab for advanced hepatocellular carcinoma

  To evaluate the efficacy of combination therapy with ICI and RT in patients, a Phase II trial (CA209-678) was conducted to investigate the efficacy and safety of Y90-RE followed by nivolumab in patients with advanced HCC (NCT03033446, n = 36). Interestingly, the ORR was found to be 30.6% in all patients and 43.5% when restricted to patients with only intrahepatic tumors, suggesting possible synergism between Y90-RE and ICI. Here we present whole exome sequencing (WES) and RNA-seq data for 33 patients treated with Y90 radioembolization followed with Nivolumab.

  Study EGAS00001006834

• Estonian Microbiome Project second time point dataset

  Out of the 2,509 Estonian Microbiome Project participants, a sub-cohort of over 300 individuals provided an additional stool sample after a median follow-up period of 4.4 years. All participants of the EstMB cohort gave informed consent for the data and samples to be used for scientific purposes. In the second time point, the participants were instructed to send the samples by post immediately after taking the sample and time their sample collection to avoid shipping on the weekends. The median time between sampling and arrival at the freezer in the core facility for the second time point was 53 hours and 1 minute (mean: 59 hours and 22 minutes; minimum: 34 minutes; maximum: 168 hours and 7 minutes [note: additionally, one outlying measurement was 508 hours and 27 minutes. The shotgun metagenomics paired-end sequencing was performed by Novogene Bioinformatics Technology Co., Ltd., using Illumina NovaSeq6000 platform, resulting in 4.62 ± 0.44 Gb of data per sample (insert size 350 bp, read length 2 × 250 bp).

  Dataset EGAD50000001686

• Shallow Whole Genome Sequencing of Patient Derived Xenografts

  Chemotherapy is the standard-of-care treatment for metastatic colorectal cancer (mCRC) and benefits some patients, but what distinguishes responders from non-responders is unclear. In this study, we leveraged a comprehensive collection of 27 molecularly annotated patient-derived xenografts to uncover functional predictors of response to 5-FU and irinotecan combination therapy (FOLFIRI) in mCRC. Genetic analyses revealed that treatment sensitivity was marked by genomic scars indicative of BRCAness, suggesting homologous recombination (HR) deficiency as a key determinant. Accordingly, we surveyed a manually curated panel of 44 genes with a documented role in HR for the potential presence of pathogenic mutations. We did not observe a specific enrichment of HR gene mutations based on response to FOLFIRI. This result, combined with the absence of widespread biallelic inactivation of the analyzed genes and the predominance of mutations categorized as variants of unknown significance, suggests that FOLFIRI sensitivity is not primarily governed by underlying mutations in HR genes responsible for mitigating the genotoxic effects of this therapeutic regimen.

  Dataset EGAD50000000277

• RNA-seq of Toxoplasma gondii response in human macrophages

  Toxoplasmosis is a zoonotic disease caused by a ubiquitous protozoan parasite called Toxoplasma gondii, which can infect all mammal and bird species throughout the world. seroprevalence varies widely between countries. Studies have estimated that between 7-34% of people in the UK have been infected with T. gondii. The vast majority of these people will not have noticed any symptoms, however about 10% of people develop a mild to moderate self limiting flu-like illness. Following the acute active stage of the infection the parasite persists in the body in the form of cysts, particularly in heart and skeletal muscle and nervous system tissues, for many years, and usually for life. In immunocompetent persons these cysts do not pose a health risk. We will use RNA-seq to quantify the transcriptional response of macrophages to T gondii infection. 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 EGAD00001003241

• Autozygosity pilot - Born in Bradford (2017-05-11)

  The offspring of first cousin marriages have ~6% of their genome autozygous, i.e. homozygous identical by descent, or even more if there was further consanguinity in their ancestry. In the UK there are large populations with very high first cousin marriage rates of 20-50%. Sequencing the exomes of a sample of these individuals has the potential both to support genetic health programmes in these populations, and to provide genetic research information about rare loss of function mutations. This pilot study based on existing cohort samples from the Born In Bradford study will identify homozygous individuals for almost all variants down to an allele frequency around 1%, plus individuals carrying hundreds of new homozygous rare loss-of-function variants, and will support development of community relations and ethics for a wider study currently being designed. The data deposited in the EGA consist of low coverage whole exome sequencing on these samples. This dataset contains all the data available for this study on 2017-05-11.

  Dataset EGAD00001003329

• Targeted resequencing of Cardiomyopathies associated genes

  In this study, we present the results of a custom “pan-cardiomyopathy panel” in a molecular screening of 38 unrelated patients, 16 affected by DCM, 14 by HCM, and 8 by ARVC. The panel was designed using the Design Studio Tool (Illumina, San Diego, CA,USA). Coding regions and intron–exon boundaries of 115 genes, known to be associated with 7 DCM, HCM, and ARVC as well as channelopathies, were selected for targeted gene enrichment. For genes with multiple transcripts, all exons included in transcripts expressed in cardiac muscle were considered in the gene panel design. Total DNA was extracted from peripheral blood samples using the Wizard Genomic DNA Purification Kit (Promega, Mannheim, Germany) according to the manufacturer’s instructions, quantified, and qualitatively checked using NanoDrop 2000c (Thermo Fisher Scientific, Waltham, MA, USA). Custom targeted gene enrichment and DNA library preparation were performed using the Nextera Capture Custom Enrichment kit (Illumina) according to the manufacturer’s instructions. Targeted regions were sequenced using the Illumina MiSeq platform, generating approximately two millions of 150-bp paired-end reads for each sample (Q30 ≥90%).

  Dataset EGAD00001003359

• Sequencing data for oesophageal and related samples - ICGC DCC release 28 earmarked (WGS)

  WGS sequencing for 43 cases (86 samples) from the ICGC ESAD-UK project Tumours 50x Normals 30x HiSeq X BAM files These samples are earmarked for inclusion in ICGC release 28

  Dataset EGAD00001004029

• MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

  Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carry MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that they lead to TMZ resistance both in vitro and in vivo. Lastly we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.

  Dataset EGAD00001006281

• FASTQ files of the polyA+ (oligo-dT) RNA-Seq dataset from the POPS SGA (Small for Gestational Age) samples and their matched controls.

  FASTQ files of the polyA+ (oligo-dT) RNA-Seq dataset from the POPS SGA (Small for Gestational Age) samples and their matched controls. The POP study placental biopsies were collected within 30 minutes of birth and flash frozen in RNAlater (ThermoFisher). For each biopsy, total placental RNA was extracted from approximately 5 mg of tissue using the “mirVana miRNA Isolation Kit” (Ambion) followed by DNase treatment (“DNA-free DNA Removal Kit”, Ambion). RNA quality was assessed with the Agilent Bioanalyzer and all the samples with RIN values ≥ 7.0 were used in the downstream experiments. RNA-libraries were prepared from 1g of total placental RNA with the TruSeq Stranded mRNA Library Prep Kit (Illumina) which captures polyA-tailed transcripts by oligo-dT beads, then pooled and sequenced (single-end, 50bp) using a Single End V4 cluster kit and Illumina HiSeq2500

  Dataset EGAD00001006304

• Targeted Myeloid DNA-Panelsequencing, DKFZ

  Targeted myeloid DNA-Panelsequencing from purified bone marrow blasts of 104 treatment naive AML patients from the discovery cohort. For more details, we refere to Jayavelu, Wolf, Buettner et al. Libraries were prepared from 40 ng DNA using the QIASeq Human Myeloid Neoplasms Panel (Qiagen) according to the manufacturer’s protocol. Samples were tagged with the QIAseq 96-Unique Dual Index Set A for Illumina platforms (Qiagen) to yield unique combinations of i5 and i7 barcodes for each sample. Sample fragment size distribution and concentration was estimated using the Agilent High Sensitivity DNA kit on a 2100 Bioanalyzer (Agilent). Samples were pooled in an equimolar fashion, denatured, and diluted to 1.5 pM according to Illumina’s recommendations. The diluted library was sequenced on a NextSeq 500 benchtop sequencer (Illumina) using NextSeq High Output cartridges. Demultiplexing was performed using the BaseSpace cloud platform (Illumina).

  Dataset EGAD00001008501

• Comparison of single/pooled CTCs and bulk exome sequencing

  Single cell technologies allow the interrogation of tumor heterogeneity, providing insights into tumor evolution and treatment resistance. To better understand whether circulating tumor cells (CTCs) could complement metastatic biopsies for tumor genomic profiling, we characterized 11 single CTCs and 10 pooled CTC samples at the mutational and copy number aberration (CNA) levels, and compared these results with matched synchronous tumor biopsies from 3 metastatic breast cancer patients with triple-negative (TNBC), HER2-positive and estrogen receptor-positive (ER+) tumors. Similar CNA profiles and the same patient-specific driver mutations were found in bulk tissue and CTCs for the HER2-positive and TNBC tumors, whereas different CNA profiles and driver mutations were identified for the ER+ tumor, which presented two distinct clones in CTCs defined by mutations in ESR1 Y537N and TP53, respectively. Furthermore, de novo mutational signatures derived from CTCs described patient-specific biological processes. These data suggest that tumor tissue and CTCs provide complementary clinically relevant information to map tumor heterogeneity and tumor evolution.

  Dataset EGAD00001009052

• Pediatric Patient-Derived-Xenograft development in MAPPYACTS – international pediatric cancer precision medicine trial in relapsed and refractory tumors

  Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient’s tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Paediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This new PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and new treatments development in advanced pediatric malignancies.

