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• Deep multi-region WGS of lung cancer tumours

  Deep WGS (germline and 2-5 tumour regions) was performed on 20 patients: 13 lung adenocarcinoma, 5 squamous cell carcinoma, 2 small-cell lung cancers. A total of 68 BAM files are provided, where tumours were sequenced to 60x or 150x depth.

  Dataset EGAD00001005287

• A comprehensive characterisation and analysis of human breast cancers through whole-genome sequencing

  We propose to definitively characterise the somatic genetics of breast cancer through generation of comprehensive catalogues of somatic mutations in breast cancer cases by high coverage genome sequencing.

  Dataset EGAD00001002740

• RNA sequencing of Human Organoid Lines

  The study will use RNA sequencing to aid in benchmarking different culture conditions in a set of genetically annotated human organoid lines. The data will be used to assess whether there are any clonal differences introduced when culturing these lines in different conditions.

  Dataset EGAD00001007971

• Exome Sequencing of Spanish Patients with rare genetic diseases.

  Whole Exome sequencing of a set of Spanish patients suffering rare genetic diseases. The set consists of 3 patients, two were diagnosed with Aniridia (ANI-0006 and ANI-0023) and another one was diagnosed with Retinitis Pigmentosa (RP-0247).

  Dataset EGAD00001005498

• WES data generated in multifocal ileal NETs study

  This dataset includes whole-exome sequencing data for multifocal ileal tumor samples from two patients. Exonic sequences were enriched using the Agilent V2 capture probe set and sequenced by 76-bp paired-end reads using the Illumina Genome Analyzer IIx system with a mean coverage of 80x for each base

  Dataset EGAD00001006408

• Epichaperome - Englander Institute for Precision Medicine - Weill Cornell Medicine DAC

  This dataset accompanies the publication of Sugita M et al. "Targeting the Epichaperome As an Effective Precision Medicine Approach in a Novel PML-SYK Fusion Acute Myeloid Leukemia" Npj Precision Oncology 2021

  Dataset EGAD00001006904

• Single-cell RNA-seq of matched pediatric AML tumors

  Single-cell RNA-seq of pediatric AML tumours from patients enrolled in the clinical trial AAML1031. Obtained using the 10X Chromium Single Cell 3’ Reagent Kit, v3.0. A total of 75 samples were obtained from biopsies at diagnosis, remission and relapse from 28 patients.

  Dataset EGAD00001011195

• SCLC CTC genomic analysis data set

  The data set consists of low-pass whole genome sequence data of single CTCs, pools of CTCs and germline controls for a cohort of 31 SCLC patients at both baseline, and for 5 patients at relapse. In addition 9 CDX models and associated germline controls (where available) are included.

  Dataset EGAD00001002678

• The identification of genetic vulnerabilities in head and neck cancers for the development of novel therapies (2020-01-15)

  CRISPR/Cas9 lethality screens in a set of Asian head and neck cancer cell lines to identify novel targets. . This dataset contains all the data available for this study on 2020-01-15.

  Dataset EGAD00001005784

• Single-cell ATAC-seq of matched pediatric AML tumors

  Single-cell ATAC-seq of pediatric AML tumours from patients enrolled in the clinical trial AAML1031. Obtained using the 10X Chromium NextGEM Single Cell ATAC Reagent Kit, v1.1. A total of 64 samples were obtained from biopsies at diagnosis, remission and relapse from 25 patients.

  Dataset EGAD00001011194

• Panel sequencing data for Molecular Characterization of ETMRs

  This dataset contains panel sequencing data from 33 samples. Targeted sequencing was performed by creating libraries using the Agilent SureSelect XT technology. Libraries were sequenced using molecular barcode-indexed ligation-based sequencing using a NextSeq500 (Illumina) instrument. Between three and six lanes per sample have been sequenced resulting in 262 Fastq files (paired end).

  Dataset EGAD00001006208

• Mixture of 2

  Mixture of 2 unrelated individuals sequenced by 10x as a scRNA-seq. The dataset was then processed by Cell Ranger and deconvoluted to yield each individuals genetic profile. The clustering of SNPs is submitted as the processed file. The Sequencing fastqs are submitted as unprocessed files.

  Dataset EGAD00001008726

• AML-PMP miRNA-Seq

  miRNA libraries of the AML-PMP project were sequenced on the Illumina HiSeq 2000 instrument, approximately 16 samples per HiSeq lane, to a median depth of 5.7 million reads per library.

  Dataset EGAD00001009772

• Pseudodiastrophic dysplasia exome sequencing dataset

  This dataset contains 7 paired end fastq files obtained with Illumina Hiseq and Nextseq sequencing of whole exomes relevant to a study of pseudodiastrophic dysplasia (PDD). It includes 3 patients from 2 unrelated families diagnosed with PDD, together with the four parents.

  Dataset EGAD00001005775

• Cohort of NGS lymphoma samples used as control

  Control cohort of lymphoma samples sequenced with a hybrid capture panel designed to be able to detect translocations and mutations in lymphoma samples. used in the paper "Robust detection of translocations in lymphoma FFPE samples using Targeted Locus Capture-based sequencing"

  Dataset EGAD00001007711

• Platelet RNAseq data for SLFN14 K219N patients

  RNAseq dataset containing 20 control and 2 SLFN14 K219N patient samples, derived from platelets. Sequencing libraries were constructed using an Illumina TruSeq stranded Ribo Zero Gold kit and paired end sequenced at a read depth of 30 million reads on an Illumina NovaSeq 6000 platform.

  Dataset EGAD00001008965

• DigiPico sequencing data for the study of active mutational processes in HGSOC

  The dataset contains Bam files from DigiPico runs as well as bulk sequencing data used in the "A highly accurate platform for clone-specific mutation discovery enables the study of active mutational processes" publication.

  Dataset EGAD00001005118

• Predictor_RIO_TNBC (2019-04-03)

  In this study, samples fom a window study of the PARP inhibitor rucaparib in patients with primary triple negative or BRCA1/2 related breast cancer (RIO trial) will be investigated. Samples will undergo whole genome sequence and analysis, including use of HR Predict. . This dataset contains all the data available for this study on 2019-04-03.

  Dataset EGAD00001004894

• Pacbio HiFI Whole-Genome Sequecing of Trios with Intellectual Disability

  6 trios and 1 proband were whole genome sequenced with PacBio Sequel II to a depth of 30X, using the HiFi chemistry. For each trio the proband was affected with severe ID, and the parents were unaffected. Samples are grouped by trio.

  Dataset EGAD00001009109

• A molecular atlas of the human postmenopausal fallopian tube and ovary from single-cell RNA

  This datasets contains raw sequencing fastq data of 17 samples from 7 donors of single cell RNA using10x genome technology of human postmenopausal fallopian tube and ovary tissues.

  Dataset EGAD00001010076

• Non-coding mutations reveal cancer driver cistromes in luminal breast cancer

  A dataset of ER+PR+ breast tumor samples that were analyzed in order to identify mutation enrichment in cis-regulatory elements and cistrome. The repository includes sequencing data from 88 patients. 26/88 were sequenced using ATAC-seq

  Dataset EGAD00001007650

• Exome sequencing data

  Libraries were constructed using SureSelect HS XT Target Enrichment System v6 (Agilent). For each patient a library of CD3- cells (myeloid cells, considered tumor cells) and CD3+ cells (T cells, considered healthy) were generated.

  Dataset EGAD00001010190

• Whole exome sequencing of 27 Greenlanders

  The data contain whole exome sequencing of 27 Greenlanders in nine trios. Data were produced by Agilent SureSelect capture followed by paired-end Illumina HiSeq 2000 sequencing to a depth of 90.1X. More details on processing and analysis can be found in Moltke et al, Nature 2014 (PMID 25043022).

  Dataset EGAD00001003813

• RNAseq data for 6 samples from the DEV cell line

  - Six samples from the DEV cell line: 2 controls, 2 transduced with IL4R WT and 2 transduced with IL4R mutant (I242N) - This DEV cell line is not commercially available and was acquired from a colleague in the Netherlands

  Dataset EGAD00001003908

• Ewings Sarcoma Rearrangement Screen

  Cancer is driven by mutations in the genome. We will uncover the mutations that give rise to Ewing's sarcoma, a bone tumour that largely affects children. We will use second generation Illumina massively parallel sequencing, and bespoke software, to characterise the genomes and transcriptomes of Ewing's sarcoma tumours.

  Dataset EGAD00001000389

• Whole Genome Sequencing of Mutifocal HCC tisue

  The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy.

  Dataset EGAD00001003348

• Whole-exome sequencing of additional thyroid disease cases (2018-08-13)

  Whole-exome sequencing of a cohort of families (probands and affected/unaffected relatives) suffering from one of two rare thyroid disorders: congenital hypothyroidism (CH) and resistance to thyroid hormone (RTH). . This dataset contains all the data available for this study on 2018-08-13.

  Dataset EGAD00001004293

• Next generation sequencing of liver cancer cell lines

  Whole genome sequencing was performed for 81 liver cancer cell lines. Additional whole exome sequencing was performed for a subset of 11 liver cancer cell lines. SK_HEP_1 was also provided, though considered not hepatic origin. These sequencing data provided the detailed genomic characterization of liver cancer models.

  Dataset EGAD00001003165

• RNAseq of patients with Ewings sarcoma

  Cancer is driven my mutations in the genome. We will uncover the mutations that give rise to Ewing's sarcoma, a bone tumour that largely affects children. We will use second generation Illumina massively parallel sequencing, and bespoke software, to characterise the genomes and transcriptomes of Ewing's sarcoma tumours.

  Dataset EGAD00001000444

• Characterization of iPSC derived macrophages - cardiovascular pilot (2017-05-24)

  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 2017-05-24.

