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• Isala Flow 1 DAC

  Dac EGAC00001003048

• EGAD00010000642

  CLL Expression Array

  Dataset EGAD00010000642

• MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

  Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long non-coding RNAs (lncRNAs), on the way MYC is able to influence cellular transcriptome. To this aim we have intersected RNA-sequencing data from two MYC-inducible cell lines and from a cohort of 91 mature B-cell lymphomas carrying, or not carrying, genetic variants resulting in MYC over-expression. By this approach, we identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them we focused on a lncRNA that we named MINCR, for MYC-Induced long Non-Coding RNA, showing a strong correlation with MYC expression in MYC-positive lymphomas and also in pancreatic ductal adenocarcinomas. To understand its cellular role we performed RNA interference (RNAi) experiments and found that MINCR knock-down is associated with a reduction in cellular viability, due to an impairment in cell cycle progression. Differential gene expression analysis following RNAi showed a strongly significant enrichment of cell cycle genes among the genes down-regulate following MINCR knock-down. Interestingly these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of MYC transcriptional program. Accordingly, following MINCR knock-down, we observed a reduction in the binding of MYC to the promoters of selected cell cycle genes. Finally we provide evidences that down-regulation of AURKA, AURKB and CTD1 may explain the reduction in cellular proliferation observed upon MINCR knock-down. We therefore suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.

  Dataset EGAD00001001441

• Whole exome sequencing of advanced gastric cancer

  To define the cellular characteristics of malignant ascites of advanced gastric cancer patients and search for therapeutic strategies, we obtained 5 malignant ascites and 1 cerebrospinal fluid from five patients with gastric cancer. We analyzed 180 cells from 4 malignant ascites and 1 cerebrospinal fluid metastasis. The results indicate that the anti-inflammatory characteristics of the tumor associated macrophages are concocted by the tumor cells. By constructing reference transcriptomes for M1 and M2 type macrophages, we found a strong non-inflammatory property of macrophages recovered from the malignant ascites of gastric cancer.

  Study EGAS00001004086

• Gene expression profiling of nasopharyngeal carcinoma

  We retrospectively collected 150 non-metastatic, pretreatment, formalin-fixed, paraffin-embedded (FFPE) nasopharyngeal carcinoma (NPC) samples as validation cohort 1. Also, we prospectively collected 32 FFPE samples from NPC patients enrolled in a trial evaluating anti-PD-1 antibody as validation cohort 2. Total RNA was extracted and hybridised to an Affymetrix HTA 2.0 microarray. In this study, we investigated the immune status of the tumour microenvironment (TME) based on gene expression profiles to classify NPC into biologically distinct immune subtypes, and clarify their associations with prognosis and immunotherapy response.

  Study EGAS00001004542

• Multi-region whole-exome sequencing of 10 neuroblastoma cases

  To investigate intratumour heterogeneity and to better understand tumour evolution in neuroblastoma, we have performed a multi-region whole-exome sequencing on a total of 51 spatially separated tumor samples from 9 primary neuroblastomas (2 low-risk, 1 intermediate-risk and 6 high-risk) and 1 relapsed neuroblastoma. We also assessed the impact of chemotherapy on the clonal expansion by sequencing tumour regions from one medium risk and one high-risk tumour for which we had matched samples obtained at diagnosis and after chemotherapy.

  Study EGAS00001004735

• Spatiotemporal immune atlas of the first clinical-grade gene-edited pig-to-human kidney xenotransplant

  Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. We transplanted a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and studied the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells were uncommon in the porcine kidney cortex early after xenotransplantation and consisted of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages expressed genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft was detected. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression is sufficient to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.

  Dataset EGAD50000000359

• The chemotherapeutic CX-5461 is extremely mutagenic and may increase cancer risk

  The chemotherapeutic agent CX-5461 or pidnarulex has been fast-tracked by the US FDA for treatment of BRCA1-, BRCA2-, and PALB2-mutated cancers. It is under investigation in Phase I/II clinical trials. Here we find that although CX-5461 exhibits synthetic lethality in BRCA1-/BRCA2-deficient cells, it also causes extensive, non-selective, collateral mutagenesis in all cells, to magnitudes that exceed known environmental carcinogens, raising public health concerns regarding its potential for promoting secondary cancers.

  Study EGAS50000000023

• Genomic Data Access Committee for Early and Late Onset Colorectal Cancer Study

  This Data Access Committee (DAC) manages access to genomic data generated from the study "A Clinically and Genomically Annotated Early Onset Colorectal Cancer and Late Onset Colorectal Cancer." The study focuses on identifying the distinct genomic profiles of early-onset colorectal cancer (EOCRC) compared to late-onset colorectal cancer (LOCRC) through whole-genome sequencing (WGS) of both tissue and blood samples. The DAC is responsible for reviewing and approving access requests from researchers who wish to utilize this data for non-commercial, academic purposes related to colorectal cancer research. The committee ensures that all data access is granted in compliance with ethical standards and that the data is used solely for the approved research objectives. Researchers requesting access to this data must provide a detailed research proposal, institutional review board (IRB) approval, and demonstrate relevant expertise in genomic research. All data will be stored in secure, encrypted environments, and any further sharing or use of the data requires additional DAC approval.

  Dac EGAC50000000359

• Testicular large B-cell lymphoma is genetically similar to PCNSL and distinct from nodal DLBCL

  Next generation sequencing (NGS) data analyzed in Rivas-Delgado, López, et al. HemaSphere 2024. Single nucleotide variants (SNVs) and short insertions /deletions (indels) were evaluated in 42 samples using a B-cell malignancy-oriented targeted panel covering 115 genes (SureSelectXT, Agilent Technologies and sequenced in a MiSeq instrument (Illumina; 2x150bp; mean coverage of 599x). The NGS data of 39 samples is provided here. The 3 additional samples were previously published. Please, see the original publication for additional details.

  Study EGAS50000000521

• Peking University BIOPIC Data Access Committee (PUBDAC).The DATA ACCESS AGREEMENT is provided at https://github.com/zhangyybio/single-T-cell-data-access. Applicants can request access to the data by directly downloading it or by sending an email to cancerpku@pku.edu.cn. The process that is used to approve an application includes verifying the institution, participants and research purposes of the application. In general this process will take about two weeks. In principal, any academic research institutions complying with the laws and bioethic regulation policies of China will be approved.

  Dac EGAC00001000551

• Whole genome sequencing of Sinonasal hemangiopericytoma and patient derived cell line model

  Solitary fibrous tumor/Hemangiopericytoma (SFT/HPC) is a rare subtype of soft tissue sarcoma associated with NAB2-STAT6 gene fusions. This study established and characterized a novel SFT/HPC patient-derived cell line called SFT-S1 using whole genome sequencing.

  Study EGAS50000000025

• Gut 16S rRNA/FINRISK 2002

  The main goal of the project is the study the associations between the gut 16S rRNA and human health. The dataset contains data for FINRISK 2002 participants (a random sample of individuals living in six geographic areas in Finland) who underwent fecal sampling.

  Study EGAS50000000198

• Brigham and Women's Hospital Multiple Sclerosis Genetic Collection

  The main objective of this GWA study is to identify Multiple Sclerosis (MS) susceptibility loci. Whole-genome association analysis was performed on 924 individuals genotyped on the Affymetrix 6.0 Genechip. The cohort consisted of 860 clinically diagnosed MS patients and 64 control subjects.