  Dataset EGAD00001011048

• Familial breast cancer targeted sequencing with ONT

  A large cohort of 600 cases with familial breast cancer as classified by the Spanish Society of Medical Oncology (SEOM) Clinical Guidelines Update that were recruited during 6 years at Hospital Universitario Morales Meseguer (Murcia, Spain) were retrospectively evaluated to select 16 cases with no positive finding in NGS analysis of 20 genes implicated in this disease. These 16 cases were selected for further investigation using nanopore sequencing. This method involved the use of adaptive sampling enrichment, targeting a panel of 18 human genome regions, which contained the 20 genes (PTEN, ATM, BRCA2, PALB2, CDH1, TP53, NF1, RAD51D, BRCA1, RAD51C ,BRIP1, STK11, CHEK2, EPCAM, MSH2, MSH6, BARD1, MLH1, PMS2, NBN). In 5 samples (P1, P2, P4, P15 and P16) no selection of long reads was performed. Additionally, in 3 samples (P7, P9 and P10), both procedures were performed in two independent runs, and for the second run of P7, the DNA was previously fragmented using g-TUBE Covaris® (ref 520079) according to the protocol for 6 kb fragments.

  Dataset EGAD00001011106

• NEOPREDICT-Lung: longitudinal whole exome sequencing of non-small cell lung cancers under immunotherapy

  In 43 patients pretreatment tumor biopsies, resected tumors and normal tissue of sufficient quality and quantity were obtained to longitudinally explore the mutational profiles of a comprehensive set of cancer-related genes. For tumor samples, one to four FFPE sections (10 µm thickness, number depending on sample size) were lysed for genomic DNA isolation. Isolation was performed semi-automatically on the Maxwell purification system (Maxwell RSC DNA FFPE Kit, AS1450, Promega) as specified by the manufacturer. DNA was eluted in 50 µl RNase-free water and quantified fluorescently for library preparation using a Qubit 2.0 fluorometer (Life Technology) with its appertaining DNA broad-range assay. Corresponding normal DNA was isolated from blood or PBMCs using routinely available QIAGEN technology. DNA was stored at -20°C before use. Whole-exome sequencing (WES) was performed using the Twist Human Core + RefSeq + Mitochondrial Panel (Twist Bioscience), and 2 x 100 bp fragment sizes were sequenced using a NovaSeq6000 (Illumina). Demultiplexing of sequenced reads was achieved using bcl2fastq (version 2.2).

  Dataset EGAD00001015362

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

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

  Dataset EGAD00001015453

• Accelerating Medicines Partnership-Systemic Lupus Erythematosus (AMP-RA/SLE)

  This project is analyzing tissue and blood samples from people with rheumatoid arthritis (RA) and lupus to pinpoint genes, proteins, chemical pathways, and networks involved at a single cell level. This type of modular, molecular analysis will allow comparisons across the diseases and will provide insights into key aspects of the disease process. The project will identify differences between those RA patients who respond to therapies and those who do not, as well as provide a better systems level understanding of disease mechanisms in both RA and lupus. This knowledge is essential for the development of targeted therapies and for the application of existing and future therapies to appropriate patient populations. Additional datasets can be accessed through ImmPort (http://www.immport.org/immport-open/public/home/studySearch), accession: SDY997

  Study phs001459

• High Glucose Macrophage Exosomes Enhance Atherosclerosis by Driving Cellular Proliferation and Hematopoiesis

  In this study, we aimed to explore whether hyperglycemia alters inflammatory properties and microRNA levels in immune cells as well as their extracellular vesicles (EVs) as a mode of intercellular communication in cardiovascular disease. To this end, we isolated EVs from the plasma of diabetic mice as well as from human subjects that included 7 healthy individuals (control), 5 individuals with diagnosed peripheral arterial disease but no diabetes, 9 diabetic individuals with no vascular disease and 5 diabetic subjects with established vascular disease. The human plasma EVs were examined for the content of microRNA and their capacity to communicate signaling when incubated with cultured human THP1 macrophages. Subsequently, the plasma EV-exposed macrophages were examined for total RNA sequencing to identify inflammatory and molecular pathways targeted by the human EVs. 

  Study phs002401

• Genomic sequencing of Pediatric Rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood accounting for approximately 350 newly diagnosed cases yearly in the United States. With the development of multimodal chemotherapy regimens, relapse-free survival rates have improved to 70-80% in patients with localized disease albeit with significant toxicity. Unfortunately, despite aggressive treatment, patients with metastatic or recurrent disease continue to suffer from high mortality. Further characterization of the genetic events underlying this tumor type is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. In a collaborative effort between the National Cancer Institute, the Children's Oncology Group, and the Broad Institute, we use a combination of whole-genome and whole-exome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs.

  Study phs000720

• Defining and Overcoming Intrinsic T Cell Dysfunction to Enable Pediatric Immunotherapy

  T-cells from 71 children and young adults with B-cell malignancies on trial to receive anti-CD19 CAR T-cell therapy were analyzed. These T-cells represent the pre-manufacture T-cells that were subsequently used for CAR T manufacture. Bulk RNA-Seq was performed on sorted T-cell subsets for all patients, in addition to CITE-Seq and single-cell ATAC-Seq on a subset of 6 patients. The primary clinical outcome was duration of B-cell aplasia, a surrogate measure of functional CAR T-cell persistence. From these data, molecular signatures associated with long and short-term CAR T-cell persistence were identified. This data submission includes bulk RNA-Seq, CITE-Seq, and single-cell ATAC-Seq data from this study.

  Study phs002323

• Transcriptomic and Clonal Characterization of T Cells in the Human Central Nervous System

  The cerebrospinal fluid (CSF) is thought to be a main route for immune surveillance in the central nervous system (CNS). Understanding the composition and state of CSF in healthy individuals may provide insight into perturbations present during neuroinflammation. Here, we have used single-cell RNA and TCR sequencing to profile CSF and peripheral blood mononuclear cells (PBMCs) from healthy individuals and patients with relapsing-remitting multiple sclerosis (MS), a chronic autoimmmune disease. In addition, with the goal of understanding how transcriptional artefacts are introduced in transcriptomics experiments, we have performed single-cell and TCR sequencing to profile PBMCs from a healthy individual that were processed with the same enzymatic digestion used for tissues (such as the brain) in the presence or absence of transcription inhibitors. 

  Study phs002222

• Accelerating Medicines Partnership-Rheumatoid Arthritis (AMP-RA/SLE)

  This project is analyzing tissue and blood samples from people with RA and lupus to pinpoint genes, proteins, chemical pathways, and networks involved at a single cell level. This type of modular, molecular analysis will allow comparisons across the diseases and will provide insights into key aspects of the disease process. The project will identify differences between those RA patients who respond to therapies and those who do not, as well as provide a better systems level understanding of disease mechanisms in both RA and lupus. This knowledge is essential for the development of targeted therapies and for the application of existing and future therapies to appropriate patient populations. Additional datasets can be accessed through ImmPort (http://www.immport.org/immport-open/public/home/studySearch), accession: SDY998, SDY999.

  Study phs001457

• 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. Recently we completed a genome-wide association scan on 1161 T2D cases and 1174 normal glucose tolerant (NGT) controls. Individual-level data is available here for the 919 T2D cases and 787 NGT controls who reconsented to the use of their data or are deceased. Version 3 adds individual-level data for additional phenotypic variables.

  Study phs000100

• NHLBI TOPMed - NHGRI CCDG: Intermountain INSPIRE Registry

  The INtermountain Healthcare Biological Samples Collection Project and Investigational REgistry for the On-going Study of Disease Origin, Progression and Treatment (Intermountain INSPIRE Registry) purpose is to collect biological samples, clinical information and laboratory data from Intermountain Healthcare patients. The registry originally collected samples in patients undergoing a coronary angiography as part of the Intermountain Heart Collaborative Study. It has been expanded to collect samples in patients diagnosed with all types of medical conditions, and patients from the general population including those who have not been diagnosed with health related issues. Just over 25,000 individuals have provided samples as part of this registry. The registry enables researchers to develop a comprehensive collection of information that may help in disease management, including determining best medical practices for predicting, preventing and treating medical conditions.

  Study phs001545

• MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

  Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low “variant” subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which combined with chemotherapy strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a novel targeted treatment approach for MYC-driven SCLC.

  Study EGAS00001002115

• Adeno-associated virus in the liver: natural history and consequences in tumor development

  Adeno-associated virus (AAV) is a defective mono-stranded DNA virus, endemic in human population (40-80%). AAV infection has long been considered as non-pathogenic1, however few years ago we reported for the first time recurrent clonal AAV2 insertion in the pathogenesis of human hepatocellular carcinoma (HCC) developed on normal liver. These clonal viral insertions target cancer driver genes, including CCNA2, CCNE1, TERT, TNFSF10 and MLL4, leading to their overexpression. The viral inserted sequences involved in almost all the cases the 3’ inverse tandem repeat (ITR) of AAV2, which is important for virus integration in host DNA and exhibits a promoter/enhancer activity. Here, we used RNA sequencing (RNA-seq) to investigate their functional impact on the tissue, such as fusion transcript generation events.

  Study EGAS00001003310

• Multiregional sequencing of IDH-WT glioblastoma reveals high genetic heterogeneity and a dynamic evolutionary history

  Glioblastoma is the most common and aggressive primary brain malignancy in adults. In addi-tion to extensive inter-patient heterogeneity, glioblastoma shows intra-tumor extensive cellular and molecular heterogeneity, both spatially and temporally. This heterogeneity is one of the main reasons for the poor prognosis and overall survival. Moreover, it raises the important question of whether the molecular characterization of a single bioptic sample, as performed in standard di-agnostics, actually represents the entire lesion. In this study, we sequenced the whole-exome of nine spatially different cancer regions of three primary glioblastomas. We characterized their mutational profiles and copy number alterations, with implications for our understanding of tu-mor biology in relation to clonal architecture and evolutionary dynamics, as well as therapeuti-cally relevant alterations.