  Dataset EGAD00001003347

• Whole Exome (WE) sequencing data files for H_NO-JB001

  DNA was derived from the primary tumour, lung metastasis, and peri-aortic lymph node metastasis. DNA from the spleen was used as a normal control.For WE sequencing we user Hybrid capture (Nimblegen version 3.0) of the lymph node and lung metastases, primary tumour and spleen normal; we generated ~100-fold coverage.

  Dataset EGAD00001001252

• Whole-exome sequencing of additional thyroid disease cases (2017-05-11)

  Whole-exome sequencing of a cohort of families (probands and affected/unaffected relatives) suffering from one of two rare thyroid disorders: congenital hypothyroidism (CH) and resistance to thyroid hormone (RTH). This dataset contains all the data available for this study on 2017-05-11.

  Dataset EGAD00001003331

• Breast Cancer Sequential Sampling Targeted Capture

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

  Dataset EGAD00001000784

• Microinjection of hIPSC-derived intestinal organoids with Salmonella Typhimurium

  To generate an RNA-Seq dataset for organoids apically stimulated with Salmonella Typhimurium.These data are 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 EGAD00001001363

• Low coverage WGS from plasma DNA

  Low coverage whole genome sequencing plasma DNA from 50 male, 54 female non-cancer donors. For the analysis of nucleosomal positioning all data from the non-cancer controls were merged. Furthermore, two patients with metastasized breast cancer were sequenced on a NextSeq with higher depth.

  Dataset EGAD00001002215

• Breast Cancer -Very young women with ER+ tumor

  Corresponding data set is composed of whole exome sequencing of Korean ER positive breast cancer under 35. This set provides 100 alignment files from normal-tumor paired whole exome sequencing of 50 patients. This is a part of total project data set.

  Dataset EGAD00001002256

• Whole exome sequencing (WES) of CIMP leukemias

  Whole exome sequencing of tumor material derived from 14 mixed myeloid/lymphoid leukemias with a CpG Island Methylator Phenotype (CIMP). For 4 of these patients, normal material was also sequenced and used as control (files with the same identifiers prepended by an “h”).

  Dataset EGAD00001011053

• Whole-Genome Sequences from five human populations of Sudan

  This dataset provides the first high-coverage (~30X) whole-genome sequencing (WGS) data from Sudan, encompassing 125 individuals from five ethnolinguistic groups: Copts, Beja, Fulani, Fur, and Mahas. These populations represent three major linguistic families: Afro-Asiatic, Nilo-Saharan, and Niger-Congo, offering a detailed view of the country’s genetic diversity.

  Dataset EGAD00001015636

• Exome sequencing of synchronous colorectal cancers

  The data consists of 47 exome-sequenced synchronous colorectal cancers from 23 patients. The exomes of corresponding normal samples were used to remove germline variants. All patients are Finnish (white Caucasian). All except one patient (sync_11 who belongs to a LS family) were assumed sporadic. The sequence data was produced with Illumina HiSeq 4000.

  Dataset EGAD00001004884

• Combination Therapies for Personalised Cancer Medicine in drug resistant EGFR mutant lung cancer (2019-06-10)

  This study involves mutagenizing a range of different cell lines with ENU to identify those mutations which engender resistance to targeted treatment. . This dataset contains all the data available for this study on 2019-06-10.

  Dataset EGAD00001005080

• Alopecia and Vitiligo

  exome sequencing data captured with agilent v4 (71k) and sequenced on illumina technology. data from a total of 40 samples, of which 14 are vitiligo cases with familial history of vitiligo or immune disease, and the remaining are alopecia areata cases.

  Dataset EGAD00001005289

• Whole Exome sequencing data from Shwachman-Diamond syndrome bone marrow samples

  This dataset includes paired WES from bone marrow samples of patients with SDS and paired bone marrow-derived fibroblasts as a germline reference. Some patients have multiple samples collected serially over time. There are 74 BAM files included in this dataset.

  Dataset EGAD00001006815

• PhIP-seq of Japanese subjects with SLE

  Bacteriophage Immunoprecipitation Sequencing (PhIP-Seq) datasets of three eHHV-6B-positive SLE patients (three technical replicates), six eHHV-6B-negative SLE patients (three technical replicates), and a negative control lacking sera or plasma (12 technical replicates; Illumina NextSeq) and sequencing data of HHV-6 peptide phage library (two technical replicates; Illumina NextSeq).

  Dataset EGAD00001015429

• Whole-genome sequencing of Himalayan populations

  Whole-genome sequencing of 60 individuals from 15 Himalayan populations using the Illumina-B HiSeq X platform. These data are part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/.

  Dataset EGAD00001011358

• Unraveling mutagenic processes influencing the tumor mutational patterns of individuals with Constitutional Mismatch Repair Deficiency

  Molecular characterization of 41 tumors from 17 individuals with CMMRD to gain a better understandig of mutational processes driving subsequent tumor development. The molecular characterization includes the investigation of tumor mutational load and mutational signatures.

  Dataset EGAD00001015635

• Transcriptional Response to Hypoxia in iPSC-Derived Endothelial Cells from a High Altitude Adapted Population

  We established lymphoblastoid cell lines from 10 adult individuals of Tibetan ancestry living in the Chicago area. These lines were reprogrammed to induced pluripotent stem cells (iPSC). We validated genetic ancestry by genome-wide SNP array genotyping and population genetic analyses. After being subjected to standard quality control testing iPSCs were differentiated into endothelial cells. Following differentiation, endothelial cells were isolated via a pull down protocol using beads coated with an antibody for a canonical surface cell marker of the vascular endothelium (CD144). Purified vascular endothelial cells were cultured in parallel in normoxia (20% O2) and hypoxia (1% O2) for 48 hours prior to harvesting and processing for bulk RNA-sequencing. We provide imputed genotype data and bulk RNA-sequencing data in normoxia and in hypoxia for each of the 10 individuals. We also provide multiplexed scRNA-sequencing data for the 10 Tibetan individuals pooled with 10 CHB individuals from the 1000 Genome Project. Additionally, we provide scRNAseq data for the cardiomyocytes derived from the same iPSC lines from the Tibetan individuals pooled together with cardiomyocytes derived from iPSC lines of 10 CHB individuals from the 1000 Genome Project. Lymphoblastoid cell lines from the CHB were reprogrammed to iPSCs and differentiated to cardiomyocytes using the same protocols as used for the Tibetans. The batches of 4 lines were balanced by sex and population. These iPSC-derived cardiomyocytes were cultured in hypoxia (1% O2) for 48 hours and subjected to scRNAseq in pooled batches of 3 or 4 lines. The CHB individuals included in this analysis were: NA18528, NA18531, NA18557, NA18596, NA18606, NA18608, NA18614, NA18619, NA18633, and NA18748.

  Study phs003758

• The EGA at the International Congress of Human Genetics

  Today is the start of the International Congress of Human Genetics (ICHG). This event, hosted by the African Society of Human Genetics (AfSHG) and the Southern African Society for Human Genetics (SASHG), will reunite international experts to highlight how genomic technologies are being managed to address challenges generated by the current status of Human Health and Genomics. The European Genome-phenome Archive (EGA) will be at the Congress participating in workshops, meetings and talks where topics such as data access and discovery as well as the Federated EGA will be present. Data access and discovery In the context of the “Federated data analysis workshop“ that will be held the 26ᵗʰ, managed in the context of the CINECA project, a hands-on-session on Beacon v2 Discovery will be led by Mauricio Moldes. Another session on authorisation and data access will be presented by Mallory Freeberg and Coline Thomas, with and introduction by Thomas Keane. During the workshop, an end-to-end federated data analysis use case will be presented. Data access and discovery In the context of the “ Federated data analysis workshop“ that will be held the 26ᵗʰ, managed in the context of the CINECA project, a hands-on-session on Beacon v2 Discovery will be led by Mauricio Moldes. Another session on authorisation and data access will be presented by Mallory Freeberg and Coline Thomas, with and introduction by Thomas Keane. During the workshop, an end-to-end federated data analysis use case will be presented. During the last four years, CINECA has been identifying gaps in data sharing between Africa, Canada and Europe in order to build a federated solution for data access. Thomas Keane will present the project within the sessions happening the 24ᵗʰ. The Federated EGA at the ICHG A Federated EGA poster will be shown during the Poster Session 1 that will take place the 23ʳᵈ. The objective is to bring awareness of the European Genome-phenome Archive as a resource for permanent archive and secure data sharing. In this context, the network generated by the Federated EGA is key for cases where research data cannot be shared outside local jurisdictions. The Federated EGA was officially launched on 2022 with research institutes from five countries becoming the first nodes of this network. Nowadays, with more than 20 nodes preparing to join, it aims to become the largest human omics data sharing initiative towards understanding human health and disease. The H3Africa Initiative and the African research represented in the EGA 1.1% of the EGA studies include samples from African populations. Countries such as South Africa, Kenya, Uganda or Egypt, among others, are present in the 72.577 samples from African individuals archived at the EGA. 23 EGA datasets are managed by the Human Heredity and Health in Africa Initiative (H3Africa). This Initiative will celebrate its Consortium Meeting the 27ᵗʰ and 28ᵗʰ, back-to-back with the ICHG. H3ABioNet, the Pan African Bioinformatics Network for the H3Africa consortium, will also take this context to celebrate its 10-Year Symposium during the Congress. Members of the EGA team will attend both of them, as the H3ABioNet works in conjunction with H3Africa projects, to submit data to the European Genome-Phenome Archive.