  Study phs000275

• The Placenta Harbors a Unique Microbiome

  This study is to investigate placental microbiome through 16S rDNA-based and whole genome shotgun metagenomic sequencing. Identified taxa and their gene carriage patterns were compared to other human body sites niches. The placental microbiome profiles were most akin to the human oral microbiome.

  Study phs000735

• Genetic Basis of Isolated Arhinia and Bosma Arhinia Microphthalmia Syndrome

  The goal of this project is to determine the genetic etiology of congenital arhinia and Bosma arhinia microphthalmia syndrome through a combination of whole-exome, whole-genome, and targeted sequencing followed by in silico, in vitro, and in vivo functional modeling.

  Study phs001246

• NHLBI TOPMed: Pulmonary Fibrosis Whole Genome Sequencing

  This is a set of cases diagnosed with idiopathic pulmonary fibrosis, a fatal interstitial lung disease. These cases were included in the TOPMed phase three studies. The planned study will compare these cases to within-TOPMed controls for genome-wide association studies.

  Study phs001607

• The molecular basis of inherited reproductive disorders

  The purpose of this study is to discover genetic mutations in patients who have GnRH deficient states. This includes individuals with variant forms of hypogonadotropic hypogonadism, including individuals who have somatic anomalies involving mid-line facial defects, renal agenesis, synkinesia, and ataxia, amongst others.

  Study phs000475

• Whole-Genome and Exome Sequencing in clear-cell Renal Cell Carcinoma (ccRCC)

  Study to evaluate the molecular genetics of ccRCC through integrative analyses of tumors and tumorgrafts using multiple platforms in clinically annotated samples. Genome and exome data for patients giving consent to have the information available on a public, secure, database is being submitted.

  Study phs000491

• Etiologic Studies of Macular Degeneration

  This is a genotyping study of selected participants in an ongoing study of macular degeneration and related ocular disorders. DNA samples were obtained from 1985 (study initiation) to 2018. Phenotypes were determined using the validated Clinical Age-Related Maculopathy Grading System (Ophthalmol 2006, PMID 16458093).

  Study phs001896

• Phase 2 Study of Pembrolizumab in Combination with Gemcitabine and Cisplatin as Neoadjuvant Therapy

  The purpose of the clinical trial (NCT02690558) is to evaluate whether adding pembrolizumab (Keytruda) to the combination of gemcitabine and cisplatin will improve shrinkage of the tumor before having a cystectomy, for people with muscle-invasive bladder cancer (MIBC).

  Study phs003452

• E05-Bioenvironmental Psychiatry

  The Bio-Environmental Psychiatry Group is made up of a group of clinical (psychiatry, neuroradiology) and basic (biology) researchers. The objective of our activity is the identification of determinants of mental disorders with the aim of devising interventions that improve the quality of life of patients with mental disorders. Our fields are the prediction of mental disorder, the premorbid and precise diagnosis of mental disorder, the identification of bio-environmental markers and the personalization of treatments. We also work with specific disorders such as Delusional Disorder, OCD, depression and personality disorders.

  Dac EGAC50000000222

• 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.

  Study EGAS50000000529

• Transplant Outcomes in Aplastic Anemia (TOAA): GWAS and Whole Exome Sequence Data

  The TOAA study is a research collaboration between the National Cancer Institute and the Center for International Blood and Marrow Transplant Research. The study aims to identify molecular predictors of outcomes after hematopoietic cell transplant in patients with severe aplastic anemia.

  Study phs001710

• Transrenal DNA Analysis

  Urinary cell-free DNA (ucfDNA) is an emerging marker in liquid biopsy. However, the characteristics of transrenal DNA and urinary-tract DNA are not fully understood. Therefore, we investigated the fragmentomic features and demonstrated the potential clinical utilities of ucfDNA in the current study.

  Study EGAS50000000766

• Comprehensive genomic characterization of early stage bladder cancer - nanopore sequencing

  For this project about non-muscle invasive bladder cancer (NMIBC), we analysed long read sequencing data from 4 patients using the Nanopore platform. The dataset is composed of 8 BAM files: 4 tumor samples and 4 paired blood samples.

  Study EGAS50000000510

• Comprehensive genomic characterization of early stage bladder cancer - shallow whole genome sequencing data

  For this project about non-muscle invasive bladder cancer (NMIBC), we analysed shallow WGS data from 362 patients. The dataset is composed of 392 BAM files: 362 tumor samples, 15 female normal samples and 15 male normal samples.

  Study EGAS50000000513

• A Novel APP p.V742L variant in a patient with ischemic small vessel disease enhances FE65 signalling

  We identified a novel variant in the APP gene associated with cerebral ischemic strokes, which is not seen before with APP variants. This results in increased affinity of APP for FE65, APP’s most important intracellular interactor that regulates gene transcription.

  Study EGAS50000001283

• ICARUS-BREAST01-ExomeSeq

  Efficacy, safety and biomarker analysis of ICARUS-BREAST01: a phase 2 Study of Patritumab Deruxtecan in patients with HR+/HER2- advanced breast cancer. Whole-exome sequencing (WES) is available for 43 tumor samples and 43 blood samples collected at entry into the trial.

  Study EGAS50000000542

• Biobank Japan genotype and phenotype data

  The Biobank Japan (BBJ) Project started at the Institute of Medical Science, the University of Tokyo in 2003. To date, the BBJ Project has collected around 200,000 individuals with disease cases consisting of 47 diseases. The purpose of the BBJ is to realize personalized medicine.

  Study JGAS000114

• Transcriptome sequencing, DNA methylation analysis, and SNP array analysis of acute lymphoblastic leukemia in Down syndrome

  Pathogenesis of acute lymphoblastic leukemia in Down syndrome (DS-ALL) is poorly understood. To investigate molecular basis of DS-ALL, we performed whole transcriptome sequencing, DNA methylation array, and SNP array analysis in 43 cases of DS-ALL.

  Study JGAS000147

• Development of actionable molecular targets and/or biomarkers for prognostication and patient stratification in gynecological cancer based on whole-exome sequencing and epigenomic analysis

  We collected 187 samples of normal and primary tumor tissues in 69 cases of endometrial carcinoma. The purpose of this study is to develop actionable molecular targets and/or biomarkers for prognostication and patient stratification.

  Study JGAS000174

• Phase II clinical trial of adult Philadelphia chromosome-negative precursor B-cell acute lymphocytic leukemia with combination chemotherapy

  Adults with B-ALL showed extremely inferior outcomes when compared to children. Genetic basis undelying adult B-ALL is largely unknown. We performed integrated analysis of RNA-seq and target DNA-seq for the patients enrolled in BALL213 study.

  Study JGAS000278

• Multi-omics analysis of pediatric high-risk neuroblastoma

  Neuroblastoma is the most common extracranial solid malignancy among children originating from undifferentiated neural crest cells. Despite recent intensified treatment, high-risk patients still show a high mortality rate. To explore a new therapeutic strategy, we performed integrated analysis in 30 neuroblastoma cases.

  Study JGAS000246

• DAC for STimage project

  The STimage Data Access Committee (DAC) oversees the access and distribution of datasets associated with the STimage project. This project focuses on the development and benchmarking of deep learning frameworks for spatial transcriptomics and digital pathology. The datasets managed by this DAC typically comprise paired histology images (H&E) and spatial gene expression data (e.g., 10x Genomics Visium) derived from human tissue samples. Our primary objective is to facilitate bona fide biomedical research while strictly protecting participant privacy and ensuring data is used in accordance with the original consent and ethical approvals.

