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• Knoll et al Identification of drug candidates targeting monocyte reprogramming in people living with HIV

  Introduction People living with HIV (PLHIV) are characterized by functional reprogramming of innate immune cells even after long-term antiretroviral therapy (ART). In order to assess technical feasibility of omics technologies for application to larger cohorts, we compared multiple omics layers. Methods Bulk and single-cell transcriptomics, flow cytometry, proteomics, chromatin landscape analysis by ATAC-seq as well as ex vivo drug stimulation was performed in a small number of blood samples derived from PLHIV and healthy controls from the 200-HIV cohort study. Results Single-cell RNA-seq analysis revealed that most immune cells in peripheral blood of PLHIV are altered in their transcriptomes and that a specific functional monocyte state previously described in acute HIV infection is still existing in PLHIV while other monocyte cell states are only occurring acute infection. Moreover, a reverse transcriptome approach on a rather small number of PLHIV was sufficient to identify drug candidates for reversing the transcriptional phenotype of monocytes in PLHIV. Discussion These scientific findings and technological advancements for clinical application of single-cell transcriptomics form the basis for the larger 2000-HIV multicenter cohort study on PLHIV, for which a combination of bulk and single-cell transcriptomics will be included as the leading technology to determine disease endotypes in PLHIV and to predict disease trajectories and outcomes.

  Study EGAS00001007460

• Organoid BulkRNAseq

  Here, we aim to understand early determinants of brain organoid quality and generated a set of brain organoids from 12 different hPSC lines using an adaptation of the unguided Lancaster protocol (Lancaster & Knoblich, 2014). All cell lines were obtained from healthy donors. 12 donor hPSC lines were differentiated into brain organoids and a set of 72 individual organoids (6 per line) were randomly selected morphologically diverse organoids and subjected to bulk RNA sequencing for gene expression analysis. RNA was extracted using the RNeasy kit (Qiagen, Germany) according to the manufacturer’s instructions. A total of 1000 ng per sample was sent for RNA sequencing to Azenta Life Sciences (Genewiz Leipzig, Germany) for sequencing. Library preparation was performed using the NEBNext Ultra II RNA Library Prep Kit for Illumina following manufacturer’s instructions (NEB, Ipswich, MA, USA). mRNAs were first enriched with Oligo(dT) beads. The samples were sequenced using a 2x150 Pair-End (PE) configuration v1.5 at a depth of >20 million reads in each sample. Raw sequence data (.bcl files) generated from Illumina NovaSeq6000 was converted into fastq files and de-multiplexed using Illumina bcl2fastq program version 2.20. The raw sequence reads were aligned to the human reference genome GRCh38 using the STAR aligner (Dobin et al., 2013). Gene expression levels were quantified using the FeatureCounts tool (Liao et al., 2014).

  Study EGAS50000000659

• A comprehensive DNA methylation landscape of human and mouse cell lines derived from hematological malignancies

  Human cancer cell lines constitute useful models to study the primary disease and many relevant findings in tumor biology have been originated from them since the first immortalized cell line (HeLa) was obtained. The easy experimental intervention, the purity of the transformed cells and their versatility to undergo high-throughput screenings represent advantageous features of the established cancer cell lines. In recent years, major efforts have characterized in detail the multiomics make-up of hundreds of cancer cell lines and studied their association with sensitivity to anticancer drugs. Most of these studies have been genetic-centric and have not characterized in detail the epigenetic profiles underlying the characteristics of these cells or their impact on the efficacy of antitumoral compounds. In this regard, a past version of a DNA methylation microarray or a less accessible and more time-consuming such as reduced representation bisulfite sequencing have been used in those attempts to interrogate the epigenetic setting. Herein, we have obtained the DNA methylation profiles of 210 cell lines derived from hematological malignancies utilizing comprehensive DNA methylation microarrays that interrogates more than 850,000 and 285,000 CpG sites from human and mouse genomes, respectively. Importantly, we also provide a pharmacoepigenetic example of the potential use of this resource by showing how DNA methylation can predict response to nucleoside analogues.