  Blog the-ega-at-the-international-congress-of-human-genetics

• Out with the Java, in with the Python - new EGA data download client unveiled

  We will shortly be deprecating the Java-based download client also known as API V2. The Java client began its life at the back end of 2014, and during its time has seen many developments that have served our users well. During its tenure, the Java client enabled distribution of over 6.5 million files totalling nearly 15 petabytes of data to researchers around the globe. Recent increases in genomic and phenotypic data file sizes, the number of datasets archived in the EGA, the number of users downloading data, and the diversity of download locations has meant that at times the Java client struggled to distribute data efficiently. In response, our team of developers have built a new download client with more robust features and better functionality and reliability. Enter stage left our shiny new API V3.1! The new API V3.1 will replace both API V2 and API V3. The download client for the new API V3.1 is written in Python, and the code is openly available on Github. This Python client makes https calls to the EGA AAI (https://ega.ebi.ac.uk:8443/) and to the EGA Data API (https://ega.ebi.ac.uk:8052), both of which must be accessible from the client location. In addition to general updates to improve performance, the API V3.1 has three new features enhancing the EGA distributions services. First, requested data are now downloaded over secure https connections rather than http, meaning that data can be delivered unencrypted. Instead of separately requesting, downloading, and decrypting data using the Java client, data can now be requested and downloaded using a single command without the need for decrypting. The API V3.1 also automatically verifies each file’s unencrypted md5 after download to ensure the file has downloaded correctly. Second, the new API supports segmenting and automatic resuming. To enable quicker download speeds, the API breaks files into up to four segments and downloads them in parallel. With the new resume feature, downloads - both segmented and continuous stream - will automatically resume if they encounter any errors or the connection is interrupted. These features result in both a faster and more reliable download experience. Finally, the new API V3.1 implements the GA4GH-compliant htsget protocol for supporting requests over genomic ranges. This exciting new feature means that for data files with accompanying index files (e.g. .crai for CRAM files) users can download specific regions of interest rather than the entire file saving both time and storage space. The new features of the Python-based API V3.1 represent significant improvements in security, speed, reliability, and flexibility that are sure to provide a better data download experience. To take full advantage of these features, users must update to Python 3.X. Considering the changes in the data structures with the new API, the upgrade to a new version of the Python client is also mandatory. Updating the client to the latest version can be achieved by running the following command: pip3 install pyega3 -U We are excited for users to try out the new features and take advantage of the multifariously growing EGA distribution services for human biomedical omics data. If you have any questions or feedback, please email the EGA Helpdesk team. We'd love to hear from you!

  Blog new-ega-data-download-client

• A genome scan for genes underlying adult body size differences between Central African hunter-gatherers and farmers.

  The evolutionary and biological bases of the Central African pygmy phenotype, a characteristic of rainforest huntergatherers defined by reduced body size compared with neighboring farmers, remain largely unknown. Here, we perform a joint investigation in Central African hunter-gatherers and farmers of adult standing height, sitting height, leg length, and body mass index (BMI), considering 358 hunter-gatherers and 169 farmers with genotypes for 153,798 SNPs. In addition to reduced standing heights, hunter-gatherers have shorter sitting heights and leg lengths and higher sitting/standing height ratios than farmers and lower BMI for males. Standing height, sitting height, and leg length are strongly correlated with inferred levels of farmer genetic ancestry, whereas BMI is only weakly correlated, perhaps reflecting greater contributions of non-genetic factors to body weight than to height. Single- and multi-marker association tests identify one region and eight genes associated with hunter-gatherer/farmer status, and 24 genes associated with the height-related traits. Many of these genes have putative functions consistent with roles in determining their associated traits and the pygmy phenotype, and they include three associated with standing height in non-Africans (PRKG1, DSCAM, MAGI2). We find evidence that European height-associated SNPs or variants in linkage disequilibrium with them contribute to standing- and sitting-height determination in Central Africans, but not to the differential status of hunter-gatherers and farmers. These findings provide new insights into the biological basis of the pygmy phenotype, and they highlight the potential of cross-population studies for exploring the genetic basis of phenotypes that vary naturally across populations. Pemberton et al. Human Genetics 2018 https://doi.org/10.1007/s00439-018-1902-3

  Study EGAS00001002975

• A molecular cell atlas of the human lung from single cell RNA sequencing

  Although single cell RNA sequencing studies have begun providing compendia of cell expression profiles, it has proven more difficult to systematically identify and localize all molecular cell types in individual organs to create a full molecular cell atlas. Here we describe droplet- and plate-based single cell RNA sequencing applied to ~75,000 human lung and blood cells, combined with a multi-pronged cell annotation approach, which have allowed us to define the gene expression profiles and anatomical locations of 58 cell populations in the human lung, including 41 of 45 previously known cell types or subtypes and 14 new ones. This comprehensive molecular atlas elucidates the biochemical functions of lung cell types and the cell-selective transcription factors and optimal markers for making and monitoring them; defines the cell targets of circulating hormones and predicts local signaling interactions including sources and targets of chemokines in immune cell trafficking and expression changes on lung homing; and identifies the cell types directly affected by lung disease genes and respiratory viruses. Comparison to mouse identified 17 molecular types that appear to have been gained or lost during lung evolution and others whose expression profiles have been substantially altered, revealing extensive plasticity of cell types and cell-type-specific gene expression during organ evolution including expression switches between cell types. This atlas provides the molecular foundation for investigating how lung cell identities, functions, and interactions are achieved in development and tissue engineering and altered in disease and evolution.

  Study EGAS00001004344

• Whole genome sequencing of tumor samples from advanced pre-treated NSCLC patients recruited in a phase I/II single-arm trial utilising CVA21, an oncolytic coxsackie virus, in combination with pembrolizumab.

  Acquired or de novo resistance to immune checkpoint inhibitors occurs in the majority of advanced non-small cell lung cancers (NSCLC). There is an unmet need to improve outcomes for patients with this condition. Oncolytic viruses represent an attractive treatment approach due to their dual activity in inducing tumor cell lysis directly and potentially augmenting anti-tumor immunity. Here, we present the safety, efficacy and translational findings from a phase I/II single-arm trial utilising CVA21, an oncolytic coxsackie virus, in combination with pembrolizumab in patients with advanced pre-treated NSCLC. We performed paired biopsies pre- and post-treatment in 10 patients who received intravenous CVA21 and pembrolizumab, 8 of whom had prior treatment with immune checkpoint inhibitor (ICI) therapy. Whole genome sequencing and spatial proteomics were performed to comprehensively characterise the response to CVA21. Combination CVA21/pembrolizumab (anti PD-1) therapy was well tolerated with no serious treatment-related adverse events. Partial responses were seen in two patients with prior acquired anti-PD-1 resistance and disease stabilisation in 6 patients, giving a clinical benefit rate of 80%. High baseline tumor mutational burden and PD-L1 expression were observed in patients with better response to treatment. Interestingly, an increase in antigen presentation and CD8+ T cell infiltration was observed on treatment compared with baseline in patients with better progression-free survival. This study demonstrates the potential of CVA21 to modulate the immunogenicity of tumor cells and remodelling the tumor microenvironment, providing novel insights for patient selection for trials involving novel immunotherapeutic approaches.

  Study EGAS00001008258

• SardiNIA Medical Sequencing Discovery Project

  The SardiNIA Medical Sequencing Discovery Project studies the genetics of blood lipid levels and personality in a Sardinian population cohort. The project has generated draft genome sequences for approximately 2,000 individuals using whole genome shotgun sequencing. The draft sequences will allow investigators to evaluate the contribution of common and rare single nucleotide polymorphisms, short insertions and deletions, large copy number polymorphisms and other structural variants to blood levels of low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c) and triglycerides (TG), all of which are key risk factors for cardiovascular disease, and to the 5 domains of personality as assessed by the NEO-PI-R questionnaire. The two traits represent different ends of the spectrum of medically interesting complex traits. Blood lipid levels are a risk factor for cardiovascular disease for which genetic studies have been very successful. In contrast, personality traits and other behavioral phenotypes represent a set of phenotypes that have proven more challenging to dissect using standard genetic tools. In both cases, we expect whole genome sequencing to improve our understanding of the underlying biology. The isolated Sardinian population is ideal for this type of study for several reasons, in particular because: (i) the bottleneck that occurred after colonization of the island attenuated natural selection against alleles with phenotypic consequences, increasing the odds that functional alleles will reach modest frequencies (0.5 - 5.0%) and will be detected in the present study and (ii) sharing of long haplotype stretches surrounding rare variants will facilitate imputation based analyses of shotgun sequence data, which improve the accuracy of individual genotype calls and thus increase power. This research helps advance NIH's mission by furthering our understanding of the genetic factors contributing to blood lipid levels and coronary heart disease and to personality, behavior and mental health. In addition, these data should facilitate development of analysis tools and strategies that can be used to study the genomes of hundreds to thousands of individuals and further our understanding of the genetics and biology of many different traits and conditions.

  Study phs000313

• Molecular defects in pseudohypoparathyroidism or related disorders

  Maintaining calcium levels within a narrow normal range is of critical importance for numerous different cellular functions. One of the most important regulators of blood calcium levels is parathyroid hormone (PTH), which mediates its actions through the PTH/PTHrP receptor, a Gαs-coupled receptor. Few inherited disorders are characterized by diminished blood calcium levels and elevated blood phosphate levels; some of these disorders are caused by too little PTH synthesis and/or secretion (hypoparathyroidism, HP), while others are caused by resistance towards PTH (pseudohypoparathyroidism, PHP). Only few of the inherited forms of HP (<10%) have been defined at the molecular level. In contrast, genetic mutations have been identified for several inherited forms of PHP. For example, PHP type Ia (PHP-Ia) is caused by maternally inherited mutations in those GNAS exons that encode Gαs, while autosomal dominant PHP type Ib (AD-PHP-Ib) is caused by maternal inherited deletions within or up-stream of GNAS, which are associated with abnormal GNAS methylation. However, a large number of patients with PTH-resistance and thus hypocalcemia show GNAS methylation changes, but their underlying genetic defects have not yet been defined at the DNA level. These "sporadic" patients may be affected by an autosomal recessive form of PHP-Ib (AR-PHP-Ib), which is most likely not linked to the GNAS locus. In our studies, we propose to search through exome sequence analyses for novel genetic mutations responsible for novel autosomal dominant forms of HP that are not caused by mutations in the known disease-causing genes; some of these families are large enough to perform genetic linkage studies. We furthermore propose to search for the genetic mutation(s) responsible for the autosomal recessive variant of PHP-Ib through the analysis of whole exome sequences; for these studies we focus particularly on patients, whose parents are likely to be consanguineous. The proposed efforts are expected to lead to the identification of novel genes that are involved in parathyroid development and function (HP) and genes that are involved in the establishment or maintenance of GNAS methylation (AR-PHP-Ib).