  Dac EGAC50000000867

• Long read whole genome sequencing data from brain postmortem tissue

  Dataset consisting of 172 whole genome sequencing runs from healthy controls and Parkinson's disease patients. The data was sequenced on Oxford Nanopore (PromethION) platform. The data has been mapped to T2T-CHM13v2.0 reference genome. The data processing pipeline is available on the following link: [https://zenodo.org/records/13385065](https://zenodo.org/records/13385065). The data is in CRAM format and subet of donors also have information on C (hydroxy)methylation (MM and ML tag). The reads are also phased (HP tag).

  Dataset EGAD50000001349

• Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH

  Initially IDH1 mutant gliomas are shown to have IDH1 is deletions or amplifications at recurrence yielding a higher-grade tumor with a reprogrammed epigenome. We also report systematic selection for cells with IDH1 CNA in vitro and in vivo.

  Study EGAS00001002618

• 54 metastatic colorectal cancer patients from Schleswig-Holstein in North Germany

  Personalized treatment vs standard of care is much debated, especially in clinical practice. Here we investigated whether overall survival differences in metastatic colorectal cancer patients are explained by their tumor mutation profiles or by their treatment differences in real clinical practice.

  Study EGAS00001004108

• Yemen_and_Chad_Genotyping

  HumanOmni2.5-8 data from Chad and Yemen.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001001231

• Pediatric HGG WES and RNA-Seq

  Paediatric high-grade glioma (pHGG) is the leading cause of paediatric brain tumour death. Here we performed RNA and whole exome sequencing on pHGG samples to analyse transcriptomic and genetic alterations associated with this devastating disease, and to understand the relationship between them.

  Study EGAS00001005687

• 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 Ewings’ sarcoma tumours.

  Study EGAS00001000362

• 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 Ewings’ sarcoma tumours.

  Study EGAS00001000267

• Somatic_Variation_Angiosarcoma

  Through whole genome sequencing, this study will explore the mutational profiles and signatures within an angiosarcoma tumour from a patient with xeroderma pimentosum. Very little information is known about this tumour type and it has not previously been studied within the context of xerogerma pigmentosum.

  Study EGAS00001002610

• 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 Ewings’ sarcoma tumours.

  Study EGAS00001000266

• Mexican Biobank Project

  In this study, we present the data from the Mexican Biobank Project: 50 WGS from individuals with Native American ancestry, and 6000 genotypes from samples from this project. This project highlights the necessity of better diversity representation in genomic databases is a scientific imperative.

  Study EGAS00001005797

• RNA sequencing of multiple myeloma identifies genes dysregulated by structural variants.

  Multiple myeloma is a disease of structural changes brought about by copy number abnormalities and translocations. Many of these changes result in super-enhancers being placed next to key oncogenes. Here, we have investigated which genes are commonly dysregulated by these changes.

  Study EGAS00001003411

• PROJET DREPANOCYTOSE ET PALUDISME

  The goal is to study and specify the response to treatment against Plasmodium falciparum malaria in subjects with sickle cell disease in order to propose to the National Malaria Control Program of Côte d'Ivoire effective prevention and treatment strategies for this population at risk.

  Study EGAS00001006008

• Synthetic genotypes and phenotypes of 500.000 individuals

  The goal of our study is to establish a pipeline for creating synthetic genotype and phenotype data on a Biobank scale. Such data can be used for developing new methodologies of analysis of common and rare diseases without risking de-identifying the underlying samples.

  Study EGAS00001006552

• Whole-Transcriptomic Profiling of Sorted Human Renal Cell Carcinoma Immune Populations

  It is poorly understood how the tumor immune micro-environment influences disease progression in renal cell carcinoma (RCC). Here we performed whole-transcriptomic profiling of immune cell populations which were derived from RCC patients representing distinct flow-sorted immune lineages.

  Study EGAS00001006593

• WES on tumor DNA and germline DNA in pediatric cancer

  This dataset contains whole exome sequencing (WES) data from tumor DNA samples of various pediatric cancer entities. Files are provided in fastq format. Samples were sequenced on a Novaseq6000 or Hiseq2500 (Illumina). Data analysis is available at https://github.com/rmvpaeme/sWGS_pediatric_cancer.

  Study EGAS00001005429

• Activating AKT1 and PIK3CA mutations in metastatic castration-resistant prostate cancer

  This dataset contains all available targeted exon sequencing bam files from our study, "Activating AKT1 and PIK3CA mutations in metastatic castration-resistant prostate cancer". Patient identifiers are denoted by the first segment of the sample aliases (e.g. "P1"), and additional information is appended to reflect which serial sample is referenced (1st, 2nd, 3rd, etc.), and whether the sample represents cell-free DNA ("cfdna") or paired white-blood cell control ("WBC"). All samples were sequenced using Illumina technology.

  Dataset EGAD00001006122

• De novo mutations in cell-free foetal DNA (cffDNA)

  This project is to develop and validate a method to detect de novo mutations in a foetal genome through deep sequencing of cell-free DNA from the plasma of pregnant women. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001000596

• Haukeland University Hospital Data Access Committee for ParkOme-1 datasets archvied in Federated EGA Norway

  Data Access Committee appointed by Haukeland University Hospital for omics datasets for Parkinson's disease and related disorders, generated in studies under the ParkOme-1 project. Omics datasets of different types are generated from fresh frozen brain tissue from individuals with neurodegenerative parkinsonisms and neurologically healthy controls.

  Dac EGAC50000000193

• single cell data from HPV-positive head and neck cancer patients receiving induction CTLA-4 and PD-1 immune checkpoint blockade

  Baseline and on-treatment tumor samples from human papillomavirus-positive oropharynx cancer patients receiving anti-CTLA-4 and anti-PD-1 immune checkpoint blockade were analyzed by single-cell RNA and TCR sequencing.

  Dataset EGAD50000000487

• Single Cell Genome Sequence for DLP+ library A118784A

  Single Cell Genome Sequence for high grade serous ovarian carcinoma patient-derived xenograft SA1050B passage 1, patient-derived xenograft SA1050E passage 1 on DLP+ library A118784A

  Dataset EGAD00001009436

• Single Cell Genome Sequence for DLP+ library A118804A

  Single Cell Genome Sequence for high grade serous ovarian carcinoma patient-derived xenograft SA1162B passage 1, patient-derived xenograft SA1096B passage 1 on DLP+ library A118804A

  Dataset EGAD00001009439

• RNAseq files (dataset 1 of 2) for Mullighan PAX5_B-ALL

  RNAseq files (dataset 1 of 2) for Mullighan PAX5_B-ALL paper titled "PAX5-driven Subtypes of B-cell Acute Lymphoblastic Leukemia"

  Dataset EGAD00001004461

• Clinical and Molecular Features of Acquired Resistance to Immunotherapy in Non-Small Cell Lung Cancer

  PD-(L)1 blockade has been shown to promote durable responses in non-small cell lung cancer (NSCLC) patients and has been rapidly incorporated into the treatment regimens for many with advanced disease. Despite this, mechanisms of acquired resistance (AR) to PD-(L)1 have not been well understood. To address the clinical and molecular landscape of AR to PD-(L)1 blockade in NSCLC patients, a large clinical cohort of AR to PD-(L)1 blockade in lung cancer was examined. In conjunction, a systematic genomic and transcriptomic analysis in a subset of patients (n = 29) with available tissue samples was conducted. To investigate the molecular mechanisms of AR to PD-1 blockade from pre- and/or post-treatment tumors, microarray-based whole transcriptome expression data for 29 tumor samples, and whole exome sequencing (WES) data from 34 tumor samples was generated from this subset. Microarray data was uploaded to the Gene Expression Omnibus (GEO) database. Most AR tumors showed retained or increased inflammatory characteristics with significant upregulation of IFNγ which was suggestive of persistent albeit insufficient anti-tumor immune response. This finding expounds upon the prior pre-clinical and translational data supporting the intricate role of IFNγ in sensitivity and resistance to immunotherapy. Whereas initial IFNγ exposure may be fundamental to T cell activation (a hallmark of immune response), persistent IFNγ related effects and upregulation may potentially signal immune dysfunction and IFNγ insensitivity in contrast. The inflammatory phenotypes identified have implications for future rational development of new immunotherapy strategies for patients with AR.