  Study EGAS00001005128

• UCSF Pediatric Bithalamic Glioma Genome Project

  Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. We performed targeted next-generation sequencing of approximately 500 cancer-associated genes on a cohort of 13 pediatric bithalamic diffuse gliomas, a lethal brain tumor of childhood for which the genetic basis is largely unknown. We identified that bithalamic diffuse gliomas harbor frequent mutations in the EGFR oncogene in the absence of accompanying gene amplification and only rare histone H3 mutation. These EGFR mutations were either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain). Accompanying alterations included frequent TP53 mutation, CDK6 amplification or CDKN2C mutation, and BCOR and BCORL1 mutation or deletion.

  Study EGAS00001004033

• Size-tagged preferred ends in maternal plasma DNAshed light on the production mechanism and showutility in noninvasive prenatal testing

  Cell-free DNA molecules in the plasma of pregnant women exhibit nonrandom fragmentation with preferred end sites. We studied if such preferred end sites might bear any re- lationship with fragment lengths of plasma DNA. Short and long plasma DNA molecules were associated with different preferred DNA end sites. Analysis of size-tagged preferred ends could be used for measuring fetal DNA fraction and for facilitating fetal trisomy 21 detection. Fetal preferred end sites were generally located in the nucleosome cores, while the maternal ones were located in the linker regions. This con- ceptual framework provides an explanation of the relative shortness of fetal DNA in maternal plasma and brings us closer to understanding the biological mechanisms that influence plasma DNA fragmentation.

  Study EGAS00001002831

• Cross-species genomics identifies TAF12, NFYC and RAD54L as novel choroid plexus carcinoma oncogenes

  Choroid plexus carcinomas (CPC) are poorly understood and frequently lethal brain tumors with minimal treatment options. Using a new mouse model of the disease and a large cohort of human CPCs, we performed a cross-species, genome-wide search for novel oncogenes within syntenic regions of chromosome gain. TAF12, NFYC and RAD54L, co-located on human chromosome 1p32-35.3 and mouse chromosome 4qD1-D3, were identified as oncogenes that are gained in tumors in both species and required to initiate and progress the disease in mice. TAF12 and NFYC are transcription factors that regulate the epigenome, while RAD54L plays a central role in DNA repair. Our data identify a group of concurrently gained, novel oncogenes that cooperate in the formation of CPC and unmask potential new avenues for therapy.

  Study EGAS00001000961

• Pediatric Low-Grade Glioma RNA and Targeted Sequencing

  Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS/MAPK pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. 84% of cases harbored a driver alteration, while those without an identified alteration also often exhibited up-regulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared to SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.

  Study EGAS00001004242

• A genetic compendium of human brains from the UK Medical Research Council brain tissue resource

  Common neurodegenerative diseases have a complex genetic architecture. Highly penetrant diseases alleles are found in a significant minority of cases, and common risk alleles are present in a large proportion. Given the central role of genetic factors in the pathogenesis of these disorders, it is critical that mechanistic studies in human subjects and tissue samples are interpreted in an genetically enlightened context. To address this we performed exome sequencing on 1461 human brains accessible through the Medical Research Council (UK) brain banks network. Our findings confirm the complex genetic landscape of neurodegenerative disease. Clinical, pathological and genetic data for the 1461 brains with corresponding exome sequencing data are available within this dataset, enabling the genetic stratification and selection of post-mortem tissue samples for researchers.

  Study EGAS00001001599

• Most HCCs in Taiwan show the mutational signature of aristolochic acid

  Plants in the genus Aristolochia contain the mutagen aristolochic acid (AA) and have been widely used in traditional medicines and for weight loss. AA binds covalently to genomic DNA and induces a highly distinctive mutational signature. While AA involvement in urinary-tract cancers in Taiwan is known, the possible role of AA in hepatocellular carcinomas (HCCs) in Taiwan has not been examined. Here, we whole-exome sequenced 98 unselected HCCs from Taiwan and analyzed the mutational signatures for evidence of AA mutagenesis. Remarkably, more than 78% of HCCs showed strong evidence of AA mutagenesis, often associated with high mutation burdens. Non-synonymous mutations in genes known to be HCC driver genes were detected. Importantly, we elucidated the potential of immunotherapy in this cohort of liver cancer patients.

  Study EGAS00001002301

• Transcriptomic analysis of B-cell acute lymphoblastic leukaemia (B-ALL) patients treated on the ALL09 clinical trial

  This study provides comprehensive transcriptomic analysis of adolescent and young adult (AYA) patients treated on the Australasian Leukaemia and Lymphoma Group (ALLG) ALL09 clinical trial (ACTRN12618001734257). The ALL09 clinical trial is a Phase II single arm study to assess whether substitution of blinatumomab for conventional multi-agent chemotherapy in phase 2 induction leads to improved minimal residual disease negativity rates when compared to the historical AYA ALL trial cohort. Patients treated on this trial were aged 15-40 years, demonstrated morphological diagnosis of CD19 positive B-lineage acute lymphoblastic leukaemia (B-ALL), and were negative for Philadelphia chromosome-positive disease. Transcriptomic sequencing was performed as a correlative study to determine assess patients’ genomic subtypes and enable comparison of clinical outcome in blinatumomab treated patients.

  Study EGAS50000001109

• Recording physiological history of cells with chemical labeling.

  Recordings of the physiological history of cells provide insights into biological processes, yet obtaining such recordings is a challenge. To address this, we introduce a method to record transient cellular events for later analysis. We designed proteins that become labeled in the presence of both a specific cellular activity and a fluorescent substrate. The recording period is set by the presence of the substrate, whereas the cellular activity controls the degree of the labeling. The use of distinguishable substrates enabled the recording of successive periods of activity. We recorded protein-protein interactions, G-protein-coupled receptor activation and elevations in intracellular calcium. Recordings of elevated calcium levels allowed selections of cells from heterogenous populations for transcriptomic analysis and tracking of neuronal activities in flies and zebrafish.

  Study EGAS50000000056

• Identification of germline variants in Medullary thyroid carcinoma (MTC) by whole- exome sequencing

  Medullary thyroid cancer (MTC) is a rare malignant tumor that arises from parafollicular cells. Approximately 8% of thyroid cancer cases are MTC, and about 25% of these have a hereditary component. Incorporating molecular parameters into tumor classification is important. Besides, the presence of pathogenic germline variants can impact directly on cancer prevention. Thus, the aim of this study was to perform whole exome sequencing (WES) on a consecutive series of hereditary RET wild-type MTC patients to identify genetic variants that may be involved in the carcinogenesis of this tumor. WES was performed on 28 patients negative for germline RET pathogenic variants using the NovaSeq 6000 platform. Variant classification followed American College of Medical Genetics and Genomics guidelines.Our study represents a significant advancement in gene discovery for MTC genetics.

  Study EGAS50000000061

• WGS of liver cancer in the Japanese population

  Hepatocellular carcinoma (HCC) is the third leading cancer-related cause of death and the seventh most common form of cancer worldwide, with an estimate of more than 700,000 new cases each year. The most established risk factors of HCC are chronic HBV and HCV infection. HBV infection is responsible for over 50% of the worldwide attributable risk of HCC, especially in East Asia and Africa, while in Japan and several Western countries HCV infection is the most common risk factor for HCC. To gain insights into the molecular alterations of virus-associated HCC, we performed whole genome sequencing (WGS) of 321 HCC tumors from 159 patients. This work was performed as a part of the ICGC (International Cancer Genome Consortium) project.

  Study EGAS00001000678

• RNA sequencing data from glioblastoma primary cell lines treated with indisulam

  This study aimed to develop NovumRNA, a bioinformatics pipeline designed to predict non-canonical tumor-specific antigens (ncTSAs) from human tumor RNA-sequencing data, potentially broadening the target pool for cancer neo-epitope-based immunotherapies. The splicing-modulating drug indisulam was investigated for its potential to induce aberrant transcriptomes, potentially increasing ncTSAs, subsequently predicted by NovumRNA. Four glioblastoma primary cell lines were derived from patient Cavitron Ultrasonic Aspirator (CUSA) material, cultured as neurospheres, and treated with indisulam or vehicle control. RNA was extracted at 6 and 16 hours post-treatment and sequenced using the NovaSeq platform. The resulting RNA-seq data was analyzed with NovumRNA, using healthy brain GTEx samples as controls, to identify and validate ncTSAs induced by indisulam treatment. NovumRNA is available at: https://github.com/ComputationalBiomedicineGroup/NovumRNA.

  Study EGAS50000000680

• ECM-free patient-derived organoids preserve diverse prostate cancer lineages and uncover in vitro-enriched cell types

  Patient-derived organoids (PDOs) hold promise for modeling various cancers, yet their application in prostate cancer (PCa) has been limited due to low culture success and the predominance of non-tumor-like cells. Using 164 PCa samples and optimizing culture conditions, we demonstrate that an extracellular matrix (ECM)-free culture method improves PDO take-rates, fostering cell populations with luminal and PCa-specific characteristics. Single-cell RNA sequencing (scRNA-seq) reveals that these ECM-free PDOs closely mirror their original tumors at the transcriptomic level and maintain a diverse array of tumor cell types, unlike traditional Matrigel-based cultures which predominantly yield benign-like cells. This study introduces a PCa PDO single-cell atlas, providing a valuable resource for advancing prostate cancer research.