  Study phs000476

• Effect of Breast Feeding on Immunologic Priming in Young Infants

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

  Study phs002073

• NIDDK IBD Genetics Consortium Crohn's Disease Genome-Wide Association Study

  This dataset contains data from a genome-wide association study performed with 968 Inflammatory Bowel Disease (IBD) affected cases and 995 unrelated controls using the Illumina HumanHap300 Genotyping BeadChip. Cases were selected to have Crohn's disease with ileal involvement, and controls were matched to cases based on sex and year of birth. Subjects were drawn from two cohorts: (1) persons with non-Jewish, European ancestry (561 cases and 563 controls), and (2) persons with Jewish ancestry (407 cases and 432 controls). Genotyping was performed at the Feinstein Institute for Medical Research. Seven-hundred fifty-four of the samples (468 cases and 286 controls) were taken from the NIDDK IBD Genetics Consortium cell line repository. These samples are identified in the IBD_Sample file. The subject IDs for these individuals may be used to request corresponding samples for follow-up research through the repository. In addition, complete phenotype data for these individuals are available, together with the Consortium's phenotyping manual and the forms used to collect the data. The remaining 1,209 samples were obtained from pre-existing collections ascertained through Cedars-Sinai Medical Center, Johns Hopkins University, University of Chicago, University of Montreal, University of Pittsburgh, University of Toronto, and the New York Health project (controls only). For these samples, only sex, cohort (Jewish vs. non-Jewish), and age at diagnosis (cases only) are available. Two-hundred three individuals from among the pre-existing samples did not provide consent to release their genotype data (designated as consent group 2 in the file IBD_Subject). Thus, individual genotype data are only provided for 1,760 samples. To compensate for this, we have provided summary results for each SNP. These are based on a stratified analysis testing case/control association. Fifty-one samples had a call rate less than 93% and were therefore excluded from this analysis, leaving an overall sample size of 1,963 - 51 = 1,912. X Chromosome Heterozygosity Nine samples have X chromosome heterozygosity that is neither consistent nor inconsistent with their phenotypic sex. One of these samples was found to have Turner Syndrome. The remaining 8 samples have heterozygosity ranging from 35-76%.

  Study phs000130

• National Institutes of Health The Cancer Genome Atlas (TCGA)

  The Cancer Genome Atlas (TCGA) is a comprehensive and coordinated effort to accelerate our understanding of the molecular basis of cancer through the application of genome analysis technologies, including large-scale genome sequencing. TCGA is a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), which are both part of the National Institutes of Health, U.S. Department of Health and Human Services. TCGA projects are organized by cancer type or subtype. Click here for a current list of cancer types selected for study in TCGA. Data from TCGA (e.g., gene expression, copy number variation and clinical information), are available via the Genomic Data Commons (GDC). Data from TCGA projects are organized into two tiers: Open Access and Controlled Access. Open Access data tier contains data that cannot be attributed to an individual research participant. The Open Access data tier does not require user certification. Data in Open Access tier are available in the TCGA Data Portal. Controlled Access data tier contains individual-level genotype data that are unique to an individual. Access to data in the Controlled Access data tier requires user certification through dbGaP Authorized Access. Controlled Access data types consist of the following: Individual germline variant data (SNP .cel files) Primary sequence data (.bam files), which are available at GDC Clinical free text fields Exon Array files (for Glioblastoma and Ovarian projects only) NOTE: TCGA strives to release most data in the open access tier. Individual genotype or sequence files are prominent exceptions. Commonly requested files such as descriptions of somatic mutations or clinical data are open access. Please go to this page: https://tcga-data.nci.nih.gov/docs/publications/ to access all data associated with TCGA tumor specific publications. The TCGA study is utilized in the following dbGaP substudies. To view genotypes and other molecular data collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000178 TCGA study. phs000854 Genome-wide Analysis of Noncoding Regulatory Mutations in Cancer

  Study phs000178

• Type 1 Diabetes Genetics Consortium (T1DGC): ImmunoChip Study

  The Type 1 Diabetes Genetics Consortium (T1DGC) was formed to address issues of limited sample size and consistency of phenotyping that had limited genetic investigations on risk of type 1 diabetes (T1D). The T1DGC first collected affected sib pair (ASP) families from four geographic networks (Asia-Pacific, Europe, North America, United Kingdom). In addition, T1D cases and controls were ascertained from existing and de novo collections. The T1DGC assembled 2,601 T1D ASP families and 69 Parent-T1D offspring trios, T1D cases from the UK Genetic Resource Investigating Diabetes (UKGRID, N=6,670), and controls from the British 1958 Birth Cohort (B58BC, N=6,523), the UK National Blood Services collection (NBS, N=2,893) and the NIHR Cambridge Biomedical Research Centre BioResource (CBR, N=2,846). All samples included in this series have reported or self-declared European ancestry. All DNA samples were collected after approval from relevant institutional research ethics committees. Genotyping was performed using a custom Illumina Infinium high-density genotyping array, ImmunoChip (Illumina, Inc; CA) according to manufacturer's protocols. The ImmunoChip was designed to densely genotype, using 1000 Genomes and any other available disease specific resequencing data, immune-mediated disease loci identified by common variant GWAS. The ImmunoChip Consortium selected 186 distinct loci containing markers meeting genome wide significance criteria (P<5x10-8) from twelve such diseases (autoimmune thyroid disease, ankylosing spondylitis, Crohn's disease, celiac disease, IgA deficiency, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, T1D and ulcerative colitis). All 1000 Genomes Project pilot phase CEU population variants (Sept 2009 release) within 0.1cM (HapMap3 CEU) recombination blocks around each GWAS region lead marker were submitted for array design. No filtering on correlated variants (linkage disequilibrium) was applied. Additional content included regional resequencing data (submitted by several groups) as well as a small proportion of investigator-specific undisclosed content including intermediate GWAS results. After data cleaning and quality control, a total of 154,939 single nucleotide polymorphisms (SNPs) from 186 loci on ImmunoChip were scored. Case-control and family data were analyzed independently and combined by meta-analysis.

  Study phs000911

• Longitudinal Studies of Brain Structure and Function in MPS Disorders

  Mucopolysaccharidosis (MPS) types I, II, IV, VI and VII, are inherited diseases that result from the bodies inability to break down large sugar molecules that are by-products of metabolism. MPS affects most organs of the body and causes abnormalities in the liver, spleen, bones, and brain. We are studying the central nervous system (primarily the brain) so we can better understand the nature of the problems individuals with MPS I, II, IV, VI and VII have so we can find ways of better treating these problems. We would like to find out about the changes in the brain of individuals with MPS I, II, IV, VI and VII using data from MRI and neuropsychological tests. This is a longitudinal study so patients who enroll will need to be seen 3 times over 5 years. The longitudinal nature of the study allows us to make conclusions about how changes in some structures of the brain and changes in cognitive ability are related. The research objectives are: To identify abnormalities of brain (and central nervous system) structure and function in patients with MPS I, II, IV, VI and VII, regardless of how they are being treated or have been treated in the past; and to track disease progression over time. To examine the degree to which independent variables (e.g., age at first treatment, severity of disease, types of medical abnormalities, mutation, medical events, and sensory abnormalities) have an impact on both functional and structural outcomes as well as on quality-of-life. To identify, through longitudinal study, those measures that most accurately reflect the current disease state. This is a longitudinal study of 75-100 individuals with either MPS I, II, IV, VI and VII. Those participating in the study will be evaluated 3 times over 5 years. The primary site for this study is the University of Minnesota but there are an additional 6 centers in the United States and Canada that are also participating and will provide data for analysis. You will need to be able to travel to Minnesota or one of the participating centers in order to be a part of this study.

  Study phs001328

• Childhood Cancer Data Initiative (CCDI): Molecular Characterization across Pediatric Brain Tumors and Other Solid and Hematologic Malignancies for Research, Diagnostic, and Precision Medicine

  This study contains tumor and germline WGS, RNA-Seq, Clinical Panel Sequencing, and other omics and molecular data for patients with pediatric brain tumors and other solid and hematologic malignancies. This data has been collected from multiple organizations including the multi-institute Children's Brain Tumor Network (CBTN), the Pacific Pediatric Neuro-Oncology Consortium (PNOC), and the Children's Hospital of Philadelphia Division for Genomic Diagnostics (CHOP DGD). In addition to being available pre-publication and without embargo via dbGaP and the NCI Cancer Research Data Commons, this data is made available via Cavatica, PedcBioPortal and the Kids First Data Resource Portal. Collectively, this availability strives to accelerate the research process and enable members of the scientific and patient communities to partner and make discoveries faster than ever before.In 2019, the CBTN launched the Pediatric Brain Tumor Atlas, which now comprises the largest collection of childhood brain tumor data in the world. This resource is helping accelerate not only brain tumor research, but is also empowering discovery for other rare childhood conditions. Brain tumors are the most common form of cancer in children aged 0-19 in the United States, and are the largest cause of cancer-related deaths. The estimated number of new cases in 2019 is nearly 3,800, and thus brain tumors are a rare disease. Despite their relative rarity, the years of potential life lost due to brain tumors in 2009 was estimated at 47,631 years for children and adolescents aged 0-19 in the United States; this is a disproportionate amount of life lost compared to adult cancers and represents an unrecognized societal threat. There is an urgent need to improve therapies for these children. This sequencing cohort defines the largest, clinically annotated pediatric brain tumor cohort study to date and seeks to define the intersection of germline and somatic underpinnings of pediatric brain tumors across a shared developmental context of cancer and structural birth defects.