  Study phs002834

• TIGIT is the central player in T-cell suppression associated with CAR T-cell relapse in mantle cell lymphoma

  Study EGAS00001007113

• Elevated cfDNA after exercise is derived primarily from mature polymorphonuclear neutrophils, with a minor contribution of cardiomyocytes

  Study EGAS00001007157

• DAC of the BriTROC-1 project

  Dac EGAC00001003291

• ADPKD Data Access Commitee 1

  Dac EGAC00001002838

• FFA_dataset

  Case_control_meta_analysis

  Dataset EGAD00010001683

• Single-cell RNA sequencing of blood immune cells before and after interleukin-2 immunotherapy

  Single-cell RNA sequencing of flow cytometry sorted human CD45+ immune cells from 3 systemic lupus erythematosus patients (SLE_002, SLE_004, and SLE_006) collected at baseline (day 0, before interleukin-2 immunotherpay) and day 5 (after 1 treatment cycle of interleukin-2 immunotherapy). Sorted immune cells were hash tagged and then stained with TotalSeq Human Universal Cocktail (Biolegend) before further processing for single-cell RNA sequencing using the 10X-Genomics platform. Samples from all 3 patients were pooled and loaded on 3 lanes of the chromium controller, resulting in 1 raw sequncing file for each lane.

  Dataset EGAD50000000662

• (ChIP-seq) Shifted assembly and function of mSWI/SNF family subcomplexes underlie targetable dependencies in endometriod carcinomas

  ChIP-seq data of 18 samples from the VOA1066 undifferentiated endometrial carcinoma cell-line with various pulldowns: BRG1 (abcam, ab110642, GR3255117-11), BRD9 (CST, E4Q3F, Lot 1), ARID1A (CST, D2A8U, Lot 4), SS18 (CST, D6I4Z, Lot 1), PBRM1 (CST, D3F70, Lot 3), GLTSCR1 (CST, E6I3A, Lot 1), H3K27ac (CST, C36B11, Lot 16), or none. Sample were either untreated or received doxycycline-induced ARID1A treatment. Samples were sequenced on Illumina NextSeq 500 using 37 bp single-end sequencing parameters. Raw fastq files, along with processed bigwig files containing normalized genomic coverage, and called narrow peaks, are included for each sample.

  Dataset EGAD50000001473

• RNA004 DRS METTL5 variant of patient sample

  This dataset contains RNA004 DRS data for a single patient sample with heterozygous inactivating SNPs for the methyltransferase METTL5. We provide 1) all reads in a GRCh38 aligned bam file + unaligned reads and 2) filtered reads just for the relevant part of chrR. Both bam files have been called with dorado 0.7.2 to contain the neccessary m6A methylation information. Companion datasets are 1) EGAS50000001201 for DRS of a healthy control with intact METTL5 and 2) PRJEB74238 for IVT 18S rRNA vector data as unmodified control. Please note, that both the companion datasets contain pod5 data, to faciliate re-basecalling.

  Dataset EGAD50000001882

• H3Africa AWI-GEN Phase 1 Phenotype

  The phenotypic data for ~12500 samples of the AWI-Gen Phase 1 Population cross-sectional study of older adults (mostly between 40 and 60 years), men and women. Six study sites in four sub-Saharan African counties including Ghana, Burkina Faso, Kenya and South Africa. Some groups are missing data for specific variables. Data includes questionnaire data (demography, health history, family health history, behaviour and infection data); anthropometry; and laboratory assays on blood and urine.

  Dataset EGAD00001006425

• Mucociliary Clearance Consortium (MCC) Longitudinal Study of Primary Ciliary Dyskinesia: Participants 5-18 Years of Age

  The purpose of this longitudinal study protocol is to define age-related prevalence of phenotypic characteristics and the progression of key features of lung disease in participants with one of these disorders, Primary Ciliary Dyskinesia (PCD). In PCD, the abnormal structure and function of cilia results in impaired clearance of secretions and consequent obstruction and chronic recurrent infection in the airways, sinuses and middle ears. Although it seems likely that the onset of PCD airway disease occurs early in childhood, as has been reported for cystic fibrosis (CF), the clinical course of PCD lung disease is not well defined, nor, is the time course of emergence of specific microbial pathogens, or the age of onset and rate of progression of airway disease and bronchiectasis. This longitudinal study is designed to define the rate of progression of PCD lung function in participants between 5-18 years of age using spirometry which tracks well with lung impairment and prognosis in other disorders of the airways such as cystic fibrosis. This longitudinal protocol will also systematically track other specific outcomes, including pathogens infecting the airways (assessed by respiratory cultures), and age at onset and progression of airway damage and bronchiectasis (assessed by high-resolution computerized tomography, HRCT, of the chest). Blood will be collected for DNA to test for genetic mutations. The blood samples will be processed to establish a cell line (lymphocyte transformation) for a source of DNA for future genetic studies, in participants with disease. For participants unable to provide a blood sample, a buccal sample will be obtained for DNA.

  Study phs000596

• National Cancer Institute Clinical and Laboratory Analysis of Familial Cancer

  The purpose of this study is to continue the analysis begun on 09C0079 which was focused on identification of the genetic mutation associated with a new gastric polyposis syndrome, Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS). GAPPS, first described in 2012, is an autosomal dominant gastric polyposis syndrome that confers a substantial risk for gastric adenocarcinoma. The GAPPS phenotype consists of a carpeting of greater than 100 fundic gland polyps (FGPs) in the oxyntic mucosa of the gastric body and fundus, with antral sparing with some FGPs displaying high-grade dysplasia. This is in contrast to sporadic FGPs that are benign, most often are not associated with high-grade dysplasia though low-grade dysplasia has been reported, and are fewer in number. Gastric FGPs have been found to be associated with Familial Adenomatous Polyposis (FAP) and attenuated FAP, which is an autosomal dominant condition associated with germ line mutations in APC which confers a phenotype consisting of multiple (>100) adenomatous polyps in the colon and rectum developing after the first decade of life. FGPs are reported to occur in 12-84% of patients with FAP, whereas sporadic FGPs are identified in ~5% of patients undergoing upper gastrointestinal endoscopy. Gastric adenocarcinoma arising from FGPs in individuals with FAP have been reported. Other manifestations of FAP and AFAP include polyps in the upper gastrointestinal tract, congenital hypertrophy of retinal pigment epithelium, osteomas and epidermoid cysts, supernumerary teeth, desmoid formation, and other malignancies such as thyroid, small bowel cancer, hepatoblastoma, and medulloblastoma. Thus far there are no reports in GAPPS of polyposis arising in the esophagus, gastric antrum, pylorus, small intestine, or colon.