  Study EGAS50000000807

• Genome-wide association analysis on five isolated populations - Erasmus Rucphen Family (ERF) Study

  ERF is embedded in the Genetic Research in Isolated Population (GRIP) program. Genealogy of GRIP is available from its founding (1600-1650). For ERF, we selected 22 related (first and second degree, non-consanguineous) couples living in GRIP between 1850-1900, and having at least six children baptized in the community church. All living descendants of those couples were invited to participate in ERF1. About 4,000 relatives included in the study form a very complex pedigree, which consists of more than 23,000 members. The participants aged between 18-20 years constitute a unique single family spanning over 23 generations. Around 3,000 individuals have been extensively phenotyped for several psychiatric and somatic traits. All phenotyped individuals are genotyped on genome-wide genotyping arrays.

  Study EGAS00001001134

• Genome_Diversity_in_Africa_Project___ancient_samples___standard_libraries

  Given the central importance of Africa to studies of human origins, genetic diversity and disease susceptibility, large-scale and representative characterisation of genetic diversity in Africa is needed. Analyses of ancient DNA from Africa would complement sequencing of modern African populations and provide unique opportunities to transform our understanding of the pre-history of the region. This approach would greatly refine our understanding of population structure and gene flow in Africa and globally, including genetic signatures of ancient admixture. This low coverage sequencing experiment will allow us to test and refine our pipeline for ancient DNA sequencing.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 EGAS00001001182

• Molecular sub-classification of hormone receptor-positive breast cancer

  Patients with estrogen and/or progesterone receptor-positive breast cancer benefit from hormonal treatment, yet high global death burdens due to high prevalence and long-term recurrence risk call for biomarkers to guide additional treatment approaches. From a prospective, observational study of postmenopausal early breast cancer patients treated with tamoxifen or aromatase inhibitors gene expression analyses of 612 tumors was performed using the NanoString® Breast Cancer 360 panel. We identified novel gene expression signatures, i.e. BRCAness and Tumor Inflammation Signature (associated with high tumor lymphocyte infiltration), that may aid to select high-risk patients in order to improve adjuvant treatment by targeting DNA repair deficiency or immune-checkpoints in addition to standard chemo-endocrine treatment. The overall goal is to foster novel concepts for a stratified early breast cancer management.

  Study EGAS00001004594

• Single-cell RNA sequencing of 22 Hodgkin lymphoma tumors and 5 reactive lymph nodes

  Hodgkin lymphoma (HL) is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of non-cancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding crosstalk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 HL tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the HL-specific immune microenvironment at single-cell resolution. Library preparation was performed using the 10x Genomics Chromium system, and Illumina sequencing was used to generate 3' gene expression data for every cell. Downstream analysis was performed in R to identify HL-specific microenvironment patterns and identify novel cell populations.

  Study EGAS00001004085

• Patient-derived organoids as a novel tool to study cervical cancer

  Cervical cancer is the most prevalent gynecological malignancy worldwide, often caused by infection with a high-risk human papillomavirus. Currently, there are only limited number of human-derived culture systems available that enable to study the viral infection for short-term. Here, we report on establishment of long-term human-derived organoid cultures from both healthy ecto- and endocervical epithelia that closely recapitulate the tissues of origin by maintaining the authentic histological and tissue-specific gene expression profiles. Additionally, using material from patients’ Pap-brush material, a successful panel of long-term patient-derived cancer organoids was established that maintain the causative viral infection in vitro and show differential response to common chemotherapy regimens. This study provides a promising platform for cervical cancer research and studying direct virus-host interactions.

  Study EGAS00001004439

• RP-1843 Arcagen - Gastrointestinal rare cancers (GI)

  Arcagen is an EORTC/SPECTA pan-European project that aims to recruit 1000 rare cancer patients from different tumour domains of EURACAN. This study collected samples from advanced or metastatic rare cancer from patients older than 12, and analysed them using Foundation Medicine next-generation sequencing (NGS) panels (FoundationOne CDx for FFPE samples or FoundationOne Liquid CDx for blood samples). Here we are submitting two datasets that contain NGS files from gastrointestinal rare cancers (n=119): - Dataset 1 (32 patients): Mesothelioma of the peritoneum (n=21) and Pseudomyxoma peritonei/mucinous adenocarcinoma of the appendix (n=11) - Dataset 2 (87 patients): Intra-hepatic cholangiocarcinoma (n=47), Extra-hepatic, cholangiocarcinoma (n=16), Not specified Cholangiocarcinoma (n=9), Small bowel adenocarcinoma (n=6) and other rare GI cancer (n=9)

  Study EGAS00001006299

• Single cell whole genome sequencing of high hyperdiploid acute lymphoblastic leukemia

  This dataset was collected from viable bone marrow cells obtained at diagnosis from nine patients with high hyperdiploid ALL and one normal bone marrow sample. All samples were subjected to low pass single cell whole genome sequencing with the median sequencing coverage of 0.02x. Single nuclei in G0/G1 phase were isolated using a fluorescence-activated cell sorting (FACS) cytometer. DNA libraries were constructed and associated next-generation sequencing was carried out by European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Further details regarding the DNA libraries construction are available by Bos et. al., 2019 (https://link.springer.com/protocol/10.1007/978-1-4939-8931-7_15). The dataset has been used for copy number aberrations analysis.

  Study EGAS00001006347

• ATAC-Seq of inflamed and non-inflamed biopsies

  Inflamed and non-inflamed biopsies were digested for 45 minutes at 37ºC with collagenase from Clostridium histolyticum (Sigma). Suspension cells were then stained with an antibody cocktail to sort live CD8-CD4+ T cells. After isolating crude nuclei of two thousand live CD4+ T cells, they were treated with Tagment DNA buffer and Tagment DNA Enzyme (Nextera DNA Library Prep Kit, Illumina), and then the DNA was purified by MinElute PCR Purification Kit (Qiagen). Transposed DNA fragments were amplified using specific adapters followed by purification with MinElute PCR Purification Kit (Qiagen). Fragments from 240-360pb were selected in the PippinHT system (Sage Science). The quality of the library and its DNA concentration were assessed by Bioanalyzer instruments (Agilent Technologies) and ultimately submitted for sequencing using Illumina HiSeq 2500 sequencer, V4 chemistry.

  Study EGAS00001007344

• MATISSE bulk RNA-sequencing data

  Tumor availability: Bulk RNA sequencing was performed on tumor biopsies of 48 patients at baseline and 45 patients across time points (baseline n=48, week 1 n=38, week 2 n=34, week 4 n=37), including lymph node metastasis that were sequenced in addition to the primary tumor. Tumor RNA was extracted from formalin-fixed paraffin-embedded (FFPE) primary tumor and lymph node metastasis sections containing at least 10% viable tumor cells present in the sample, except for on-treatment samples with a complete pathological response in which we isolated samples with at least 10% immune-infiltration with no viable tumor cells. A pathologist (LS) scored the tumor percentage and indicated the most tumor-dense region on a hematoxylin and eosin (H&E) stain slide for subsequent RNA isolation. According to the manufacturer's protocol, five to 10 FFPE slides (10 µm) were used for RNA isolation using the AllPrep DNA/RNA FFPE isolation kit (Qiagen, 80234) and the QIAcube. Genetic Diagnostics and Sequencing Services (CeGaT) performed RNA sequencing in Germany. Data processing: Demultiplexing of the sequencing reads was performed with Illumina bcl2fastq (v2.20). Adapters of the reads (Pico v2 SMART adapter, first three nucleotides of the second sequencing read) were trimmed with Skewer (v0.2.2), without quality trimming. RNA-sequencing data was aligned to GRCh38 (Ensembl v109) using STAR (v2.7.9) in 2-pass mode with default settings. Gene counts were generated with the HTSeq (v2.0.2). FastQC (v0.12.1) and MultiQC (v1.14) were used for assessing data quality, on FASTQ files and intermediate processing steps.

  Dataset EGAD50000001470

• EGA synthetic data

  Synthetic Data One of the limitations in genomics research is that human genomics data is not openly available; access must be controlled according to participant consent agreements and data protection regulations such as GDPR. Obtaining authorization to access such data can sometimes take a long time, resulting in delays to important research work. In this context, synthetic genomic and phenotype data can be useful resources for researchers to avoid these delays. Synthetic data are artificially generated datasets, often created with algorithms, which can be used without the need for authorization to test new products and tools, build technical demonstrators, validate data models, and train AI models. The EGA provides access to synthetic cohort datasets augmented with rich synthetic metadata that overcomes these real data usage restrictions. Whilst synthetic datasets are not included in the general EGA mandate and services, we can consider such submissions and evaluate their acceptance on the basis of their unique use cases not already covered by existing synthetic datasets. Access to synthetic data studies is managed by the EGA Helpdesk Data Access Committee. Study ID Title Located in EGAS00001002472 CINECA synthetic cohort EUROPE UK1 referencing fake samples Central EGA EGAS00001005591 Synthetic data - Genome in a Bottle Central EGA EGAS00001005042 Test Study for EGA using data from 1000 Genomes Project - Phase 3 Central EGA EGAS00001005702 Human genomic and phenotypic synthetic data for the study of rare diseases Central EGA EGAS50000000190 EOSC4Cancer Synthetic Colorectal Cancer Genomic data Central EGA EGAS50000000086 Synthetic - FEGA Sweden Heilsa synthetic dataset December 2023 Federated EGA Sweden EGAS50000000678 Synthetic - GDI synthetic data Federated EGA Spain

  Documentation synthetic-data

• Establishing Reliability for Quantitative EEG, Transcranial Doppler, Behavioral Outcomes and Optical Coherence Tomography in SWS: The Next Step toward Biomarker Development

  Sturge-Weber syndrome (SWS) is a rare, congenital syndrome with vascular malformations of the brain, skin and eye. The underlying cause of SWS is unknown and the extent of involvement varies greatly from patient to patient. Those with brain involvement present with seizures, stroke-like episodes and neurologic deficits, usually in infancy. Those with eye involvement frequently develop vision threatening glaucoma and retinal injury. Treatment has been largely symptomatic and hampered by delayed diagnosis and the rarity of the condition. The purpose of this study is to determine the reliability of non-invasive measures to be developed as biomarkers for SWS and to determine inter-rater reliability where appropriate. This includes measuring reliability for: Power asymmetry on Quantitative Electroencephalogram Asymmetry of Transcranial Doppler velocity and pulsatility Behavioral outcome measures (PEDI, Erhardt, Modified Rankin Scale) Optical Coherence Tomography Approximately 40 subjects will participate in this observational, cross-sectional study. The first version study release included data of the first n=25 subjects.