  Study EGAS50000000627

• A Cancer Cell-Line Titration Series for Evaluating Somatic Classification

  Accurate detection of somatic single nucleotide variants and small insertions and deletions from DNA sequencing experiments of tumour-normal pairs is a challenging task. Tumour samples are often contaminated with normal cells confounding the available evidence for the somatic variants. Furthermore, tumours are heterogeneous so sub-clonal variants are observed at reduced allele frequencies. We present here a cell-line titration series dataset that can be used to evaluate somatic variant calling pipelines with the goal of reliably calling true somatic mutations at low allele frequencies. Cell-line DNA was mixed with matched normal DNA at 8 different ratios to generate samples with known tumour cellularities, and exome sequenced on Illumina HiSeq to depths of >300x. The data was processed with several different variant calling pipelines and verification experiments were performed to assay >1,500 somatic variant candidates using Ion Torrent PGM as an orthogonal technology. By examining the variants called at varying cellularities and depths of coverage, we show that the best performing pipelines are able to maintain a high level of precision at any cellularity. In addition, we estimate the number of true somatic variants undetected as cellularity and coverage decrease. Our cell-line titration series dataset, along with the associated verification results, is effective for this evaluation and will serve as a valuable dataset for future somatic calling algorithm development.

  Study EGAS00001001016

• TRACERx 100: metastatic samples

  Whole exome sequencing of 10 metastatic biopsies from four TRACERx100 patients (see EGA dataset EGAS00001002247), collected either after relapse or death. The data from these samples are initially published with Abbosh, C. et al. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution. Nature http://dx.doi.org/10.1038/nature22364 (2017). Abstract: Earlier detection of relapse following primary surgery for non-small cell lung cancer and the characterization of emerging subclones seeding metastatic sites might offer new therapeutic approaches to limit tumor recurrence. The potential to non-invasively track tumor evolutionary dynamics in ctDNA of early-stage lung cancer is not established. Here we conduct a patient-specific approach to ctDNA profiling in the first 100 lung TRACERx (TRAcking Cancer Evolution through therapy (Rx)) study participants, including one patient co-recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release in early-stage non-small cell lung cancer and perform tumor volume limit of detection analyses. Through blinded profiling of post-operative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients destined to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastases, providing a new approach for ctDNA driven therapeutic studies.

  Study EGAS00001002415

• PD-L1 blockade immunotherapy rewires cancer-induced emergency myelopoiesis

  Introduction Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit. Methods In this study, we treated tumour-bearing mice with PD-L1 blockage antibody (aPD-L1) immunotherapy, to investigate its effects on cancer-induced emergency myelopoiesis, focusing on bone marrow HSPCs. We examined the impact of aPD-L1 treatment on HSPC quiescence, proliferation, transcriptomic profile, and functionality. Results Herein, we reveal that aPD-L1 in tumour-bearing mice targets the hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (ΒΜ), mediating their exit from quiescence and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces transcriptomic reprogramming in HSPCs, observed in both individuals with Hodgkin lymphoma (HL) and tumour-bearing mice, shifting towards an inflammatory state. Furthermore, HSPCs from aPDL1-treated mice demonstrated resistance to cancer-induced emergency myelopoiesis, evidenced by a lower generation of MDSCs compared to control-treated mice. Discussion: Our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer, which involves targeting of BM-driven HSPCs and reprogramming of cancer-induced emergency myelopoiesis.

  Study EGAS00001007873

• UK10K NEURO ASD MGAS

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The MGAS (Molecular Genetics of Autism Study) samples are from a clinical sample seen by specialists at the Maudsley hospital and who have had detailed phenotypic assessments with ADI-R and ADOS.For further information on this cohort please contact Patrick Bolton (patrick.bolton@kcl.ac.uk).

  Study EGAS00001000113

• Illumina HumanOmniExpress genotyping data from the TEENAGE (TEENs of Attica: Genes and Environment) study.