  Study phs001935

• Warfarin Pharmacogenetics: Pharmacogenetic Optimization of Anticoagulant Response (POAT) and Genetic and Environmental Determinants of Warfarin Response (GEDWR)

  Although the efficacy of warfarin in the treatment and prevention of thromboembolic disorders is proven, it is vastly underutilized with difficulties in management and risk of complications being the main deterrents. Recognition of genetic regulation of warfarin response has fueled efforts to quantify this influence, but the focus has been restricted to select genes and outcomes mainly in European Americans. Race appears to influence warfarin dose requirements with African Americans requiring larger and Asians requiring lower doses compared to Europeans. This variation in dose requirement by race may at least partially be explained by genetic differences. The Genetic and Environmental Determinants of Warfarin Response (GEDWR) and the Pharmacogenetic Optimization of Anticoagulation Therapy (POAT) are prospective cohort study aimed at defining the influence of CYP2C9, VKORC1 and other genes. All patients were followed at monthly intervals from initiation of therapy. At each visit factors influencing warfarin response such as warfarin dose, INR, concurrent medications, etc. were documented. Information on concurrent medications was updated at every clinic visit by self-report and verified by medical record review. Concomitant use of drugs such as drugs that alter warfarin pharmacokinetics, including CYP2C9 inhibitors (e.g., amiodarone), and pharmacodynamics such as antiplatelet agents (e.g. aspirin). Although the a priori hypothesis focused on the candidate-gene approach, with the recognition that the candidate-gene approach is bound by the assumption that our knowledge of genetic influences on warfarin response is complete. Among African Americans known variation in candidate genes (CYP2C9 and VKORC1) explain substantially less variability in warfarin dose requirements. Therefore a genome-wide association study (GWAS) was conducted on African American patients to identify novel variants associated with warfarin dose requirements.

  Study phs000708

• Lung Cancer Genetic Study Among Asian Never Smokers

  The Lung Cancer Genetic Study Among Asian Never Smokers includes data from four population-based studies conducted among Asian women: the Shanghai Women's Health Study (SWHS), the Hwasun Cancer Epidemiology Study (HCES1 and HCES2), the Female Lung Cancer Consortium in Asia (FLCCA, including sFLCA), and the Guangzhou Lung Cancer Study (GLCS). Shanghai Women's Health Study (SWHS): The SWHS is a population-based prospective cohort study of approximately 75,000 adult women who were recruited between 1997 and 2000. The cohort has been followed by a combination of record linkage and active follow-ups. Lung cancer patients identified in the SWHS and non-cases were included in the current study.Hwasun Cancer Epidemiology Study-Lung Cancer (HCES1 and HCES2): The HCES is a hospital-based case-control study whose goal is to identify factors of the cancer development and clinical progression in a Korean population. Included in this project were 299 female lung cancer cases from HCES2, who were diagnosed between April 2004 and February 2013 at Chonnam National University Hwasun Hospital, a cancer specified hospital in Jeollanam-do province, South Korea. Controls were randomly selected from women with no previous cancer diagnosis at enrollment in the Namwon Study and the Dong-gu study, ongoing community-based cohort studies in South Korea. A total of 1,103 controls (273 from HCES1 and 830 from HCES2) were genotyped by MEGA. Guangzhou Lung Cancer Study (GLCS): The GLCS is a case-control study including never-smoking women lung cancer cases and controls from Guangzhou, China.In this study, the DNA samples of 1,195 subjects from SWHS and GLCS were genotyped using whole exome sequencing (WES), and the DNA samples of 7,174 subjects from SWHS, HCES1, HCES2, FLCCA, and sFLCA were genotyped using the Multi-Ethnic Global Array (MEGA).

  Study phs002366

• Molecular subtypes of pancreatic neuroendocrine tumors mutated in MEN1/DAXX/ ATRX explain biological variability

  Pancreatic Neuroendocrine Tumors (PanNETs) most probably arise from the islets of Langerhans, although direct evidence is still lacking. About 40% of non-functioning (NF) PanNETs harbour mutations in MEN1, often in conjunction with alterations in DAXX/ATRX. Despite the homogeneous genetic background, the ADM (mutation in DAXX/ATRX and MEN1) group is heterogeneous regarding molecular features and response to treatment. To explore the molecular and clinical heterogeneity within this group, we integrated transcriptomic and DNA methylation data from 36 and 93 samples, respectively. Using a multi-omic approach we described a two-level hierarchy separating PanNET subtypes mutated in MEN1, DAXX and ATRX. First, DNA methylation discriminates ADM-PanNET from PanNET mutated in MEN1 only (α-like). Compared to α-like, all ADM tumors exhibit DNA methylation changes at enhancer and lowly methylated regions as well as at peri-centromeric and telomeric regions, associated with alternative lengthening of telomeres, increased chromosomal instability, and enhanced proliferative capacity. At a second level, transcriptomic analysis revealed three distinct ADM subtypes: ADM hypoxic, ADM NST (No Special Type), and ADM immunosuppressive. The ADM hypoxic subtype is characterized by strong hypoxia signature, likely regulated epigenetically. The ADM NST subtype appears to be primarily driven by epigenetic changes that promote proliferation. The ADM immunosuppressive is highly enriched in immune component and strong metastasis-like signature. While all the three subtypes are highly associated with liver metastasis formation and invasion, the ADM immunosuppressive are significantly smaller (<2.5 cm p.value=0.023) despite displaying aggressive molecular features. By defining these three novel ADM subtypes, our study provides a refined framework for understanding PanNET heterogeneity. This classification underscores potential diagnostic markers and highlights distinct biological vulnerabilities that may inform the development of subtype-tailored therapeutic strategies.

  Study EGAS00001008272

• Tracking the evolution of Therapy-Related Myeloid Neoplasms using chemotherapy signatures

  Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Pre-leukemic clones (i.e., clonal hematopoiesis; CH) are detectable years before the development of these aggressive malignancies, though the genomic events leading to transformation and expansion are not well-defined. Here, leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of pre-chemotherapy samples, we reconstruct the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy is revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan are hypermutated and enriched for complex structural variants (i.e., chromothripsis) while neoplasms with non-mutagenic chemotherapy exposures are genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to a discrete clinical exposure in each patient’s life, we estimate that several complex events and genomic drivers are acquired after chemotherapy is administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes chemotherapy exposure and is selected following reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA-damage. Overall, we reveal a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select pre-existing CH, but also promote the acquisition of recurrent genomic drivers.

  Study EGAS00001006903

• Tracing the origin of disseminated tumor cells in breast cancer using single-cell sequencing

  Background Single-cell micro-metastases of solid tumors often occur in the bone marrow. These disseminated tumor cells (DTCs) may resist therapy and lay dormant or progress to cause overt bone and visceral metastases. The molecular nature of DTCs remains elusive, as well as when and from where in the tumor they originate. Here, we apply single-cell sequencing to identify and trace the origin of DTCs in breast cancer. Results We sequence the genomes of 63 single cells isolated from six non-metastatic breast cancer patients. By comparing the cells DNA copy number aberration (CNA) landscapes with those of the primary tumors and lymph node metastasis, we establish that 53% of the single cells morphologically classified as tumor cells are DTCs disseminating from the observed tumor. The remaining cells represent either non-aberrant ‘normal’ cells or aberrant cells of unknown origin that have CNA landscapes discordant from the tumor. Further analyses suggest that the prevalence of aberrant cells of unknown origin is age-dependent, and that at least a subset is hematopoietic in origin. Evolutionary reconstruction analysis of bulk tumor and DTC genomes enables ordering of CNA events in molecular pseudo-time and traced the origin of the DTCs to either the main tumor clone, primary tumor subclones, or subclones in an axillary lymph node metastasis. Conclusions Single-cell sequencing of bone marrow epithelial-like cells, in parallel with intra-tumor genetic heterogeneity profiling from bulk DNA, is a powerful approach to identify and study DTCs, yielding insight into metastatic processes. A heterogeneous population of CNA-positive cells is present in the bone marrow of non-metastatic breast cancer patients, only part of which are derived from the observed tumor lineages.