  Study phs001281

• CPTAC: Microscaled Proteogenomic Methods for Precision Oncology

  Cancer proteogenomics combines genomics, transcriptomics and mass spectrometry-based proteomics to gain insights into cancer biology and treatment outcomes. To promote clinical investigation, we developed a "microscaled" proteogenomics approach for tumor-rich frozen core needle biopsies. Tissue-sparing specimen processing ("Biopsy Trifecta EXTraction", BioTExt) and microscaled proteomics (MiProt) generated deep-scale proteogenomics datasets. As a proofof- concept, biopsies were accrued from ERBB2 positive (ERBB2+) breast cancers before and 48 to 72 hours after the first dose of neoadjuvant trastuzumab-based chemotherapy. Multi-omics comparisons were conducted between samples associated with residual disease versus complete pathological response (pCR). Integrated analyses diagnosed diverse molecular causes of treatmentresistance including: 1) absence of ERBB2 amplification (false-ERBB2&#43); 2) insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification (pseudo-ERBB2&#43); 3) resistance features in true-ERBB2+ cases including androgen receptor signaling, mucin expression and an inactive immune microenvironment; 4) lack of acute phospho-ERBB2 down-regulation in nonpCR cases. We conclude microscaled cancer proteogenomics could improve diagnostic precision.

  Study phs001907

• BPH Tissues for Cell Culture and Analysis - Spatial Transcriptomics Identifies Candidate Stromal Drivers of Benign Prostatic Hyperplasia

  The study goal was to apply spatial transcriptomics to identify candidate stromal drivers of benign prostatic hyperplasia (BPH). Laser microdissection (LCM) with RNA-seq of the stroma adjacent to hyperplastic and budding BPH ducts identified secreted factors including IGF1 and CXCL13. Single‐cell RNA sequencing (scRNA‐seq) revealed their co-expression from BPH fibroblasts. Additional studies sought to define similarities to embryonic prostate development, as well as therapeutic applications. Subjects were those who underwent prostatectomy for prostate or bladder cancer, with concurrent BPH, and who consented to use of surplus tissue for research studies. LCM/RNA-seq studies included 5 patients, and scRNA-seq studies included 1 patient. Phenotypic data submitted to this study include patient age, sex, prostate size, and international prostate symptom score (IPSS). Sequencing was done on an Illumina NovaSeq 6000 (LCM/RNAseq) and Illumina HiSeq X-Ten (scRNA-seq). The data processing pipeline utilized Kallisto (LCM/RNA-seq) and Cell Ranger (scRNA-seq). Data submitted are raw sequencing (Fastq) files.

  Study phs003477

• Comprehensive Genomic Data Deposition for Pancreatic Cancer Precision Medicine Studies: Clinical Trials NCT02451982 and NCT02648282

  This submission includes specimens from 89 pancreatic cancer patients at Johns Hopkins Hospital, comprising 41 surgically resectable and 48 locally advanced pancreatic cancer (LAPC) cases. These samples originate from two clinical studies, NCT02451982 and NCT02648282, following the Johns Hopkins Medical Institution Institutional Review Board-approved registry protocol at the Pancreatic Cancer Precision Medicine Center of Excellence Program. Written consent for specimen use, obtained from participants in the original studies, covers additional research, including this one. Biopsy specimens collected through endoscopic ultrasound-guided fine needle core biopsies or surgically resected tumors are included. NCT02451982 is a platform trial evaluating immunotherapy combinations for surgically resectable pancreatic ductal adenocarcinoma in the neo-adjuvant and adjuvant settings. It investigates the GVAX pancreatic cancer vaccine with immune-boosting cyclophosphamide, exploring immune cell trafficking and the impact of PD-1 blocking. NCT02648282 focuses on the efficacy and safety of combining cyclophosphamide, pembrolizumab, GVAX, and stereotactic body radiotherapy (SBRT) in locally advanced pancreatic cancer, with an emphasis on anti-tumor activity. Both studies provide valuable insights into innovative pancreatic cancer treatment approaches.

  Study phs003600

• ABO: a 3D stroma-supported culture platform enabling full human B lymphopoiesis for disease modeling and gene therapy development

  Defective B-cell development underlies a large proportion of inborn errors of immunity, but progress in understanding disease mechanisms and of developing therapies has been limited by inadequate human in vitro models. Here, we establish a 3D aggregate culture platform composed of hematopoietic stem and progenitor cells (HSPCs) and mouse bone marrow stromal cells as an assay for efficient B-cell output (the ABO platform). ABOs supported progression through pro-B, pre-B, immature, and transitional B-cell stages, with a transcriptional profile and B-cell receptor (BCR) repertoire diversity closely resembling human bone marrow B-cell ontogeny. ABO-derived B cells exhibited functional signaling and differentiated into class-switched memory and antibody-secreting B cells following CD40-mediated stimulation. The ABO platform reproduced the arrest in B-cell development observed in RAG1-SCID patient–derived HSPCs, which was corrected by lentiviral RAG1 gene therapy. Thus, ABOs provide a clinically relevant platform for modeling B-cell immunodeficiencies and evaluating therapeutic strategies.

  Study EGAS50000001693

• Human Dicer is required for cell-intrinsic immunity to self-dsRNA

  Self-derived double-stranded RNAs (self-dsRNAs) can activate cell-intrinsic innate immune responses and contribute to autoinflammation. We uncover an essential role for human Dicer in innate immune responses to self-dsRNA. Loss of Dicer disrupts RIG-I-like receptor-dependent type I interferon (IFN-I) induction and activation of both the PKR and OAS1-3/RNAse L pathway in conditions where self-dsRNA accumulates, such as cells lacking ADAR1, PNPase, hnRNPC, or MPP8. In contrast, Dicer does not affect the IFN-I response triggered by exogenous dsRNA. Dicer interacts with LGP2, G3BP1, and Staufen1 and loss of these proteins similarly impairs IFN-I induction by self-dsRNAs. Depletion of Dicer and G3BP1 reduces the accumulation of immunostimulatory self-dsRNAs, while depletion of Dicer and Staufen1 prevents MDA5 oligomerization. We conclude that Dicer regulates self-dsRNA availability and sensing, aided by G3BP1 and Staufen1, respectively. Our findings highlight a non-canonical role for Dicer in innate immune activation by self-dsRNA and pinpoint new drug targets in autoinflammatory disorders.

  Study EGAS50000001409

• Illumina HumanCoreExome genotyping data from the British Society for Surgery of the Hand Genetics of Dupuytren’s Disease consortium (BSSH-GODD consortium) collection

  Dupuytren's Disease (DD - OMIM126900) is the most common heritable disorder of connective tissue. It is a fibroproliferative disorder of the palmer fascia, causing flexion contractures of affected digits. DD affects men more commonly than women. DD is an archetypal complex disease, with multiple genetic and environmental factors affecting the final expression of the disease phenotype. The incidence increases with age, and the prevalence of DD is therefore increasing as the UK population ages. Half of all patients present before age 60. DD causes significant functional impairment, and severe contractures can lead to permanent disability. The mainstay of current treatment is surgery, but recurrence and complications are both high. For severe contractures, the only suitable treatment option is amputation. The direct costs to the NHS are high, and underestimate the true economic costs to society. We collected salivary samples from adults in the UK who have had surgery for DD. We have genotyped these samples using the Illumina HumanCoreExome Beadchips. https://research.ndorms.ox.ac.uk/public/dupuytrens/what-is-dupuytrens-disease/

  Study EGAS00001001206

• Cell-free DNA TAPS for early cancer detection

  Multimodal, genome-wide characterization of epigenetic and genetic information in circulating cell-free DNA (cfDNA) could enable more sensitive early cancer detection. However, due to technological challenges associated with DNA methylation sequencing in low input cfDNA samples, most studies have been limited by DNA damage caused by bisulfite sequencing, or the qualitative nature of enrichment-based sequencing. Recently, we developed TET-assisted Pyridine Borane Sequencing (TAPS), which is a mild, bisulfite-free method for base-resolution direct DNA methylation sequencing. Here we optimized TAPS for cfDNA (cfTAPS) to provide high-quality and high-depth whole-genome cell-free methylomes. We applied cfTAPS to 85 cfDNA samples from patients with hepatocellular carcinoma (HCC) or pancreatic ductal adenocarcinoma (PDAC) and non-cancer controls. From just 10 ng cfDNA (1-3 mL of plasma), we generated the most comprehensive cfDNA methylome to date. We demonstrated that cfTAPS provides multimodal information about cfDNA characteristics, including DNA methylation, tissue of origin, and DNA fragmentation. Integrated analysis of these epigenetic and genetic features enables accurate identification of early HCC and PDAC.