  Study phs002517

• Integrating Genomic and Transcriptomic Data to Identify Breast Cancer Susceptibility Genes

  Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. Since 2007, common genetic variants in ~200 loci have been identified in genome-wide association studies (GWAS) in relation to breast cancer risk. However, it is often difficult to translate GWAS findings to disease prevention and treatment since causal genes in the large majority of GWAS-identified loci are unknown. Furthermore, a large fraction of breast cancer heritability remains unexplained. Recent studies suggest that nearly 80% of disease heritability can be explained by genetic variants regulating gene expression. Herein, we propose three well-powered transcriptome-wide association studies (TWAS) to systematically investigate the association of breast cancer risk with gene expression across the transcriptome of African, Asian and European descendants. In Aim 1, we will perform RNA sequencing and high-density genotyping assays using normal breast tissue samples, and build race-specific gene expression prediction models using data from 1000 women of African, Asian and European descent. These models will be applied to the GWAS data generated from approximately 320,000 breast cancer patients and controls to impute gene expression for association analyses of predicted gene expression with risk of breast cancer overall, and by estrogen receptor and HER2 status. In Aim 2, we will select the top 50 genes identified in Aim 1 for in vitro functional assays to assess their influence on major cell functions related to cancer biology. In Aim 3, we will evaluate whether TWAS-identified genes may express differently in normal breast tissues and breast cancer tissues collected from African, Asian, and European descendants to assess whether these genes may contribute to racial differences in breast cancer risk by molecular subtypes. With strong methodology and a large sample size, we believe that this proposed study should be able to identify and characterize a large number of novel genes related to breast cancer risk. Uncovering breast cancer susceptibility genes will greatly improve the understanding of the genetic and biological basis for breast cancer and accelerate the translation of genetic findings to disease prevention and patient care.

  Study phs003535

• Epi4K: Gene Discovery in 4,000 Epilepsy Genomes

  The Epi4K project began in 2011 as an international, multi-center study that seeks to identify and characterize the genetic bases of complex epilepsies. The Center without Walls Epi4K project includes three cores and four scientific projects, as well as a steering committee comprised of the primary study investigators and representatives from the National Institute of Neurological Disorders and Stroke (NINDS). The three cores include: (1) The Administrative Core which handles the overall coordination of Epi4K activities; (2) The Sequencing, Biostatistics and Bioinformatics Core which is responsible for generating the next-generation sequence data, inferring the genetic variation in each of the study participants, and performing the primary analyses to identify epilepsy genes; and (3) The Phenotyping and Clinical Informatics Core which verifies and archives all the phenotypic data from each study participant. The proposed number of patients to be sequenced and analyzed in the scientific projects is a minimum of 4,000; thus the Center was named "Epi4K: Gene Discovery in 4,000 Genomes". Project 1 addresses the genetics of rare and severe childhood epilepsies, including epileptic encephalopathies (infantile spasms and Lennox-Gastaut syndrome), and malformations of cortical development (periventricular nodular heterotopia and polymicrogyria). Exome and genome sequence data generated from DNA collected from patients will be screened for mutations (single nucleotide substitutions, small insertion-deletions, and copy number variations) that cause or contribute to the diseases. Project 2 is focused on genetic discovery in multiplex families. This study will use next-generation sequencing to identify genomic variation that influences risk for common subtypes of epilepsy including idiopathic generalized epilepsy and nonlesional focal epilepsy. Project 3 seeks to identify genetic determinants of prognosis in patients with a range of epilepsy disorders. This study will study established epilepsy cohorts with well-characterized data on seizure outcome to look for relationships between genetic variation and pharmacological control of seizures. Project 4 will use next-generation sequencing data (exome and genome) to screen for epilepsy-associated copy number variation across all Epi4K projects using novel computational algorithms.

  Study phs000653

• Effectiveness and Safety of Intermittent Antimicrobial Therapy for the Treatment of New Onset Pseudomonas Aeruginosa Airway Infection in Young Patients With Cystic Fibrosis (EPIC-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: To investigate the efficacy and safety of 4 antipseudomonal treatments in children with cystic fibrosis (CF) with recently acquired Pseudomonas aeruginosa (PA) infection.Background: CF is an inherited disease that causes mucus to build up in the lungs and digestive tract, which can cause lung infections and digestive problems. It is the most common type of chronic lung disease in children and young adults and may result in early death. There is no cure for this disease. The primary cause of death in individuals with CF is progressive obstructive pulmonary disease associated with chronic Pseudomonas aeruginosa (PA) infection. PA infection can occur early in life and can become highly resistant to antibiotics. Once an individual has been diagnosed with chronic PA infection, it is almost impossible to manage effectively. The need exists for an effective treatment to control and eliminate PA infection. Past research has shown that if PA infection is treated early, there is a greater likelihood that it may be eliminated completely.Participants: There were 304 participants.Design: Participants were randomized to 1 of 4 antibiotic regimens for 18 months (six 12-week quarters) between December 2004 and June 2009. Participants randomized to cycled therapy received tobramycin inhalation solution (300 mg twice a day) for 28 days, with oral ciprofloxacin (15-20 mg/kg twice a day) or oral placebo for 14 days every quarter, while participants randomized to culture-based therapy received the same treatments only during quarters with positive P aeruginosa cultures. The primary end points were time to pulmonary exacerbation requiring intravenous antibiotics and proportion of PA - positive cultures.Conclusions: No difference in the rate of exacerbation or prevalence of PA positivity was detected between cycled and culture-based therapies. Adding ciprofloxacin produced no benefits (Arch Pediatr Adolesc Med 2011; 165(9):847-856).

  Study phs004067

• 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

• Psychophysiological Investigation of Myocardial Ischemia (PIMI-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: To investigate psychophysiological factors related to both symptomatic and asymptomatic cardiac ischemia.Background: An important hypothesis has been generated from current research in this area: manifestations and expressions of cardiac ischemia are influenced by specified psychophysiological mechanisms.Participants: The study population consisted of 196 participants recruited from four clinical units, all of which were clinical units for the Asymptomatic Cardiac Ischemia Pilot (ACIP). Participants eligible for PIMI were identified throughout the screening process established for the enrollment of participants in ACIP.Design: The primary goal of PIMI was to test the hypothesis, "Manifestations and expressions of cardiac ischemia are influenced by specific psychophysiological mechanisms." The specific relationships investigated were:Patients who are susceptible to mental stress ischemia (indexed by new left ventricular wall motion abnormalities) would display more ischemia during daily activities and would have ambulatory ischemia at lower heart rate and activity level thresholds than patients who are not susceptible. Cardiovascular and catecholamine reactivity to mental stress would be a predictive of severity of mental stress ischemia and of ambulatory ischemia. Β-edorphin responses to mental stress and to exercise would be predictive of asymptomatic ischemia. Patients with systematic ischemia and those with asymptomatic ischemia would show differences in each of the following at rest and after response to stresses (exercise and/or mental tests). Mental stress would produce different hormonal and perceptual responses than exercise. Asymptomatic ischemia would be associated with a lesser severity of ischemia than symptomatic ischemia. The location of the ischemic myocardium would be inferior in a higher proportion of patients with asymptomatic ischemia than of patients with symptomatic ischemia. The latency internal that would be the onset of ST segment depression and the onset of ischemic pain would be related to somatic sensory perception, autonomic nervous system reflux control of the heart, Β-endorphin responses, and psychosocial characteristics.

  Study phs004183

• Lindsey E. Jones et al. Patient-derived cells from recurrent tumors that model the evolution of IDH-mutant glioma. Neuro-Oncology Advances, 2020. We established robust, versatile, and well-characterized Patient Derived Cells (PDC) of an IDH1-mutant astrocytoma and an IDH1-mutant oligodendroglioma that represents defined evolutionary stages of chemotherapy-induced hypermutation. The PDCs retain tumor subtype defining features over time as well as classic hallmarks of cancer, including anchorage independent growth and cell immortality. The integrated phylogenies composed of PDCs,single-cell-derived PDCs, patient-derived xenografts, and corresponding spatiotemporal tumor tissue samples also provide new insight into the clonality, evolutionary pattern, and immense mutational load of hypermutated IDH mutant gliomas.

  IDH-mutant lower-grade gliomas can undergo malignant progression via temozolomide-driven hypermutation. Patient-derived cells (PDC) that model the genetically distinct hypermutated (HM) tumor subgroup are generally lacking, and few if any human brain tumor cell models are from defined evolutionary time points. Here, we characterize multiple PDC derived from independent surgical specimens of IDH1-mutant recurrences, including an ATRX and TP53-mutant astrocytoma and a 1p/19q co-deleted and TERT promoter-mutant oligodendroglioma. We determined the evolutionary time points represented by each PDC using exome sequencing and phylogenetic reconstruction, comparing the PDC and single cell clones of the PDC (scPDC) to multiple spatiotemporal tumor tissue samples, PDC-derived xenografts (PDX) and patient-matched blood. The tumor samples exhibited TMZ-induced mutagenesis and a branching pattern of evolution. We found clear evidence of two fully independent founder HM clones in the tumor tissue that are faithfully represented by independent PDC. The PDC, scPDC and PDX also shared the mutagenesis signature and represent the mid and later evolutionary time points of their corresponding tumors. The PDC maintained the tumor subtype-defining features over many passages, including heterozygosity of the IDH1 R132H mutation, production of 2-hydroxyglutarate (2-HG), and subtype-specific telomere maintenance mechanisms. The PDC from both tumors exhibited anchorage-independent growth in soft agar. The oligodendroglioma PDC formed infiltrative intracranial tumors with characteristic oligodendroglioma histology, initially with a long period to tumor formation. We conclude that the PDC, scPDC and PDX faithfully model the heterogeneous clonal origins of the corresponding tumor tissue. The multilevel analysis also provides new insight into the intratumoral heterogeneity and vast mutational load of HM glioma. The PDC from multiple evolutionary time points presented in the context of full clinical timelines may be useful to model evolution and intratumoral heterogeneity, important sources of therapeutic failure.