  Study EGAS00001002102

• Transcriptional_profiling_of_tauopathies_in_human_IPS_derived_neurons

  This project is a pilot study, in collaboration with Maria Grazia Spillantini and Mariangela Iovino (Cambridge Centre for Brain Repair), to investigate the utility of IPS-derived neurons for the study of neurodegenerative disorders. Our aim is to characterise the transcriptional consequences of tauopathies using neurons derived from differentiated IPSCs as a model system. We will use IPS cells derived from six individuals, four with known mutations in the tau protein, 2 without. RNA will be extracted at Day 0 and Day 65 of differentiation by which time the neuronal tauopathy is apparent. RNA will be extracted and the transcriptome of each line characterised using RNAseq. We will then search for genes that are differentially expressed between the transcriptomes of individuals with tau mutations versus those in controls. My lab will analyse the RNAseq data, comparing both affected and controls and both time-points, to establish candidate genes. Darren Logan’s lab, along with our collaborators, will experimentally verify and further investigate these genes in additional lines and animal models. From this analysis we will generate a list of candidate genes that are differentially expressed between cases and controls. This study will not only help us understand the molecular basis of tauopathies, but also identify gene candidates for biomarkers of neurodegenerative disease. It will serve as a proof of principle for future planned studies into generating and transcriptomically analysing an allelic series of Tau mutations in IPSCs with a controlled genetic background.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001000382

• Altered oligodendrocyte heterogeneity in Multiple sclerosis revealed by single nuclei RNA sequencing

  This study is currently hosted by the European Nucleotide Archive. To access the data contained within the Study please follow the link below: https://www.ebi.ac.uk/ena/browser/view/PRJEB39323 Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases, as they are involved in metabolic support of axons and functional cross-talk with other brain cells. Rodent OLs are heterogeneous, with developmental and biological differences, but the extent of heterogeneity in the normal human brain and its contribution to any changes to disease remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and multiple sclerosis (MS) patients. We identified several sub-clusters of oligodendroglia in the Ctr human WM, some similar to those in mouse, and defined new markers for these cell states. Strikingly, some of these sub-clusters were under-represented in MS tissue, while others were more prevalent than in controls. We found a lack of OL precursor cells (OPCs) and an OL subcluster in an intermediate stage of differentiation in MS lesions and in normal appearing white matter (NAWM), suggesting either depletion by the disease or by a regenerative response. The differences in mature OL sub-clusters indicate different functional states of OLs in MS tissue and, as this is similar in NAWM to lesions, that MS is a more diffuse brain disease than the focal demyelinating lesions suggest. We were also able to identify new putative markers of different MS lesion subtypes. Our findings of an altered heterogeneity of oligodendroglia in MS may have an important contribution to our understanding of disease progression and may alter therapeutic approaches to MS.

  Study EGAS00001003412

• Comprehensive characterization of pre- and post-treatment samples of breast cancer reveal potential mechanisms of chemotherapy resistance

  When locally advanced breast cancer is treated with neoadjuvant chemotherapy, the recurrence risk is significantly higher if no complete pathologic response is achieved. Identification of the underlying resistance mechanisms is essential to select treatments with maximal efficacy and minimal toxicity. Here we employed gene expression profiles derived from 317 HER2-negative treatment-naïve breast cancer biopsies of patients who underwent neoadjuvant chemotherapy, deep whole exome and RNA-sequencing profiles of 22 matched pre- and post-treatment tumors, and treatment outcome data to identify biomarkers of response and resistance mechanisms. Molecular profiling of treatment-naïve breast cancer samples revealed that expression levels of proliferation, immune response and extracellular matrix (ECM) organization combined predict response to chemotherapy. Triple negative patients with high proliferation, high immune response and low ECM expression had a significantly better treatment response and survival benefit (HR 0.29, 95% CI 0.10-0.85; p=0.02), while in ER+ patients the opposite was seen (HR 4.73, 95% CI 1.51-14.8; 0=0.008). The characterization of paired pre-and post-treatment samples revealed that aberrations of known cancer genes were either only present in the pre-treatment sample (CDKN1B) or in the post-treatment sample(TP53, APC, CTNNB1). Proliferation-associated genes were frequently down-regulated in post-treatment ER+ tumors, but not in triple negative tumors. Genes involved in ECM were upregulated in the majority of post-chemotherapy samples. Genomic and transcriptomic differences between pre- and post-chemotherapy samples are common and may reveal potential mechanisms of therapy resistance. Our results show a wide range of distinct, but related mechanisms, with a prominent role for proliferation- and ECM-related genes.

  Study EGAS00001005876

• Genetic immune escape landscape in primary and metastatic cancer

  Immune surveillance escape is a hallmark of tumorigenesis1. Multiple studies have characterized the immune escape landscape across several untreated early-stage primary cancer types2–4. However, whether late-stage treated metastatic tumors present differences in genetic immune escape (GIE) prevalence and dynamics remains unclear. Here, we performed a pan-cancer characterization of GIE prevalence across six immune escape pathways in 6,457 uniformly processed Whole Genome Sequencing (WGS) tumor samples including 58 cancer types from 1,943 primary untreated patients and 4,514 metastatic patients. To effectively address the complexity of the Human Leukocyte Antigen (HLA-I) locus and to characterize its tumor status, we developed LILAC, an open-source integrative framework. We demonstrate that one in four tumors harbor GIE alterations, with high mechanistic and frequency variability across cancer types. GIE prevalence is highly consistent between primary and metastatic tumors for most cancer types with few exceptions such as prostate and thyroid carcinomas that have increased immune evasion frequencies in metastatic tumors. Positive selection analysis revealed that GIE alterations are frequently selected for in tumor evolution and that focal LOH of HLA-I, unlike non-focal LOH of HLA-I, tends to lose the HLA allele that presents the largest neoepitope repertoire. We also unraveled tumor genomic features contributing to immune escape incidence, including DNA repair deficiency, APOBEC activity, tobacco associated mutation load and viral DNA integration. Finally, there is a strong tendency for mid and high tumor mutation burden (TMB) tumors to preferentially select LOH of HLA-I for GIE whereas hypermutated samples favor global immune evasion strategies. Our results indicate that genetic immune escape is generally a pre-metastatic event during tumor evolution and that tumors adapt different strategies depending on their neoepitope burden.

  Study EGAS00001006123

• Dynamics of circulating tumor DNA in acute myeloid leukemia (AML) patients who undergo allogeneic transplantation

  Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative option for many patients with acute myeloid leukemia (AML). With the increasing use of non-myeloablative conditioning regimens, it is widely assumed that the cytotoxic conditioning itself does not eradicate all leukemia cells. Instead, the donor-derived immune cells are believed to eliminate residual leukemia cells over time. This so-called graft-versus-leukemia (GvL) is postulated to be the primary mechanism by which allo-HCT achieves sustained remissions in patients with AML. However, the precise quantification of GvL effects and its contribution to leukemia eradication has not yet been demonstrated by sequential, highly sensitive measurements of residual disease at various time points following allo-HCT. In the current study, we employed a novel, highly sensitive and specific plasma-based assay to track mutations in the leukemia cells of 14 patients before and after allo-HCT. If the primary therapeutic benefit of allo-HCT is truly mediated through a GvL effect, we hypothesized that leukemia cells would persist following cytotoxic conditioning and would often be reduced after post-transplant immunosuppression was discontinued. In the majority of patients (11 of 14, 79%), the conditioning used for allo-HCT did not eradicate the leukemia cells. In seven of these 11 patients, the leukemia cells persisted until immunosuppression was discontinued, at which time the persistent leukemia cells were reduced or eradicated. These results demonstrate the feasibility of using circulating tumor DNA (ctDNA) as a dynamic marker of GvL as well as minimal residual disease for patients with AML undergoing alloHCT, and have substantial implications for their management.