  Study EGAS00001004962

• WES of adult intellectual disabilities with co-morbid psychiatric disorders (2019-08-07)

  ost adults with intellectual disabilities (ID) do not undergo genetic diagnostic investigation as part of their clinical care and have 'missed the boat' with regard to the WES and WGS genetic testing that is now being provided for children with ID. There is a dramatically increased risk of psychistric disorders in adults with ID, e.g. the risk of psychoses is 10X higher than in the general population. It remains an open question as to how much of adult ID is genetic in origin and how similar the genetic forms of adult ID are to those being diagnosed in children, in part due to survivor bias. There is also the opportunity to identify adults with treatable forms of ID, of which over 80 have been described, thus improving their clinical management. Furthermore, analysis of medical records of adults with genetic forms of ID can help to characterise the 'natural history' of individual disorders, resulting in more accurate prognoses for diagnosed children and identifying opportunities for improved management and possibly therapeutic intervention (e.g. optimal anti-epileptic therapy). Here we propose to exome sequence (to ~50X coverage) 200 adults with ID and co-morbid psychiatric disorders. This cohort has previously been assayed with chromosomal microarrays (Wolfe et al 2017 EJHG, 25, 66-72) identifying a diagnostic yield of ~11% which is comparable to the CNV diagnostic yield in various child ID cohorts (10-15%). The authors observed no substantive biases in diagnostic yield between different psychiatric diagnostic classes. The WES data will be analysed using the diagnostic workflows developed in the DDD study to ensure comparability between child and adult ID datasets. This study is intended as a pilot study to demonstrate the value of WES in adults with ID. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2019-08-07.

  Dataset EGAD00001005236

• How to encrypt files with Crypt4gh

  File preparation Hello Due to the processes used at the EGA for file archival the use of non-alphanumeric characters in a filename will cause issues in archival. By convention whitespaces in filenames are to be avoided and should be replaced with the underscore character (_). Before encrypting your files please make sure that any files that will be uploaded to EGA do not use special characters such as # ? ( ) [ ] / \ = + < > : ; " ' , * ^ | & Crypt4gh EGACryptor Files encrypted with Crypt4gh must be uploaded via INBOX Before uploading If you are not a registered EGA user, you will first need an EGA user account. Please note that it may take a few days for your account to be activated, as it needs to be vouched for by the EGA Helpdesk. Once your account is validated you will be able to request a submitter role. Meanwhile, you can create and add your public key to your EGA account profile. This option is not available for old submission accounts (e.g. ega-box-NNN). As soon as you have been granted a submitter role, you will be able to connect with your username and password to the EGA inbox using the SFTP protocol. If you have also registered a public key in your profile, you can also connect using this key. Encrypting your files Please note that you can also encrypt your files by uploading them directly to the "to-encrypt" folder in your upload area If your connection is unstable, please encrypt them using Crypt4gh The EGA encryption of this inbox is based on Crypt4GH. You can install a python implementation of it, with pip install crypt4gh or directly from the Github repository pip install git+https://github.com/EGA-archive/crypt4gh.git Save now the following Crypt4GH public key, into a file, say ingestion.pubkey. __EGA_INGESTION_PUBKEY__ Encrypt a given file with the following command: crypt4gh encrypt --recipient_pk ingestion.pubkey < file_to_encrypt > encrypted_file.c4gh The command reads the file from stdin (with < ) and output the encrypted version to stdout (with > ). Replace file_to_encrypt and encrypted_file.c4gh with the appropriate filenames but make sure to not use the same filename for both reading and writing because your SHELL would then truncate both files before you even read or write.

  Documentation submission/data/file-preparation/crypt4gh

• Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Autism - Simons Simplex Collection (SSC)

  In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants both in coding and noncoding regions will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of New York Genome Center (NYGC). WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal. An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

  Study phs001676

• Rb and p53-Deficient Myxofibrosarcoma and Undifferentiated Pleomorphic Sarcoma Require Skp2 for Survival

  Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) are highly genetically complex soft tissue sarcomas. Up to 50% of patients develop distant metastases, but current systemic therapies have limited efficacy. MFS and UPS have recently been shown to commonly harbor copy number alterations or mutations in the tumor suppressor genes RB1 and TP53. As these alterations have been shown to engender dependence on the oncogenic protein Skp2 for survival of transformed cells in mouse models, we sought to examine its function and potential as a therapeutic target in MFS/UPS. Comparative genomic hybridization (CGH) and next-generation sequencing (NGS) confirmed that a significant fraction of MFS and UPS patient samples (n=94) harbor chromosomal deletions and/or loss-of-function mutations in RB1 and TP53 (88% carry alterations in at least one gene; 60% carry alterations in both). Tissue microarray (TMA) analysis identified a correlation between absent Rb and p53 expression and positive expression of SKP2. Downregulation of SKP2 or treatment with Skp2 Inhibitor C1 revealed that Skp2 drives proliferation of patient-derived MFS/UPS cell lines deficient in both Rb and p53 by degrading p21 and p27. Inhibition of Skp2 using the neddylation-activating enzyme (NAE) inhibitor pevonedistat decreased growth of Rb/p53-negative patient-derived cell lines and mouse xenografts. These results demonstrate that loss of both Rb and p53 renders MFS and UPS dependent on Skp2, which can be therapeutically exploited and could provide the basis for promising novel systemic therapies for MFS and UPS.

  Study phs001982

• Center for Common Disease Genomics [CCDG] - Neuropsychiatric: Victorian Collaborative AuTism Study (CATS): Family and Community Study of the Genetics of Autism Spectrum Disorder

  In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants both in coding and noncoding regions will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of NYGC. WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal. An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

  Study phs002044

• NCI Cancer Model Development for the Human Cancer Model Initiative (HCMI)

  The Cancer Model Development Center (CMDC) project is part of the Human Cancer Model Initiative (HCMI) and is managed by the Office of Cancer Genomics within the Center for Cancer Genomics at the National Cancer Institute (NCI). The goal of the HCMI is to generate approximately 1000 novel human "next generation" tumor-derived models as a community resource. The models aim to faithfully recapitulate the cellular complexity and heterogeneity of human tumors. The CMDCs are tasked by the NCI with producing a proportion of the cancer models. Wellcome Sanger Institute (WSI) is a contributing member of the HCMI. Models developed by HCMI are being derived from a number of tumor types and subtypes (see below), including rare adult, pediatric and understudied cancers. The number of models and the clinical sites from which patient samples are acquired is increasing. Normal tissue, originating tumor, and tumor-derived models are sequenced. The next generation cancer models are associated with rich clinical and genomic data through the NCI Genomic Data Commons for all researchers to advance cancer research. The CMDC and HCMI models will serve as excellent tools in research to provide insight into the pathways that influence tumor growth and progression, how tumors respond to therapy, etc. Ultimately, the data generated using these models will support the development of personalized oncology. There is a delay between registered IDs and model availability. The current model count is found in The HCMI Searchable Catalog which is updated when new models are available for distribution to the research community.

  Study phs001486

• 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

• Human genomic and phenotypic synthetic data for the study of rare diseases

  The purpose of this dataset is to facilitate development of technical implementations for rare disease data integration, analysis, discovery, and federated access. This synthetic dataset includes clinical and genomic data from 6 rare disease cases. It consists of 18 whole genomes (6 index cases with their parents) which have genetic background based on public human data sequenced in the context of the Illumina Platinum initiative (Eberle, MA et al. (2017)) and made available by the HapMap project (https://www.genome.gov/10001688/international-hapmap-project). In each of the cases, real causative variants correlating with the phenotypic data provided were spiked-in. The cases included in this synthetic dataset correspond to the following type of disorders: CASE 1- Congenital myasthenic syndrome (Autosomal Dominant -de novo variant) CASE 2- Macular dystrophy (Autosomal Dominant) CASE 3- Muscular dystrophy (Autosomal Recessive-compound heterozygous variants) CASE 4- Mitochondrial disorder (Autosomal Recessive-consanguineous case - homozygous variant) CASE 5- Breast cancer (Autosomal Dominant) CASE 6- Similar as case 1 for patient matchmaking tests: Congenital myasthenic syndrome (Autosomal Dominant-de novo variant) For each case you will be able to download the following data: clinical information (phenopackets per individual and pedigree per family), raw genomic data (FASTQ and BAMs) and processed genomic data (vcfs). When using the data, the following should be acknowledged: the RD-Connect GPAP (https://platform.rd-connect.eu/), EC H2020 project EJP-RD (grant # 825575), EC H2020 project B1MG (grant # 951724) and Generalitat de Catalunya VEIS project (grant # 001-P-001647).