  Study EGAS00001003992

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

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

  Study EGAS00001007115

• Genome-Wide Association Study of Patients with Coccidioidomycosis

  BackgroundValley Fever is typically an infection of the lungs caused by the fungi Coccidioides immitis and Coccidioides posadasii. The incidence of Coccidioidomycosis (CM), or infection with Coccidioides, has dramatically increased over the last 20 years. This is particularly true in the Southwest of the United States, where people often breathe fungal spores that arise from the soil. Reasons for increased infection rates are thought to include population growth and construction in these endemic regions, an increase in the number of people whose immune systems are compromised due to infection or treatment with drugs required for organ transplants, climate change, as well as improved testing practices and greater physician awareness. Mild CM most commonly presents itself with flu-like symptoms and rashes, which can last weeks to months. Individuals with compromised immune systems, specifically-- substantial suppression of the immune cells known as T cells, can develop severe pulmonary and disseminated disease. Infection that remains localized to the lungs is referred to as pulmonary disease, but when the infection spreads out of the lungs into other parts of the body it represents a more serious condition referred to as a disseminated disease, or disseminated CM. In nature, Coccidioides spp. exists as mold and lives in dust and soil. When the contaminated soil or dust is disturbed by human activity, animals, or weather, the Coccidiodies spores are released into the air. Airborne spores are taken up by breathing and settle in the lungs. Once in the moist and warm environment of the lung, spores transform into spherules, which divide and become filled with smaller spores, called endospores. When the spherules get large enough, they rupture and release these endospores, which can spread and disseminate to surrounding tissue. The cycle then repeats itself as these endospores develop into new spherules3. Different ethnic groups have been described to vary in their susceptibility to developing disseminated CM after initial infection with Coccidioides. For example, evidence suggests that African-American and Filipino patients suffer the disseminated disease at a greater rate than other ethnicities. The suggestion that race plays a role in the clinical expression of the disease is still a source of debate amongst the scientific community and any genetic mechanisms responsible for these differences have yet to be fully elucidated. If our genetic makeup influences our ability to limit the spread of infection, finding which DNA differences cause these variances could provide clues to how the body successfully fights infection, and provide opportunities to boost the body’s ability to do this. Further, if we are able to identify the specific genetic risk factors that correlate with the development of disseminated infection, physicians could perform genetic screenings to identify high-risk patients and provide them with preemptive antifungal therapy prior to developing disseminated disease.The genome, made up of DNA, contains all of the information needed for humans to develop and grow. Genome-wide association studies (GWAS) allow us to look for inherited differences that are more common between people who share a particular trait, for example, height or susceptibility to certain diseases, compared to those who do not share the trait. Although some traits and diseases are controlled by a single gene, the majority are influenced by contribution from several, or even many, different genes. To find evidence of genes that contribute to specific traits, GWAS typically compares genome information from large numbers of people who have a particular disease (referred to as “cases”) looking for DNA sequences that are common among these samples, and are different from DNA sequences seen in large numbers of people who lack the trait, but are as much like the cases as possible (referred to as “controls”). The DNA sequence data from each group, cases versus controls, are analyzed to see if there are specific genomic differences that tend to be associated with the disease. MethodsTwo separate GWAS approaches were taken to look for genetic differences that could be responsible for the observed differences between the different patient populations we are studying. The first method, known as genotyping, scans for differences at a set of positions across the genome, which includes both the genes that encode our proteins and the larger amount of DNA that does not. The second method, known as exome sequencing, allows us to compare the entire sequence of the portion of the genome that codes for proteins.  For this study, DNA from patients with either pulmonary or disseminated CM were genotyped and exome sequenced to look for DNA differences that are associated with one condition or the other. All patients were at least 18 years old, had no evidence of immunosuppression, and had proven or probable pulmonary coccidioidomycosis according to established diagnostic criteria. Of these patients, a subset demonstrated disseminated disease, i.e., they showed evidence of coccidioidal infection outside of the thorax by biopsy/aspiration, had radiographic imaging, and show positive coccidioidal serology. Our criteria for including patients with the pulmonary disease were that they must not require ongoing antifungal treatment or show evidence of active CM (in skin test positive patients), show no evidence of extrapulmonary dissemination, and have no evidence of ongoing pulmonary infection (pulmonary nodules are accepted) beyond six months from diagnosis.Patient DNA was purified from blood or from sputum samples by the labs of our collaborators, Drs. George Thompson (UC Davis School of Medicine) and John Galgiani (University of Arizona Health Sciences). Genome-wide association (GWAS) analysis was carried out to look for candidate loci associated with pulmonary versus disseminated disease, taking into account the population structure of the samples. Single nucleotide or insertion/deletion variants were identified from whole-exome sequences (WES) using the Picard/BWA/GATK pipeline. ResultsTable 1. Pulmonary versus Disseminated Cases of Coccidiomycosis for GWAS, Sorted by EthnicityEthnicityPulmonary CasesDisseminated CasesAsian85Black/African American1664Caucasian/White4015Filipino03Hispanic/Latino3414Indian21Mexican American1039Pacific Islander01Samoan03Vietnamese10Unknown16917More than one race02Total373134Table 1 shows the number of samples analyzed from patients with pulmonary versus disseminated disease, and patient ethnicity, where known. In all, we worked with 507 samples, including 134 samples from patients with disseminated disease and 373 samples from patients with pulmonary disease. Of these, 505 samples were genotyped using the Multi-Ethnic Global Array from Illumina Inc. In addition, we were able to generate whole-exome sequence from 498 patient samples. No significant associations were detected that differed between samples from patients with pulmonary versus disseminated disease; that is, no particular DNA sequences were found to be significantly enriched in patients with disseminated disease compared to patients with pulmonary disease. The ability to detect genetic association between specific sequences and genetically determined traits is influenced by several factors, including how many patient samples are available to compare, how many different genes contribute to the trait and how strong their contributions are. When the number of genes is small and the contribution of each gene is great, smaller numbers of patient samples are needed to detect an association. When more genes are involved, or the contribution from each gene is more modest, larger numbers of patient samples must be examined. While we were not able to detect any associated within this study, it does not mean that subsequent studies would not find this connection. Our study suggests significantly more samples should be analyzed in further studies.Whole-exome sequences were generated from 498 samples and were aligned to reference sequences to identify positions where the sequences differed from the reference. These data are being analyzed to determine if any variants are associated with pulmonary, versus disseminated, disease. 

  Study phs002170

• The subclonal architecture of metastatic breast cancer: Results from a prospective community-based rapid autopsy program 'CASCADE'

  Background: Understanding the cancer genome is seen as a key step in improving outcomes for cancer patients. Genomic assays are emerging as a possible avenue to personalised medicine in breast cancer. The majority of work in this area has targeted primary tumours however, and very few studies have performed comprehensive profiling of advanced disease. Evolution of the cancer genome during the natural history of breast cancer is largely unknown, as is the profile of disease at death. We sought to study in detail these aspects of advanced breast cancers that have resulted in lethal disease. Methods and Findings: Three patients with ER-positive, HER2-negative breast cancer and one patient with triple negative breast cancer underwent rapid autopsy as part of an institutional prospective community-based rapid autopsy program. Cases represented a range of management problems in breast cancer, including late relapse after early stage disease; de novo metastatic disease; discordant disease response and disease refractory to treatment. Between 5 and 12 metastatic sites were collected at autopsy together with available primary tumours and longitudinal metastatic biopsies taken during life. Samples underwent paired tumour-normal whole exome sequencing and single nucleotide polymorphism arrays. Subclonal architectures were inferred by jointly analysing all samples from each patient. Mutations were validated using high depth amplicon sequencing.Between cases, there were significant differences in mutational burden, driver mutations, mutational processes and copy number variation. Within each case, we found dramatic heterogeneity in subclonal structure from primary to metastatic disease and between metastatic sites, such that no single lesion captured the breadth of disease. Metastatic cross seeding was found in each case and treatment drove subclonal diversification. Subclones displayed parallel evolution of treatment resistance in some cases, and apparent augmentation of key oncogenic drivers as an alternative resistance mechanism. We also observed the key role of mutational processes in subclonal evolution.Limitations of this study include the potential for bias introduced by joint analysis of formalin fixed archival specimens with fresh specimens, and the difficulties in resolving subclones with whole exome sequencing. Other alterations that could define subclones such as structural variants or epigenetic modifications were not assessed. Conclusions: This study highlights the variety of mechanisms that shape the genome of metastatic breast cancer, and the value of studying advanced disease in detail. Treatment drives significant genomic heterogeneity in breast cancers which has implications for disease monitoring and treatment selection in the personalised medicine paradigm.

  Study EGAS00001002153

• Complete Genomics Deep Whole-Genome Sequencing of Circulating Tumor Cells from a Patient with Metastatic Breast Cancer

  Circulating tumor cells (CTCs) are considered to be informative non-invasive biopsy for the early detection, diagnosis or therapy guidance of cancer. CTCs also contain most of the heterogeneity found across multiple metastatic sites. In this study, we combine recently improved CTC isolation methods, resulting in almost pure CTCs, with advanced whole genome sequencing (WGS) based on Long Fragment Read (LFR) technology to demonstrate, for the first time, the research and clinical utility of an accurate, comprehensive, phased, and quantitative genomic analysis of CTCs. In particular, genomes of 34 CTCs, collected at two different time points from a patient whose metastatic breast cancer ultimately became resistant to standard treatments, were analyzed as 3072 barcoded sub-genomic compartments of long DNA. An average read coverage of 23X per cell enabled the high-resolution detection of somatic variants, cancer copy number variations (CNVs) and structural variants, including 133 CNVs shorter than 1Mb and an early chromothripsis-like event.