  Study EGAS00001007969

• Multi-omic analysis of Down Syndrome in thyroid

  Background: Down syndrome (DS) is a chromosomal disorder characterized by trisomy of chromosome 21 and is associated with various health problems. Congenital thyroid dysfunction is a common endocrine abnormality in DS, but its exact cause remains unknown. This work aimed at studying the etiology of congenital thyroid dysfunction in DS. Methods: Thyroid tissue of fetuses with DS (n=4) and fetuses without a genetic/developmental abnormality (n=5) were analyzed using histopathological evaluation, RNA sequencing (RNA-seq), and DNA methylation (DNAm) profiling. Results: Histological examination showed abnormally developed DS thyroid tissue compared to non-DS/healthy tissue. RNA-seq analysis showed numerous differences in gene expression between DS and healthy thyroid tissue, including significant downregulation of thyroid genes FOXE1, IYD and DIO2. Gene set enrichment analysis showed disruption of vital cellular processes and functions in DS fetal thyroid tissue. Analysis of DNAm and expression quantitative trait methylation (eQTM) analysis identified functional and biologically relevant associations, that can be linked to plausible disrupted pathways in DS. Conclusions: Based on these observations, we conclude that congenital non-autoimmune thyroid dysfunction in DS is probably a DS-specific form of thyroid dysfunction, characterized by abnormal thyroid development, altered expression of genes that regulate thyroid development and hormone production, and altered expression and DNAm of genes pertaining to numerous vital pathways leading to significant metabolic disturbances. The disturbances as investigated by multi-omics analyses (RNA-seq, DNAm and eQTM analyses) are widely spread over the genome, and presumably caused by the direct and downstream effects of overexpressed chromosome 21 genes (dosage effect), and (epi)genomic disturbances.

  Study EGAS00001007677

• The Genetic Architecture of Smoking and Smoking Cessation

  This study includes samples from two projects: Collaborative Genetic Study of Nicotine Dependence (COGEND; PI: Laura Bierut) and University of Wisconsin Transdisciplinary Tobacco Use Research Center (UW-TTURC; PI: Timothy Baker). Data are available for an additional 1420 COGEND subjects through the Study of Addiction: Genetics and Environment (SAGE), dbGaP study accession phs000092. The majority of these subjects are independent from the current study, but there is a small amount of overlap between the two samples (n=29 subjects) for quality control purposes. It should be noted that the case definition in the SAGE study is DSM-IV alcohol dependence. The case definition in the current study is nicotine dependence by a current score of 4 or greater on the Fagerström Test for Nicotine Dependence (FTND). The overall goal of this project is to identify and characterize genetic variants that contribute to the development of nicotine dependence, related smoking behaviors, and smoking cessation. The COGEND sample includes unrelated cases and controls for a genetic association study of nicotine dependence. Cases are defined by a commonly used definition of nicotine dependence, a current score of 4 or more (maximum score of 10) on the Fagerström Test for Nicotine Dependence (FTND). Control status is defined as an individual who smoked at least 100 cigarettes during their lifetime, yet never became dependent (lifetime FTND=0). By selecting controls who smoked, those genetic effects that are specific to nicotine dependence can be examined. The UW-TTURC sample includes nicotine dependent smokers from three smoking cessation studies. Subjects had to smoke at least 10 cigarettes per day (confirmed smoking by an alveolar carbon monoxide (CO) level greater than 9) and report being motivated to quit smoking. Participants were excluded based on evidence of psychosis history, clinically significant depression symptoms, other severe mental illness, or contraindications to smoking cessation medications. COGEND: COGEND was initiated in 2001 as a three-part program project grant funded through the National Cancer Institute (NCI; PI: Laura Bierut). The three projects included a study of the familial transmission of nicotine dependence, a genetic study of nicotine dependence, and a study of the relationship of nicotine dependence with nicotine metabolism. The primary goal is to detect, localize, and characterize genes that predispose or protect an individual with respect to heavy tobacco consumption, nicotine dependence, and related phenotypes and to integrate these findings with the family transmission and nicotine metabolism findings. The primary design is a community based case-control family study. Nicotine dependent cases and non-dependent, smoking controls were identified and recruited from Detroit and St. Louis. In addition, one sibling for each case and control subject was recruited in a subset of the sample. More than 54,000 subjects aged 25-44 years were screened by telephone; more than 3,100 subjects were personally interviewed; and more than 2,900 subjects donated blood samples for genetic studies. UW-TTURC: The UW-TTURC was initiated in 2001 as a study of nicotine dependence and smoking cessation treatment. The second round of UW-TTURC was initiated in 2005 as a study of efficacy of smoking cessation and long term outcomes. Nicotine dependent smokers seeking cessation treatment were identified and recruited from Madison and Milwaukee, WI. Over 9,000 adult smokers were screened by telephone; 2,575 individuals were enrolled and randomized to treatment conditions that involved use of different smoking cessation medications. Participants from the UW-TTURC smoking cessation clinical trials had the option of participating in a genetic substudy, and approximately 2,000 donated blood samples for genetic studies. The goal of the genetic studies of smokers seeking cessation treatment is to detect, localize, and characterize genes that predispose or protect an individual with respect to heavy tobacco consumption, nicotine dependence, and related phenotypes including cessation, withdrawal, and relapse. Both studies (COGEND and UW-TTURC) include measures of basic socio-demographic variables, including age, sex, race/ethnicity, family income, and educational attainment. Information on nicotine dependence, as assessed by the Fagerström Test for Nicotine Dependence (FTND) is available for all subjects. In addition, participants also completed the Nicotine Dependence Syndrome Scale (NDSS; Shiffman et al., 2004) and the Wisconsin Inventory of Smoking Dependence Motives (WISDM-68; Piper et al, 2004). Coding for both individual variables and indices has been standardized across studies. All subjects were assessed in person by trained research assistants. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to the genetic architecture of smoking through large-scale genome-wide association studies of two well-characterized cohorts. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000404

• Rapid Acceleration of Diagnostics - Underserved Populations (RADx-UP): CO-CREATE-Ex: Community-engaged Optimization of COVID-19 Rapid Evaluation And TEsting Experiences