  Study EGAS00001005702

• Combination of ribociclib and gemcitabine for the treatment of medulloblastoma

  Group 3 (G3) medulloblastoma (MB) is one of the deadliest forms of the disease for which novel treatment is desperately needed. Here we evaluate ribociclib, a highly selective CDK4/6 inhibitor, with gemcitabine in mouse and human G3 MBs. Ribociclib CNS penetration was assessed by in vivo microdialysis and by immunohistochemistry and gene expression studies. Survival studies to determine the efficacy of ribociclib and gemcitabine combination were performed on mice orthotopically implanted with luciferase labelled mouse and human G3 MB. Pharmacokinetic-pharmacodynamic outcomes and univariable survival models were analyzed to estimate survival. Gene activity inference using NetBID and tumor differentiation analysis investigated the effects of the combination after short and long-term treatments. Tumors from mice treated with oral ribociclib displayed inhibited RB phosphorylation, downregulated E2F target genes, and decreased proliferation. Treatment of mice with the combination of ribociclib and gemcitabine was well tolerated, slowed tumor progression and metastatic spread, and increased survival. Molecular analysis of treated versus untreated tumors showed a significant decrease in the activity and expression of genes involved in cell cycle progression and DNA damage response, and an increase in activity and expression of genes implicated in neuronal identity and neuronal differentiation. Ribociclib is CNS-penetrant. When administered/combined with gemcitabine in orthotopic G3 MB models resulted in improved survival. Our findings, with both mouse and human patient-derived-orthotopic xenograft models, suggest that this combination therapy has promise for children with G3 MB and may represent an effective treatment strategy for other CNS malignancies.

  Study EGAS00001006001

• NICHD Genomic and Proteomic Network for Preterm Birth Research (GPN)

  We performed genome-wide association studies (GWAS) to study the Spontaneous Preterm birth (SPTB). Maternal and neonatal DNA from 743 SPTB (20 to and less than 34 weeks), and 752 controls (39 to and less than 42 weeks) who fully consented for public research usage were collected from participants in several clinical centers in Alabama, Illinois, New York, North Carolina, Rhode Island, Texas, and Utah. Cases were 1:1-matched with controls according to race/ethnicity (White, Hispanics, African Americans, and Others), maternal age (&#60;20, 20-29, 30-39, 40+), and parity (yes or no). To determine the case-control status for each participant, a Gestational Age (GA) was determined. DNA samples were taken from blood or saliva if blood was not available. Automated DNA extractions were performed on the Qiagen M48 robot, and samples were organized in 96-well plates with barcoding and sample tracking systems. Subsequent manipulations were performed on the Biomek FX liquid handling workstation with 96-channel pipetting. DNA quantitation was performed by dye-based assay on a Molecular Devices SpectraMax Plus plate reader. Samples were genotyped using Affymetrix Genome-Wide Human SNP Array 6.0. This work was conducted at the Microarray Facility at the University of Pennsylvania. Patient data were collected through chart reviews and patient interviews, which included Demographic information (parental age, race, ethnicity, etc.); Medical history (pre-pregnancy weight, height, medications, STD history, medical conditions, etc.); Social history (marital status, years of education, alcohol use and tobacco use); Obstetrical history including outcome of all prior pregnancies and dates of termination; History of preterm labor or premature rupture of membranes symptoms, evaluation or hospitalization for those symptoms in current pregnancy; Medications taken during current pregnancy; History of cervical evaluation (manually or ultrasonographically) or fetal fibronectin measurements; Pregnancy complications; Labor (type, indications, membrane status, and induction method); Delivery type and indications for cesarean section; Neonatal outcome (sex, weight, length, Apgar score, neonatal complications, admission to intensive care unit, etc.); and Maternal family history of SPTB.

  Study phs000714

• HudsonAlpha Institute for Biotechnology Clinical Sequencing Exploratory Research (CSER): Genomic Diagnosis in Children with Developmental Delay

  The overarching goal of this project is to explore the ability for whole exome and genome sequencing technologies to identify the genetic causes of unexplained developmental delay, intellectual disability (DD/ID), and related congenital anomalies in children. Such information may be useful as an endpoint to the otherwise fruitless "diagnostic odyssey" that many DD/ID affected families undergo and in some cases, identification of these genetic variants may point to better therapeutic or educational options by precisely defining the root cause(s) of the child's condition. We seek to identify causal, diagnostically relevant, genetic variants in children with developmental delay and/or intellectual disability (DD/ID). In addition, because our analytical approach includes sequencing probands and their parents (parent-offspring trios and duos; parents are sequenced when available), secondary findings will be returned to adults (parents) at their request. The aims of this research project include: 1) Use exome and whole genome sequencing to identify genetic variation that results in DD/ID. 2) Return primary genetic results (DD/ID causative) as well as secondary findings to probands and their parents, respectively. 3) Understand how the return of genomic test results affects the health and well-being of study participants. The children participating in this study are patients at, or referrals to, North Alabama Children's Specialist (NACS) in Huntsville, Alabama. All blood samples from probands and their parents will be collected at NACS (project 1). Sequencing will be completed at the HudsonAlpha Institute for Biotechnology, with validation (via Sanger sequencing) conducted at Emory University for all returned variants (project 2). The University of Louisville will oversee questionnaires, surveys and interviews aimed at understanding study participants' perception of, and response to, genetic test results, in addition to assessment of secondary findings preferences (project 3).A subset of variants, largely those determined to be diagnostic or variants of uncertain significance for study participants at the time of disclosure, have been submitted to ClinVar. These variants are listed as part of the "CSER-HudsonAlpha" study within the database.

  Study phs001089

• NSIGHT North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS)

  Since newborn screening (NBS) began in the 1960s, technological advances have resulted in its use in an increasing number of disorders. Recent developments in whole-genome sequencing and its simpler corollary, whole-exome sequencing (WES), now afford the opportunity to comprehensively define the variation within an individual's genome in a rapid and affordable manner. Many challenges arise with the clinical application of genome-scale sequencing and in deriving practical benefits to infants and children. Its utility in NBS has yet to be demonstrated and its application in the pediatric population requires special examination, not only for potential clinical benefits but also for the unique ethical challenges it presents. In this proposal, we outline a highly interdisciplinary approach to identify, confront, and overcome the major challenges that must be met in order to implement deep sequencing technology to enhance current newborn screening in a diverse pediatric population. Overarching Aim 1 will evaluate the utility of WES as a diagnostic tool to extend the utility of current NBS. Using diverse cohorts of infants and young children with known conditions identified through NBS, we will examine the sensitivity and specificity of WES. We will also utilize WES in cohorts of children with known conditions not currently screened as potential candidates for NBS in the future. Overarching Aim 2 will develop and assess a framework for analyzing WES in a clinically oriented framework based on principles of ethics and evidence-based medicine. We will develop strategies to guide clinicians, clinical laboratories, and patients/families in their decisions regarding the inevitable incidental findings that will be detected, in ways that respect the child and protect his/her future autonomy, while also respecting parental interests and rights. Overarching Aim 3 will explore ethical, legal, and social issues (ELSI) involved in informed decision making and develop best practices regarding the return of results after testing. We will develop novel decision support tools and evaluate their usefulness in parental decision making, and examine the burdens placed on clinicians as this new technology is deployed in the vulnerable and special population that are newborns and their families.

  Study phs002095

• Profiling Genome-Wide Circulating ncRNAs for the Early Detection of Lung Cancer

  Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Although imaging techniques such as low-dose computed tomography (LDCT), combined with tissue biopsies, have improved early detection rates, current diagnostic approaches are often limited by high false-positive rates, invasiveness, and radiation exposure, which lead to misdiagnosis and increased patient burden. Therefore, there is an urgent need for minimally invasive, accurate, and safe diagnostic biomarkers, particularly those derived from liquid biopsies such as blood-based exosomal RNA.This dataset specifically focuses on plasma-derived exosomal small non-coding RNAs (sncRNAs).A total of 233 de-identified plasma samples were obtained from Rush University Medical Center, including 116 NSCLC patients and 117 non-cancer controls. Exosomes were isolated from plasma, RNA was extracted, and small RNA sequencing was performed using the Illumina NextSeq 500 platform. Data available through dbGaP include individual-level raw sequencing files (FASTQ) and basic phenotype annotations of the plasma cohort.A diagnostic model was initially developed using small RNA-seq data from 1,446 tissue samples obtained from TCGA and GEO, identifying a robust sncRNA signature that distinguished NSCLC from non-cancer samples with an AUC of 0.90 in hold-out tissue validation. This signature was subsequently validated in the plasma exosome cohort, achieving an AUC of 0.84 in independent validation. The model demonstrated consistent diagnostic performance across subgroups stratified by age, sex, smoking history, cancer stage, and NSCLC subtype. Survival and functional analyses further supported the clinical and biological relevance of the identified sncRNAs. It is hoped that this resource will contribute to a better understanding of the sncRNA expression landscape in NSCLC and promote the development of non-invasive biomarkers for early cancer detection. These data may be applied to the investigation of transcriptomic and other risk factors, provide insight into cancer screening, tumor progression mechanisms, and prognosis prediction, and ultimately support precision medicine for NSCLC.