  Study phs001028

• L1-Seq and Genome-Wide SNP Genotyping in a Multiethnic Asian Population

  Insertions of the human-specific subfamily of LINE-1 (L1) retrotransposon are highly polymorphic across individuals and can critically influence the human transcriptome. We hypothesized that L1 insertions could represent genetic variants determining important human phenotypic traits, and performed an integrated analysis of L1 elements and single nucleotide polymorphisms (SNPs) in several human populations. We found that a large fraction of L1s were in high linkage disequilibrium (LD) with their surrounding genomic regions and that they were well-tagged by SNPs. However, L1 variants were only partially captured by SNPs on standard SNP arrays, so that their potential phenotypic impact would be frequently missed by SNP array-based genome-wide association studies. We next identified potential phenotypic effects of L1s by looking for signatures of natural selection linked to L1 insertions; significant extended haplotype homozygosity (EHH) was detected around several L1 insertions. This suggests that some of these L1 insertions may have been the target of recent positive selection.

  Study phs000732

• A Phase III Randomized Study of Nivolumab Plus Ipilimumab Versus Nivolumab in Stage IV Squamous Cell Lung Cancer

  Lung-MAP (S1400, NCT02785952) was a multicenter, open-label, phase III randomized clinical trial. The Lung-MAP-I substudy (S1400I) was conducted from December 2015 to April 2018, through the National Clinical Trials Network and led by the SWOG Cancer Research Network. The trial compared nivolumab plus ipilimumab (nivo+ipi) with nivolumab monotherapy (nivo) in patients with chemotherapy-pretreated, immunotherapy-naïve, advanced squamous non-small cell lung carcinoma (sqNSCLC). Two hundred fifty-two patients were randomly assigned to receive nivo+ipi (n = 125) or nivo (n = 127). The clinical efficacy endpoints were overall survival, progression free survival, duration of response, and best objective response by RECIST 1.1. Multi-omic translational analysis was performed in collaboration with the the CIMAC–Cancer Immunologic Data Commons (CIDC) Network using available tumor tissue samples and blood samples (n = 160) submitted for Lung-MAP screening and provided by the SWOG tissue bank.

  Study phs003412

• Monosomy 7 delineates a primitive acute myeloid leukemia with adverse prognosis and responsiveness to epigenetic therapy

  The mechanistic basis for adverse risk associated with monosomy 7 remains undetermined in AML. In contrast to del(7q), monosomy 7 conferred adverse prognosis independent of TP53 and complex karyotype. Single-cell RNA and ATAC-seq revealed an epigenetically remodeled landscape and expansion of multipotent progenitor (MPP)-like cells. Monosomy 7 derived progenitors were distinguished by reduced chromatin accessibility and expression of STK17A and NT5C3A, which conferred resistance to cytotoxic and venetoclax-based therapy. To circumvent resistance mediated by monosomy 7 and deficient TP53, histone deacetylase inhibitors (HDACi) effectively restored apoptotic potential and augmented the activity of venetoclax. In a randomized clinical trial including older unfit patients with AML and monosomy 7, responses were observed in the majority that received low-dose cytarabine, venetoclax and the HDACi pracinostat, some with durable remissions exceeding 3 years. Longitudinal studies highlighted diminution of MPP-like cells, linking epigenetic remodeling to clinical response and therapeutic vulnerability of monosomy 7 AML.

  Study EGAS50000001641

• EuCANCan: EUropean-CANadian Cancer network

  The EUropean-CANadian Cancer network (EuCANCan) is a project aiming to develop a federated network of aligned and interoperable infrastructures for the homogeneous analysis, management and sharing of genomic oncology data for Personalized Medicine. This initiative, funded by the European Commission and the Canadian Institutes of Health and coordinated by the Barcelona Supercomputing Center (BSC), is expected to process and provide the scientific community with around 30-35 thousand patient samples from different types of cancer, coming from different nodes involved in this project, during the four years of the project. Data generated as part of primary studies, often in small hospitals or research centers, is hardly reused by other projects or groups. EuCANCan is proposed to foster the homogenisation and discoverability of cancer samples from very different sources for the whole community. These efforts will help paving the way to future standardised and global genomics projects, specially for those participant countries that eventually integrate the methodology and infrastructure generated during the project. “The more data we have access to the more and better discoveries. We attempt to overcome the legal and technical limitations in order to generate, gather and exploit bigger datasets as well as answer more ambitious questions”. These were some of the words Dr. David Torrents, main coordinator of the project, shared with a regional radio during the kick-off meeting of the project, on February 11th, 2019. The EUCANCan network will be composed of reference nodes in Amsterdam, Barcelona, Berlin, Heidelberg, Paris and Toronto which have established strong research and clinical programs in the field of genomic oncology. The Centre for Genomic Regulation (CRG), specifically the European Genome-phenome Archive (EGA), is among the leading institutions. Its exhaustive experience in biomedical data archival and secure distribution is considered key for crucial developments within the project. It is also notable the recent inclusion of EUCANCan in the list of GA4GH driver projects. Further information and details can be found in the following links: InsideHPC BSC official description Techweek (Spanish)

  Blog eucancan

• Trans-ethnic genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

  We carried out a trans-ethnic genome-wide association and replication study of blood pressure phenotypes amongst up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 novel loci to be associated with blood pressure (P=3.9x10-11 to P=5.0x10-21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that at some of the loci identified DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 novel loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7, TBX2) function. The novel and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, cardiovascular and all-cause mortality (P=0.04 to 8.6x10-6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

  Study EGAS00001001427

• A Genomics-Based Classification of Human Lung Tumors

  We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

  Study EGAS00001000647

• High number of somatic mutations found in the healthy blood compartment of a 115-year-old woman reveals oligoclonal hematopoiesis

  The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole genome sequencing, we estimate that ~450 somatic mutations accumulated in the non-repetitive genome within the healthy blood compartment of a 115-year old woman. The detected mutations appear to have been harmless passenger mutations: they were enriched in non-coding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes.The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

  Study EGAS00001000660

• Feasibility and safety of a multi-cancer blood test for screening and intervention

  We evaluated the feasibility and safety of blood testing for cancer in an interventional study of 10,006 women. Positive tests for DNA or protein were independently confirmed and diagnostic PET-CT imaging was used to localize disease. During the study, 26 cancers were first detected by blood testing, 24 more by standard-of-care screening, and 46 by neither approach. Surgicalexcision of the primary tumors was performed on 12 cancers first detected by blood testing.1.0% of participants underwent PET-CT imaging based on false positive blood tests, and 0.22% underwent a futile invasive diagnostic procedure. These data demonstrate that multi-cancer blood testing, when followed by PET-CT localization, can be safely incorporated into routineclinical care, in some cases leading to surgery with intent to cure. Further studies will be required to determine the clinical validity and utility of multi-cancer blood testing.

  Study EGAS00001004372

• Gut metagenome associations with extensive digital health data in a volunteer-based EstMB cohort

  Microbiome research is starting to move beyond the exploratory phase towards interventional trials and therefore well-characterized cohorts will be instrumental for generating hypothesis and providing new knowledge. As part of the Estonian Biobank, we established the Estonian Microbiome Cohort which includes stool, oral and plasma samples from 2,509 participants and is supplemented with multi-omic measurements, questionnaires, and regular linkages to national electronic health records. In this study, we analyzed stool data from deep metagenomic sequencing together with rich phenotyping, including 71 diseases, 136 medications, 21 dietary questions, 5 procedures, and 19 other factors. The data revealed numerous relationships with different microbiome features. Additionally, the long-term antibiotic usage, independent from recent administration, has a significant impact on the microbiome composition, partly explaining the common associations between diseases. Overall, this study extends the understanding of microbiome–host interactions and facilitates the development of microbiome-related studies.

  Study EGAS00001005900

• Malignant progression of an ancestral bone marrow clone harboring a CIC-NUTM2A fusion in isolated myeloid sarcoma

  Myeloid sarcoma is a rare condition consisting of extramedullary myeloid blasts found in association with acute myeloid leukemia (AML) or, in the absence of bone marrow involvement. We identified an infant with isolated myeloid sarcoma whose bone marrow was negative for involvement by flow cytometry. Sequencing revealed the fusion oncogene CIC-NUTM2A and identified the sarcoma to be clonally evolved from the bone marrow which carried the fusion despite the absence of pathology. Murine modeling confirmed the ability of the fusion to transform hematopoietic cells and identified receptor tyrosine kinase signaling activation consistent with disruption of the CIC transcriptional repressor. These findings extend the definition of CIC-rearranged malignancies to include hematologic disease, provide insight into the mechanism of oncogenesis, and demonstrate the importance of molecular analysis and tracking of bone marrow involvement over the course of treatment in myeloid sarcoma, including patients that lack flow cytometric evidence of leukemia at diagnosis.

  Study EGAS00001006833

• GATA6 expression distinguishes classical and basal-like subtypes in advanced pancreatic cancer.