  The TEENAGE study is a cross-sectional study comprising healthy Greek adolescents. The study was conducted according to the guidelines specified in the Declaration of Helsinki and all procedures involving human subjects were approved by the Institutional Review Board of Harokopio University and the Greek Ministry of Education, Lifelong Learning and Religious Affairs. The TEENAGE study target population comprised adolescent students aged 13 to 15 years attending the first three classes of public secondary schools located in the wider Athens area of Attica. The regions across Attica from which students were recruited were physically similar and all urban in nature. Sampling of regions and schools selected to participate was random. Students were enrolled from the wider urban region to ensure that they were coming from families with varying educational background and socio-economic status. Moreover, in order to exclude any vast economic disparities, all participating schools were exclusively public schools, which are free of charge. A total of twenty-four schools participated in the study out of 285 junior secondary public schools in Attica. Anthropometric, medical and dietary information was obtained. DNA samples were genotyped using Illumina HumanOmniExpress BeadChips (Illumina, San Diego, CA, USA) at the Wellcome Trust Sanger Institute, Hinxton, UK. Genotype calling algorithm used was Illuminus (Teo et al., 2007).

  Study EGAS00001000996

• Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment.

  Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.

  Study EGAS00001001179

• Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment

  Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortical tubers are believed to represent the neuropathological substrates of these disabling manifestations in TSC. In the presented study we used high-throughput RNA sequencing in combination with systems-based computational approaches to investigate the complexity of the TSC molecular network. Overall we detected 438 differentially expressed genes and 991 differentially expressed small non-coding RNAs in cortical tubers compared to autopsy control brain tissue. We observed increased expression of genes associated with inflammatory, innate and adaptive immune responses. In contrast, we observed a down-regulation of genes associated with neurogenesis and glutamate receptor signaling. MicroRNAs represented the largest class of over-expressed small non-coding RNA species in tubers. In particular, our analysis revealed that the miR-34 family (including miR-34a, miR-34b and miR-34c) was significantly over-expressed. Functional studies demonstrated the ability of miR-34b to modulate neurite outgrowth in mouse primary hippocampal neuronal cultures. This study provides new insights into the TSC transcriptomic network along with the identification of potential new treatment targets.

  Study EGAS00001002485

• UK10K NEURO ASD TAMPERE

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The Tampere Autism sample set consists of samples from Finnish subjects with ASD (autism spectrum disorders) with IQs over 70 recruited from a clinical centre for the diagnosis and treatment of children with ASD. For further information on this cohort please contact either Terho Lehtimaki (terho.lehtimaki@uta.fi) or Kaija Puura (kaija.puura@pshp.fi).

  Study EGAS00001000115

• Homozygous loss-of-function variants in European cosmopolitan and isolate populations

  Homozygous loss of function (HLOF) variants provide a valuable window on gene function in humans, as well as an inventory of the human genes that are not essential for survival and reproduction. All humans carry at least a few HLOF variants, but the exact number of inactivated genes that can be tolerated is currently unknown-as are the phenotypic effects of losing function for most human genes. Here, we make use of 1432 whole exome sequences from five European populations to expand the catalogue of known human HLOF mutations; after stringent filtering of variants in our dataset, we identify a total of 173 HLOF mutations, 76 (44%) of which have not been observed previously. We find that population isolates are particularly well suited to surveys of novel HLOF genes because individuals in such populations carry extensive runs of homozygosity, which we show are enriched for novel, rare HLOF variants. Further, we make use of extensive phenotypic data to show that most HLOFs, ascertained in population-based samples, appear to have little detectable effect on the phenotype. On the contrary, we document several genes directly implicated in disease that seem to tolerate HLOF variants. Overall HLOF genes are enriched for olfactory receptor function and are expressed in testes more often than expected, consistent with reduced purifying selection and incipient pseudogenisation.