  Study phs004166

• Characterization of Cell Free Plasma Methyl-DNA From Xenografted Tumors to Guide the Selection of Diagnostic Markers for Early-Stage Cancers

  Circulating cell-free methyl-DNA (mcfDNA) contains promising cancer markers but its low abundance and possibly diverse origin pose challenges toward the accurate diagnosis of early stage cancers. By whole-genome bisulfite sequencing (WGBS) of cell-free DNA (cfDNA) from about 0.5 mL plasma of mice xenografted with human tumors, we obtained and aligned the reads to the human genome, filtered out the mouse and carrier bacterial sequences, and confirmed the tumor origin of methyl-cfDNA (mctDNA) by methylation-sensitive restriction enzyme digestion prior to species-specific PCR. We estimated that human tumor-specific reads (ctDNA) or mctDNA comprised about 0.29 or 0.01%, respectively of the xenograft mouse cfDNA, and about 0.029 or 0.001% of the cfDNA of human early stage cancer patients. Similar WGBS of early stage (0-II, node- and metastasis-free) breast, lung or colorectal cancer samples identified hundreds of specific DMRs (differentially methylated regions) compared to healthy controls. Their association with tumourigenesis was supported by stage-dependent methylation, tumor suppressor or oncogene clusters, and genes also identified in the xenograft samples. Using 20 three-cancer-common and 17 colorectal cancer-specific DMRs in combination (top 0.0018% of the WGBS methylation clusters) was sufficient to distinguish the stage I colorectal cancers from breast and lung cancers and healthy controls. Our data thus confirmed the tumor origin of mctDNA by sequence specificity, and provide a selection threshold for authentic tumor mctDNA markers toward precise diagnosis of early stage cancers solely by top DMRs in combination. Biological Materials were provided by the Ontario Tumour Bank, which is funded by the Ontario Institute for Cancer Research Reference for citation: Ling Liu, Jinghua Feng, Julian Polimeni, Manli Zhang, Hai Nguyen, Urmi Das, Xu Zhang, Harminder Singh, Xiao-Jian Yao, Etienne Leygue, Sam K.P. Kung, and Xie J. Characterization of cell free plasma methyl-DNA from xenografted tumours to guide the selection of diagnostic markers for early-stage cancers. Frontiers in Oncology, 2021 Feb. 5. DOI: 10.3389/fonc.2021.615821.

  Study EGAS00001006175

• Long-Term Outcome in Offspring and Mothers of Dexamethasone-Treated Pregnancies at Risk for Classical Congenital Adrenal Hyperplasia Owing to 21-Hydroxylase Deficiency

  Summary The purpose of this study is to perform the first long-term follow up study both of adolescents and young adults with a history of prenatal treatment with dexamethasone and of their mothers and to test for adverse medical or behavioral side effects. The emphasis will be on the outcome of this prenatal treatment in those fetuses who are not affected with steroid 21-hydroxylase deficiency (21OHD) form of congenital adrenal hyperplasia (CAH) and are either heterozygotes or homozygote-unaffected. Prenatal treatment of 46,XX fetuses with 21OHD (via administration of dexamethasone to the pregnant mother) has been shown to reduce the masculinization of the genitalia and, thereby, the later need for &#39;corrective&#39; feminizing genital surgery and potential impairment of sexual functioning. Along with the suppression of excess prenatal androgen production and reduction of prenatal masculinization of the genitalia in 46,XX fetuses with 21OHD, prenatal dexamethasone treatment may reduce the behavioral masculinization that is well documented in untreated 46, XX patients with 21OHD. Those fetuses who are partially treated until diagnosis of an unaffected status (heterozygous or homozygous-unaffected) will be studied as well. This latter group is of importance because these fetuses are being unnecessarily treated, but we have no way of diagnosing the unaffected status before the 8th week of gestation when treatment must begin for the female fetus who is affected. As treatment is necessary only until term in the female fetus affected with classical CAH, male fetuses and unaffected or heterozygous female fetuses do not require treatment. Thus, only one out of eight fetuses will require prenatal treatment until term. Findings of adverse effects of glucocorticoid treatment in non-human mammals [1, 2] have raised concerns among other clinicians and investigators about potential adverse side effects of such treatment on the developing human. Thus, this study will address this concern and investigate the potential adverse side effects of prenatal treatment. Detailed Description Females with classical CAH owing to 21-hydroxylase deficiency are born with ambiguous genitalia due to the production of excess androgens in utero. Prenatal treatment with dexamethasone was inaugurated in 1978 by Maguelone Forest and has been the standard of practice in the United States since 1986. Dexamethasone, which crosses the placental barrier, suppresses the fetal adrenal gland production of androgens, thus preventing ambiguous genitalia in the affected female. Children of both sexes are prenatally treated as soon as pregnancies at risk are confirmed. Treatment in females with 21OHD continues to term, but is discontinued in males and unaffected females. To date, 685 pregnancies have been diagnosed, of which 366 fetuses were treated. These investigators will study prenatally treated adolescents and adults 12 years and older with respect to medical and behavioral outcomes (see Table 5). In addition, mothers of children prenatally treated for varying periods of time for suspected 21OHD will be studied for long-term side effects of dexamethasone treatment administered during pregnancy. The long-term outcome in these children and their mothers has never before been studied.

  Study phs001317

• SEARCH for Diabetes in Youth Study - Genetic Risk Score

  Genetic risk scores (GRS) quantify polygenic disease risk into a single measure and can aid in disease classification. GRS studies have focused primarily on adult populations of recent European ancestry. We aimed to assess the utility of GRS in classification of diabetes type among racially/ethnically diverse youth in the United States. We used data from SEARCH baseline visits and follow up visits for which key data elements were available. 2260 participants are included. Phenotypic Data to be submitted here include: Self-reported sex, race and ethnicity Diabetes type determined by provider Etiologic diabetes type T1D (antibody positive, or antibody negative/missing and insulin sensitive) T2D (antibody negative and insulin resistant) Diabetes duration (years) Age at diagnosis (years) Measures from baseline, SEARCH 3 (follow-up) and SEARCH 4 (follow-up): Age Height Weight Waist circumference HbA1c Fasting/non-fasting glucose C-peptide Triglycerides HDL LDL Systolic Blood Pressure Diastolic Blood Pressure Measures from SEARCH 3 and 4:Arterial stiffness as characterized by PWVRetinopathy Measures from SEARCH 4 only: LV structure and diastolic function measurements from echocardiogram GAD autoantibody IAD autoantibody ZnT8 autoantibody We performed genotyping using the Illumina Multi-Ethnic Global Array (MEGA) array with 1,697,069 genotyped variants including 748,291 with minor allele frequency &lt;0.01. Genotyping and preliminary quality control checks were performed at the Colorado Center for Personalized Medicine. After additional quality control, 2,238 samples and 900,743 variants remained for analyses. Samples genotyped on the MEGA array were categorized using SEARCH etiologic type and consisted of predominantly type 1 diabetes cases (n=2,051) but also those with other diabetes (n=133 type 2 diabetes, n=52 other diabetes including monogenic diabetes; genetic confirmation with either a genetic clinical test or test performed as an ancillary study to SEARCH). The median reported age at DNA collection was 11.2 years (interquartile range 7.6 &#8211; 14.1) with a minimum age of 1.9 years and maximum of 21.9 years. We used additional data genotyped on the Affymetrix 500K imputation scaffold chip with 239,279 genotyped variants. This cohort consisted of predominantly type 2 diabetes cases (n=417) but also those with type 1 (n=104), and other diabetes types (n=16). After additional quality control, 537 samples and 235,967 variants remained. The median reported age at collection was 11.2 years (quartile range 8.1 &#8211; 14.2) with a minimum of 2.0 years and a maximum of 21.1 years. About 100 type 2 diabetes cases were also genotyped using the MEGA chip to ensure concordance between the data sets and facilitate strand alignment between the two chips before genotypic imputation. The data sets had n=230,228 genotyped variants in common and concordance between the genotypes was high (mean correlation r2 for SNPs used in GRS=0.95). We used the 1000 Genomes reference panel to impute each data set separately, resulting in a total of 34.5M and 27.8M well-imputed variants (r2&gt;0.8) for the MEGA and Affymetrix data sets respectively. We combined high quality imputed variants for analysis.

  Study phs002703

• DAC for high resolution genomic data generated by the Gisselsson Group at the Department of Clinical Genetics, Lund University.

  Dac EGAC00001000534

• The data access committee for Multimodal Genomic Features Predict Outcome of Immune Checkpoint Blockade in Non-small Cell Lung Cancer

  Dac EGAC00001001331

• Data Access Commitee for study Fine-Scale Genomic Analyses Of Admixed Individuals Reveal Unrecognized Genetic Ancestry Components In Argentina

  Dac EGAC00001001634

• Access to aligned sequencing data for study "Loss of SNAI2 in prostate cancer correlates with clinical response to androgen deprivation therapy".

  Dac EGAC00001001809

• Okayama University Hospital, CGM center, DAC

  Okayama University Hospital, Japan Centre for Comprehensive Genomic Medicine (CGM) Data Access Committee

  Dac EGAC50000000250

• Next generation sequencing of plasma cell neoplasms

  Includes raw data for genome sequencing studies performed at the University of Miami

  Dac EGAC50000000593

• CDK4 phosphorylation status and rational use for combining CDK4/6 and BRAF/MEK inhibition in advanced thyroid carcinomas

  Study EGAS00001007577

• An approach for evaluating the effects of dietary fiber polysaccharides on the human gut microbiome and plasma proteome

  Study EGAS00001005330

• Ampliseq library dataset

  This is the dataset for Ampliseq sequencing

  Dataset EGAD50000000536

• PDX WES for #039 and #049

  Exome sequencing of PDX and matched patient blood

  Dataset EGAD50000000034

• PDX WGS for #264

  WGS of tumour PDX and matched patient blood

  Dataset EGAD50000000033

• BreastCancer_Control_Micorarays

  Genotyping array data for normal mammary gland control samples

  Dataset EGAD00010002250

• Genotypes_Farmers

  Genotype data for Palanan farmers Philippines

  Dataset EGAD00010002141

• Genotypes_BaYaka

  Genotype data for BaYaka hunter-gatherers Congo

  Dataset EGAD00010002139

• DATA FILES FOR PCGP SJACT WGS

  Dataset EGAD00001001874

• Global Anaplastic Thyroid Cancer Initiative

  Raw exome sequence data(fastq) for the GATCI project

  Dataset EGAD00001003235