  PURPOSE: To determine the impact of basal-like and classical subtypes in advanced PDAC and to explore GATA6 expression as a surrogate biomarker. EXPERIMENTAL DESIGN: Within the COMPASS trial patients proceeding to chemotherapy for advanced PDAC undergo tumour biopsy for RNA sequencing. Overall response rate (ORR) and overall survival (OS) were stratified by subtypes and according to chemotherapy received. Correlation of GATA6 with the subtypes using gene expression profiling, in situ hybridization (ISH) were explored. RESULTS: Between December 2015-May 2019, 195 patients (95%) had enough tissue for RNA sequencing; 39 (20%) were classified as basal-like and 156 (80%) as classical. RECIST response data were available for 157 patients; 29 basal-like and 128 classical where the ORR was 10% vs. 33% respectively (p=0.02). In patients with basal-like tumours treated with modified FOLFIRINOX (mFFX) (n=22) the progression rate was 60% compared to 15% in classical PDAC (p= 0.0002). Median OS in the intention to treat population (n=195) was 9.3 months for classical vs. 5.9 months for basal-like PDAC (HR 0.47 95% CI 0.32-0.69, p=0.0001). GATA6 expression by RNAseq highly correlated with the classifier (p<0.001) and ISH predicted the subtypes with sensitivity of 89% and specificity of 83%. In a multivariable analysis, GATA6 expression was prognostic (p=0.02). In exploratory analyses, basal-like tumours, could be identified by keratin 5, were more hypoxic and enriched for a T cell inflamed gene expression signature. CONCLUSIONS: The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression.

  Dataset EGAD00001006081

• Distribution of ctDNA levels in plasma of early-stage non-small cell lung cancer patients measured using personalised ctDNA analysis

  Blood-based assays have shown increasing ability to detect circulating tumour DNA (ctDNA) in patients with early-stage cancer. However, detection of ctDNA in patients with non-small cell lung cancer (NSCLC) has continued to prove challenging. We performed retrospective analysis to quantify ctDNA levels in a cohort of 100 patients with early-stage NSCLC prior to treatment with curative intent. Where tumour tissue was available for whole exome sequencing, mutations identified were used to define patient-specific sequencing assays. For those 90 patients, plasma cell-free DNA was sequenced to high depth across capture panels targeting a median of 328 mutations specific to each patient. Data was analysed using Integration of Variant Reads (INVAR), detecting ctDNA in 66.7% of patients, including 52.7% (29 of 55) patients with stage I disease and >88% detection for patients with stage II and III disease (16/18 and 15/17). ctDNA was detected in plasma at fractional concentrations as low as 9.1x10-6, and in patients with tumour volumes as low as 0.23 cm3. A 36-gene sequencing panel (InVisionFirst-LungTM) was used to analyse plasma DNA in 27 samples including the 10 cases without tumour exome data, and detected ctDNA in 59% of samples tested (16 of 27). Across the entire cohort, detection rates were higher in squamous cell carcinoma patients compared to adenocarcinoma patients (81% vs. 59%). Detection of ctDNA prior to treatment was associated with significantly shorter time free from relapse, across all patients and in patient subgroups, with Hazard Ratios ranging from 2.25 to >11. Our analysis indicates that for patients with stage I NSCLC, the median ctDNA fraction in plasma is approx. 12 parts per million (0.0012%). This indicates the limits of detection that would be required for ctDNA-based liquid biopsies to detect ctDNA in the majority of patients with early-stage NSCLC.

  Dataset EGAD00001006230

• Natural history of clonal haematopoiesis (2017-09-04)

  The incidence of acute myeloid leukemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 60. Only 10-15% of cases evolve from a pre-existing myeloproliferative or myelodysplastic disorder; the remaining cases arise de novo without a detectable prodrome and are diagnosed upon development of bone marrow failure. Analysis of diagnostic blood samples has demonstrated that de novo AML is preceded by the accumulation of somatic mutations in pre-leukemic hematopoietic stem and progenitor cells (preL-HSPCs) that subsequently undergo clonal expansion. If individuals in this pre-leukemic phase could be identified, methods for determination of risk and monitoring for progression to overt AML could be developed. However recurrent AML mutations also accumulate during aging in healthy individuals who never develop AML, referred to as age related clonal hematopoiesis (ARCH). To distinguish individuals with preL-HSPCs at high risk of developing AML from those with ARCH, we undertook deep targeted sequencing of genes recurrently mutated in AML in blood samples from 133 individuals in the European Prospective Investigation into Cancer and Nutrition (EPIC) study taken on average 6 years before they developed AML (pre-AML group), together with 683 matched healthy individuals (Control group). Pre-AML cases displayed accelerated age-correlated accumulation of somatic mutations.The identity, number and variant allele frequency (VAF) of mutations differed between the two groups, and were incorporated into a computational model of AML risk prediction that accurately distinguished pre-AML cases from controls on average 7 years prior to AML development. Our findings provide proof of concept that early prediction of AML development is feasible in high-risk populations, paving the way for early disease detection, monitoring, and potentially prevention.

  Dataset EGAD00001003703

• Exome sequencing of patients with Ewings sarcoma

  Cancer is driven by mutations in the genome. We will uncover the mutations that give rise to Ewing's sarcoma, a bone tumour that largely affects children. We will use second generation Illumina massively parallel sequencing, and bespoke software, to characterise the genomes and transcriptomes of Ewing,s sarcoma tumours.

  Dataset EGAD00001000333

• DNA methylation-based classification of sinonasal tumors [Proteomics data]

  This dataset includes raw label-free mass spectrometry proteomics data of different sinonasal tumor entities as well as normal sinonasal tissue. 72 samples were processed on a Q Exactive HF-X instrument coupled to an easy nanoLC 1200 system using one microgram of peptides and an 110 minutes gradient.

  Dataset EGAD00010002381

• Set_of_human_mesenchymal_CSA

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

  Dataset EGAD00010002515

• Single-cell RNA-sequencing of peripheral blood mononuclear cells from patients with achalasia

  The data published here contains single-cell RNA-sequencing (scRNAseq) data as obtained using the 3' scRNAseq using Chromium Single Cell 3’ Reagent from 10X Genomics on peripheral blood mononuclear cells (PBMC) from patients with achalasia. Sequencing was performed in a paired-ended fashion on the NovaSeq6000.

  Dataset EGAD50000000250

• A Pilot Study Using Next Generation Sequencing in Advanced Cancers: Feasibility and Challenges

  In this study, we used NGS to identify somatic events in advanced stage cancer patients to demonstrate the feasibility for using this approach to improve patient treatment.

  Study phs000657

• Investigating differential diagnostic and prognostic biomarkers in primary cutaneous follicle center lymphoma and follicular lymphoma using low-coverage whole-genome sequencing

  In this study, we analyzed 28 primary cutaneous follicle center lymphoma samples from 20 patients and compared the copy number profiles to a cohort of diagnostic samples of 64 nodal follicular lymphoma patients using low-coverage whole genome sequencing (lcWGS).

  Dataset EGAD50000000199

• Etiology of congenital thyroid dysfunction in Down Syndrome: a multi-omics investigation

  The goal of this study was to investigate dfiferences in the thyroid DNA methylome and transcriptome between fetuses with Down syndrome and fetuses with no genetic/developmental abnormality.

  Study EGAS50000000264

• Transcriptome atlas of brain organoid developent

  Single-cell Cut&Tag of three histone modifications and chromatin accessibility over a timecourse of brain organoid development from pluripotency. We profiled 5 time points of brain organoid development and 2 time points of retinal organoid development. We used scRNA-seq to profile transcriptome. Library preparation was carried out with the 10x genomics platform.

  Dataset EGAD50000000223

• BAM files from capture-based targeted sequencing of 4 agressive B-cell lymphoma tumour samples (DLBCL-panel)

  This dataset contains BAM files from capture-based targeted sequencing of 4 agressive B-cell lymphoma tumour samples for cases 2, 3, 4 and 13. The sequencing panel used is a DLBCL-oriented panel containing 136 genes, described in Mozas P. et al., Hematol Oncol 2023.

  Dataset EGAD50000000802

• Moroccan Genome Project: Sequencing Data from 109 Whole Genomes of Moroccan Individuals

  This study is the first phase of the Moroccan Genome Project, which included the complete sequencing of 109 genomes from the Kingdom of Morocco. The sequencing was performing using the Illumina NovaSeq6000 platform, with a mean coverage of 30X.

  Dataset EGAD50000000750

• Early and Late Onset Colorectal Cancer Genomic Data

  A clinically and genomically annotated Early onset colorectal cancer and late onset colorectal cancer. This study aimed to identify genomic characteristics of early-onset colorectal cancer (EOCRC) compared to late-onset cases. Whole-genome sequencing (WGS) was performed on EOCRC and late-onset colorectal cancer (LOCRC) tissues and blood samples to analyze their genomic profiles.

  Dataset EGAD50000000774

• Expression quantitative trait loci influence DNA damage-induced apoptosis in cancer

  Dataset with eQTL and e2QTL metadata. The analyses were performed using CD8+ T cells from 461 healthy European participants stimulated with high doses of 5 different carcinogens to induce early apoptosis. These include Methyl-methanesulfonate (MMS), tert-butyl-hydroperoxide (TBOOH), benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE), 4-hydroxycyclophosphamide (HC) and UVC radiation.

  Dataset EGAD50000000941

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

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

  Dataset EGAD50000001005

• miRNASeq profiles from Indian HFrEF Cohort

  The dataset contains miRNA profiling from a cohort of 49 HFrEF patients. The myocardium samples were collected from these patients during heart transplant of LVAD implantation procedure. The RNA samples were collected in RNAlater. Small RNA libraries were prepared using QIAseq miRNA Library Kit, Qiagen and sequenced on Illumina HiSeq4000.

  Dataset EGAD50000001194

• Deciphering novel TCF4-driven mechanisms underlying a common triplet repeat expansion-mediated disease

  short and long read data generated from cultured corneal endothelial cells (CECs) of unaffected controls, expansion positive Fuchs Endothelial Corneal Dystrophy (FECD) and expansion negative FECD individuals.

  Study EGAS50000000303

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

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

  Dac EGAC50000000468

• HIV-phyloTSI: PANGEA (veSEQ-HIV)

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

  Dataset EGAD50000001309

• HIV-phyloTSI: PANGEA (PCR amplicon)

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

  Dataset EGAD50000001308