  Study EGAS00001001606

• Bulk-tissue RNA-sequencing of anterior cingulate cortex samples derived from Lewy body disease patients

  Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

  Study EGAS00001005305

• scRNA-seq of HGSC tumor and ascites

  Immune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few notable exceptions, their identities remain largely unknown. We uncovered the immune regulatory metabolic states and metabolomes of sorted tumor and stromal, CD4+, and CD8+ cells from the tumor and ascites of patients with high-grade serous ovarian cancer (HGSC) using high-dimensional flow cytometry and metabolomics supplemented with single cell RNA sequencing. Flow cytometry revealed that tumor cells show a consistently greater uptake of glucose than T cells, but similar mitochondrial activity. Cells within the ascites and tumor had pervasive metabolite differences, with a striking enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared to ascites. Despite the elevated levels of MNA in T cells, the expression of nicotinamide N-methyltransferase, the gene encoding the enzyme that catalyses the transfer of a methyl group from S-adenosylmethionine to nicotinamide, was restricted to fibroblasts and tumor cells. Treatment of T cells with MNA resulted in an increase in T cell-mediated secretion of the tumor promoting cytokine tumor necrosis factor alpha. Thus, the TME-derived metabolite MNA contributes to an alternative and non-cell autonomous mechanism of immune modulation of T cells in HGSC. Collectively, uncovering the tumor-T cell metabolome may reveal metabolic vulnerabilities that can be exploited using T cell-based immunotherapies to treat human cancer.

  Study EGAS00001004829

• Targeted de-methylation of the FOXP3-TSDR

  CD4+ regulatory T cells (Tregs) are key mediators of immunological tolerance and promising effector cells for immuno-suppressive adoptive cellular therapy to fight autoimmunity and chronic inflammation. Their functional stability is critical for their clinical utility and has been correlated to the demethylated state of the TSDR/CNS2 enhancer element in the Treg lineage transcription factor FOXP3. However, proof for a causal contribution of the TSDR de-methylation to FOXP3 stability and Treg induction is so far lacking. We here established a powerful transient-transfection CRISPR-Cas9-based epigenetic-editing method for the selective de-methylation of the TSDR within the endogenous chromatin environment of a living cell. The induced de-methylated state was stable over weeks in clonal T cell proliferation cultures even after expression of the editing complex had ceased. Epigenetic editing of the TSDR resulted in FOXP3 expression, even in its physiological isoform distribution, proving a causal role for the de-methylated TSDR in FOXP3 regulation. However, successful FOXP3 induction was not associated with a switch towards a functional Treg phenotype, in contrast to what has been reported from FOXP3 overexpression approaches. Thus, TSDR de-methylation is required, but not sufficient for a stable Treg phenotype induction. Therefore, targeted demethylation of the TSDR may be a critical addition to published in vitro Treg induction protocols which so far lack FOXP3 stability.

  Study EGAS00001004867

• 5- FU treated organoids

  5-Fluorouracil (5-FU) is a chemotherapeutic drug component that is commonly used for the treatment of solid cancers. The anticancer properties of 5-FU have been attributed to interference with nucleotide synthesis and through direct incorporation into the DNA as being a pyrimidine analog. As both mechanisms of action may have a mutational impact on surviving tumor cells, we performed three independent analyses to characterize the genomic consequences of 5-FU treatment: i) in vitro treatment of intestinal organoids with 5-FU followed by whole genome sequencing, ii) genome-wide mutation analyses in tumor samples from 5-FU treated patients with breast or colorectal cancer, and iii) analysis of paired biopsies from patients treated with 5-FU between biopsies. Our results demonstrate that both in vitro and in vivo 5-FU causes a mutational pattern that is dominated by T>G substitutions in a CTT context and with strong resemblance to COSMIC signature 17. Interestingly, this signature is also found in non 5-FU treated patients, most prominently in esophageal tumors, indicating that distinct endogenous and exogenous triggers can converge into highly similar mutational signatures. Furthermore, our results suggest that 5-FU may have adverse mutagenic effects on healthy cells and contributes to genetic variability in surviving cancer cells thereby contributing to tumor evolution.