  Cases of COVID-19 infection in San Diego have persistently remained high in the county's central and southern communities near the US/Mexico border, home to primarily Latino residents who have been one of the ethnic minority communities most impacted by COVID-19. To address this, our Phase I RADx-UP project partnered with San Ysidro Health (SYH), a federally qualified health center, and the Global Action Research Center (Global ARC), a social change organization, to co-create and demonstrate the impact of a PCR-based COVID-19 testing program in San Ysidro. To date, we have administered approximately 15,000 PCR tests for >10,000 community members (92% Latino) and received requests from SYH to scale-out the testing program to additional primary care clinic sites. Responsive to RFA-OD-22-006, we will continue working with our community (Global ARC) and clinical (SYH) partners to refine, specify, implement, and evaluate an implementation strategy bundle that optimizes COVID-19 testing, expanding beyond current PCR testing to focus on FDA-authorized COVID-19 rapid antigen testing. Use of self-administered rapid antigen tests will allow participants to build capacity to self-test and use health information technology to access additional clinic services. Based on initial implementation mapping with the project's established Community and Scientific Advisory Board, three implementation strategies were prioritized to accelerate sustained uptake of rapid COVID-19 testing. These three strategies include: (1) current, walk-up onsite free testing; (2) promotores-led COVID-19 test counseling and preventive care reminders; (3) vending machines that dispense FDA-authorized self-testing kits. Our primary objectives are to: 1) refine and operationalize our multi-component implementation strategy bundle and a related set of measures of success for rapid FDA- authorized COVID-19 testing and 2) implement and evaluate impact of our innovative, multilevel, and multicomponent implementation strategy bundle to optimize COVID-19 rapid testing among underserved, Latino communities using a roll-out implementation optimization study design across four clinics over 18 months. The COVID-19 pandemic has underscored the urgent and essential need to engage invested community parties continuously and meaningfully in public health research to reduce health disparities. This proposal is well-positioned to provide a set of strategies and measures of success that can be used in settings serving underserved communities while maintaining flexibility to adjust to the changing COVID-19 landscape.

  Study phs003686

• Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

  Study EGAS00001004615

• EGAD00000000033

  NcOEDG Helsinki 2 samples

  Dataset EGAD00000000033

• EGAD00000000034

  NcOEDG Helsinki 3 samples

  Dataset EGAD00000000034

• EGAD00000000035

  NcOEDG Helsinki 4 samples

  Dataset EGAD00000000035

• EGAD00000000037

  NcOEDG Stockholm 2 samples

  Dataset EGAD00000000037

• EGAD00000000038

  NcOEDG Stockholm 3 samples

  Dataset EGAD00000000038

• EGAD00000000039

  NcOEDG Malmo - Lund samples

  Dataset EGAD00000000039

• EGAD00000000040

  GenomEUtwin Danish (DK) samples

  Dataset EGAD00000000040

• EGAD00000000041

  GenomEUtwin Swedish (SWE) samples

  Dataset EGAD00000000041

• EGAD00000000042

  GenomEUtwin Finnish (FIN) samples

  Dataset EGAD00000000042

• EGAD00010000764

  Ovarian tumor samples using Illumina

  Dataset EGAD00010000764

• EGAD00010000791

  Illumina HumanOmni2.5-8 BeadChip

  Dataset EGAD00010000791

• Exome Sequencing of a family with thrombocytopenia, red cell macrocytosis, and lymphoblastic leukemia predisposition

  A family with a history of bleeding, variable thrombocytopenia, red cell macrocytosis and two cases of pre B-cell acute lymphoblastic leukemia was studied in a single visit. The family was assessed for bleeding history using a bleeding questionnaire. Additionally, complete blood counts were measured and whole blood was collected from five affected individuals and three unaffected individuals for DNA extraction and whole exome sequencing. The goal of this study is to determine the genetic cause of thrombocytopenia, red cell macrocytosis, and predisposition to leukemia in a family. It is hoped that the information obtained from this study will help researchers understand the genetic and molecular basis of platelet and red cell production, as well as leukemia predisposition.

  Study phs000873

• Pharmacogenomics of Metformin Dose Response in T2DM Patients

  Type 2 Diabetes Mellitus (T2DM) is a chronic and sometimes debilitating disease that affects millions of adults in the USA. Metformin is commonly prescribed for T2DM; yet some T2DM patients do not tolerate it or respond well. This pharmacogenomics study will examine response, as both change in T2DM patients' weight and hemoglobin A1c (HbA1c) levels, to different doses of metformin, by extracting this data from the electronic health record (EHR), for T2DM subjects taking metformin found by prescription orders in the EHR, and identified as cases with the EHR phenotype algorithm published by Kho et. al. in 2012 (PMID: 22101970 as part of the eMERGE (electronic Medical Records and Genomics; dbGaP phs000237, phs000297, phs000360, phs000368, phs000888, and phs000948) project.

  Study phs000984

• Homozygous Duplication Identified by Whole Genome Sequencing Causes LRBA Deficiency

  In more than one third of primary immunodeficiency (PID) patients, extensive genetic analysis including whole exome sequencing (WES) fails to identify the genetic defect. Whole genome sequencing (WGS) is able to detect variants missed by other genomics platforms, enabling the molecular diagnosis of otherwise unresolved cases. Here, we report two siblings, offspring of consanguineous parents, who experienced similar severe events encompassing early onset of colitis, lymphoproliferation and hypogammaglobulinemia, typical of lipopolysaccharide (LPS)-responsive and beige-like anchor protein (LRBA) or cytotoxic T-lymphocyte-associated protein 4 (CTLA4) deficiencies. WGS of these patients detected a 12.3 kb homozygous tandem duplication that was absent in control cohorts and is predicted to disrupt the reading frame of the LRBA gene.

  Study phs002557

• Pan Cancer Investigation of Human Leukocyte Antigen Loss of Heterozygosity

  Cancer cells can escape immune recognition through human leukocyte antigen (HLA) loss of heterozygosity (LOH) which results in deletion of HLA alleles, causing a reduction in presentation of tumor neoantigens. Despite its influence on immunotherapy response, few methods exist to detect HLA LOH, and accuracy of the approaches is poorly defined. Here, we present DASH (Deletion of Allele-Specific HLAs), a machine learning-based algorithm developed to detect HLA LOH from paired tumor-normal sequencing data. Using DASH to characterize HLA LOH in 610 patients across 15 cancer types, we found that 18% of patients had loss of heterozygosity in at least one HLA allele, suggesting the HLA LOH is a widespread, and potentially key immune resistance strategy in multiple cancers.

  Study phs002783

• Early Onset and Progression of Primary Ciliary Dyskinesia Lung Disease Prior to 10 Years of Age

  Primary Ciliary Dyskinesia (PCD) is a genetic defect in airway host-defense, and typically results in chronic infection of the airways. Patients with PCD have chronic lung, sinus and ear infections. This longitudinal study is designed to define the rate of progression of PCD lung function in participants prior to 10 years of age using special lung function tests, which help to track lung impairment and prognosis in other disorders of the airways such as cystic fibrosis. This longitudinal protocol will also systematically track other specific outcomes, including pathogens infecting the airways (assessed by respiratory cultures), and age at onset and progression of airway damage and bronchiectasis [assessed by high-resolution computerized tomography (HRCT) of the chest].

  Study phs001310

• Exome sequencing of autosomal recessive progressive external ophthalmoplegia (arPEO)

  Progressive external ophthalmoplegia (PEO) is an inherited mitochondrial disease that follows either autosomal dominant or recessive forms of inheritance (adPEO or arPEO). AdPEO is a genetically heterogeneous disease and several genes including POLG1 and C10orf2/Twinkle have been identified as responsible genes. On the other hand, POLG1 was the only established gene causing arPEO with mitochondrial DNA deletions. We previously reported a case of PEO with unidentified genetic etiology. The patient was born of a first-cousin marriage. Therefore, the recessive form of inheritance was suspected. To identify the disease causing variant in this patient, we subjected the patient's DNA to whole-exome sequencing and narrowed down the candidate variants using public data and runs of homozygosity analysis.

  Study phs000392