  Study EGAS00001003592

• Uncovering tumor intrinsic and extrinsic factors that regulate hepatocellular carcinoma growth using patient derived xenograft assays

  Several major factors limit our understanding of hepatocellular carcinoma (HCC). First, human HCCs are infrequently biopsied for diagnosis and thus are not often biologically interrogated. Second, HCC initiation and progression are strongly influenced by the cirrhotic microenvironment, and the exact contributions of intrinsic and extrinsic tumor factors are unclear. A powerful approach to examine the personalized biology of liver cancers and the influence of host tissues is with patient derived xenograft (PDX) models. In Asia, HCCs from hepatitis B virus patients have been efficiently converted into PDXs, but few parallel efforts from the west have been reported. In a large-scale analysis, we implanted 93 HCCs and 8 cholangiocarcinomas (CCAs) to systematically analyze host factors and to define an optimized platform for PDX development from both surgical and biopsy samples. NSG mice that had undergone partial hepatectomy (PHx) represented the best combination of engraftability, growth, and passageability, but overall rates were low and indicative of a unique intrinsic biology for HCCs in the US. PDX models preserved the histology and genetic features of parental tumors, and ultimately, 9 new models were usable for pre-clinical studies. Intriguingly, HCC PDXs were differentially sensitive to regorafenib and sorafenib and CCA PDXs were also highly sensitive to regorafenib. PDX models functionalize early and advanced stage HCCs and revealed unique biological features of liver cancers from the US.

  Study EGAS00001004020

• Implementation, Adoption, and Utility of Family History in Diverse Care Settings

  The purpose of this study is to address the key question of whether and how family health history (FHH) is adopted as a tool to more efficiently manage patients at risk for breast, colon, ovarian, and hereditary cancer syndromes as well as thrombophilia and coronary heart disease (CHD) and to provide evidence supporting clinical utility -- improved health behaviors in patients and physician screening recommendations. Five health care delivery organizations will participate in this demonstration project: Duke University, the Medical College of Wisconsin, the Air Force, Essentia Health, University of North Texas. Duke will serve as a coordinating center for this project (Pro00043372) as well as a site. Healthcare Effectiveness Data and Information Set (HEDIS) measures as intermediate clinical effectiveness measures for Coronary Heart Disease (CHD) and selected cancers as well as survey/formative data and electronic medical record (EMR) data will be used as outcomes measures. The research model is purposely designed to mimic clinical delivery as an important step toward widespread implementation and sustainability. In addition, a cost-effectiveness analysis comparing usual care to the FHH guided preventive health model will be used. The completion of this project will result in an optimal strategy for integration of FHH data collection and clinical decision support (CDS) tools into an EMR and demonstrate the utility of the FHH intervention among diverse primary care patients, their settings, their providers, and the health systems that deliver their care. Specific Aim 1: To optimize the collection of patient entered FHH in diverse clinical environments for coronary heart disease, thrombosis, and selected cancers Specific Aim 2: To export FHH data to an open clinical decision support (open CDS) platform and return CDS results to providers and patients (and to EMRs where relevant). To explore the integration of genetic risk and FHH data at selected sites. Specific Aim 3: To assess the clinical and personal utility of FHH using a pragmatic observational study design to assess reach, adoption, integrity, exposure, and sustainability, and to capture, analyze, and report effectiveness outcomes at each stakeholder level: patient, provider, and clinic/system. Specific Aim 4: To take a leadership role in the dissemination of guidelines for a FHH intervention across in diverse practice settings. AAA Hypertension Lupus Multiple sclerosis Obesity Osteoporosis Thyroid disease Rheumatoid arthritis Blood clotting (6): Blood Clot (high risk features) Factor V PT mutation AT III deficiency Protein S deficiency Protein C deficiency Brain Disorders (5): Dementia Hemorrhagic stroke Ischemic stroke Macrocephaly Seizure Cancer/Adenomas (32): Bone cancer Brain cancer Breast cancer Colon cancer Adrenal cortex tumor Neuroendocrine tumor Paraganglioma Pheochromoctyoma Pituitary adenoma Medullary thyroid cancer Non-medullary (follicular or papillary) thyroid cancer Don't know type of thyroid cancer Thyroid nodule Other type of endocrine cancer Esophageal cancer Kidney cancer Leukemia Lipoma Liver cancer Muscle cancer Ovarian cancer Pancreatic cancer Prostate cancer Rectal cancer Retinoblastoma Melanoma Non-melanoma skin cancer Do not know type of skin cancer Small bowel cancer Stomach cancer Uterine cancer Other type of cancer Cardiovascular/heart/artery disease (5): Atrial fibrillation Carotid stenosis Heart attack/coronary artery disease Peripheral arterial disease Other heart disease Diabetes (3): Gestational diabetes Diabetes type I Diabetes type 2 Digestive Disorders (5): Colon polyp Crohn's disease Irritable bowel syndrome Ulcerative colitis Other digestive disorder Eye Disorder (3): Blindness Glaucoma Macular degeneration Hereditary Cancer Syndromes (22): Birt-Hogg-Dube syndrome Cowden syndrome Familial adenomatous polyposis Hereditary breast and ovarian cancer syndrome Hereditary diffuse gastric cancer Hereditary leiomyomatosis and renal cell carcinoma syndrome Hereditary melenoma Hereditary papillary renal cancer syndrome Hereditary paraganglioma-pheochromocytoma syndrome Hereditary retinoblastoma Juvenile polyposis Li-Fraumeni syndrome Lynch syndrome Mutyh-associated polyposis Malignant hyperthermia susceptibility Multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 2 Nevoid basal cell carcinoma syndrome Peutz-Jeghers syndrome Tuberous Sclerosis complex Von-Hippel Lindau syndrome Other hereditary cancer Hereditary Cardiovascular syndromes (10): Long qt Brugada Catecholaminergic polymorphic ventricular tachycardia Hypertrophic cardiomyopathy Dilated cardiomyopathy Left ventricular non-compaction syndrome Arrhythmogenic right ventricular dysplasia Ehlers-Danlos syndrome Marfan syndrome Other hereditary cardiovascular syndrome High cholesterol (2): Hyperlipidemia Familial hypercholesterolemia Kidney Disease (6): Cystic kidney disease Diabetic kidney disease Kidney nephrosis Nephritis Nephrotic syndrome Other kidney disease Liver Disease (6): Alpha 1 antitrypsinase deficiency Auto-immune hepatitis Hereditary hemochromatosis Primary biliary cirrhosis Sclerosing cholangitis Wilson's disease Lung Disease (3): Asthma COPD/chronic bronchitis/emphysema Other lung disease Psychological disorder (14): Addiction ADHD Autism Bipolar Depression Eating disorder Intellectual disability Obsessive compulsive disorder Panic disorder Personality disorder PTSD Schizophrenia Social phobia Sickle cell/thalassemia (3): Sickle cell disease Sickle cell trait Thalassemia

  Study phs001641

• Lung Tissue Research Consortium (LTRC-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. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from LTRC include DNA, Plasma, Serum, Tissue - FFPE Cassettes, Tissue – RNALater Frozen, and Tissue - Snap Frozen. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: The LTRC was a biobank resource established by the NHLBI to collect and distribute lung tissue, blood samples, clinical data, and radiographic studies from participants with chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), other related idiopathic interstitial pneumonias (IIP) and interstitial pneumonias associated with connective tissue diseases who undergo medically-indicated lung resection. All tissue and blood specimens and clinical data were banked centrally and stored for distribution to external investigators who have approved study proposals to investigate the pathogenesis or management of lung diseases. The ultimate goal of this program was to enable research that illuminates the pathobiology of lung diseases and leads to novel interventional treatments for these conditions. Background: Chronic lung diseases are a main cause of death and disability in the United States. COPD affects over 14 million individuals in the United States and represents the third leading cause of mortality. Cigarette smoking is a major risk factor. However, only one of six individuals who smoke develops COPD. This could imply either an individual susceptibility or an additional immunologic or infectious injury to lung cells. Current treatments offer symptomatic relief, but do not prevent disease progression. Better understanding of disease pathogenesis, including the potential roles of lung parenchymal cell apoptosis, immunologic injury, and inflammation may lead to therapies that improve survival and quality of life. Interstitial pneumonias, including IPF and those associated with connective tissue disease, are less common than COPD, but for many of these diseases there are poor outcomes. For example, IPF has a 50% survival rate 2-3 years following diagnosis, and currently no treatment exists which prolongs survival. The prevalence of IPF is approximately 28 cases per 100,000. The underlying histology of IPF is usual interstitial pneumonia (UIP), which can also occur in connective tissue diseases. The incidences of other interstitial pneumonias such as non-specific interstitial pneumonia (NSIP) or acute interstitial pneumonia (AIP) are less frequent but also occur as an expression of interstitial lung disease in the connective tissue diseases. Moreover, there is significant crossover of these three interstitial pneumonias so that cases of IPF/UIP may also reveal fibrotic NSIP and be complicated by episodes of AIP. This implies common injuries but dissimilar histological responses. All of these processes are characterized by epithelial injury, uncontrolled fibroproliferation and the deposition of collagen, irrespective of the histology. It is clear that a better understanding of the genesis of the interstitial pneumonias is required before effective interventions can be developed. Participants: A total of 4,486 participants were enrolled, and lung tissue was obtained from 3,333 of these participants.Design: Written informed consent of each participant was required before any LTRC procedure was performed. Phenotypic data were then obtained that included recording of relevant medical information, a limited exposure history, radiological evaluation, and pulmonary physiological and lung function testing. Questionnaires were administered to determine the extent of symptoms, associated medical illnesses, smoking, environmental and occupational exposures, and quality of life. Laboratory testing included pulmonary function testing, a six-minute walk test, and chest x-ray CT. Blood specimens were collected both for defining the clinical phenotype of donors and to obtain serum, plasma, and DNA for later investigative purposes. At the time of surgery, lung tissues were collected and processed for long-term storage. The LTRC collected only the 'non-tumorous' portions of lung tissue from surgical procedures performed for primary or metastatic lung tumors and received those specimens only after the local pathologist had procured all tissue required for clinical care. Samples of appropriate size were cut and placed in formalin, RNAlater, glutaraldehyde, or liquid nitrogen within 30 minutes of excision (approximately 5% of cases exceeded this target time). Blood and tissue specimens were subsequently shipped to a central Tissue Repository for further processing and long-term storage. A Radiology Center provided quality control and quality assessment of CT data. A Data Coordinating Center managed study operations and maintained a repository of study data. Conclusions: LTRC established a biospecimen collection that is unique in its size, diseases included, standardization of methods, and extent of phenotypic data, serving as a valuable resource to facilitate research on the pathobiology of lung diseases.

  Study phs003913

• Evaluation of Ancestry Admixture among Chileans

  The purpose of this study is to investigate ancestry admixture among Chileans with and without gallbladder cancer.

  Study phs001385

• GEOCODE data access policy

  The GEOCODE Data Access Policy ensures the responsible use, security, and compliance of GEOCODE data. Access to GEOCODE data is restricted to authorized users based on role-based permissions, ensuring compliance with data protection regulations.

  Dac EGAC50000000574

• CMML_Bulk_WGS

  Whole genome sequencing to determine HSC phylogeny in MDS and clonal haematopoiesis patients undergoing treatment with hypomethylating agents.

  Study EGAS00001008237

• RNA-seq of murine osteosarcoma cell line genetically modified for CYR61

  Transcriptomic analysis of K7M2 murine osteosarcoma cells stably modified to overexpress or repress CYR61

  Study EGAS50000000526

• Primary Neuroblastoma Circle-seq

  We generated Circle-seq data for primary neuroblastoma to describe the landscape of extrachromosomal circular DNA in neuroblastoma.

  Study EGAS00001004797

• PREDICT

  PREDICT/Predicting individual response and resistance to VEGFR/mTOR pathway therapeutic intervention using biomarkers discovered through tumour functional genomics.

  Study EGAS00001000094