19276 results for "Buy fc 26 coins Buyfc26coins.com is EA Sports official for FC 26 coins This is the best service ever..VBsp"

in 51.02 milliseconds.

• The Role of CDX2 in Controlling ABCB1 Expression and Chemosensitivity in Human Colon Cancer

  This study reports the results of RNA sequencing (RNA-seq) experiments performed on two human colon cancer cell lines (HT-29, DLD-1) that were genetically engineered to achieve either the constitutive expression (in HT-29 cells) or the selective inactivation (in DLD-1 cells) of the transcription factor CDX2, a master regulator of embryonic gut development and a key regulator of multi-lineage differentiation in adult colon epithelial cells. Our previous studies had identified lack of CDX2 expression as a prognostic biomarker of poor prognosis and a predictive biomarker of benefit from adjuvant chemotherapy in Stage-II and Stage-III colon cancer patients (Dalerba et al., NEJM, 374:211-222, 2016; PMID: 26789870). The molecular basis of these associations, however, remained poorly understood. The present study was designed to identify which genes are under the transcriptional control of CDX2, in order to clarify their role in shaping colon cancer resistance to chemotherapy. Of the two lines included in this study, the first (HT-29) is CDX2-negative at baseline, and was infected with a lentivirus vector encoding for the cDNA of the human CDX2 gene under the control of a constitutive promoter (CMV). The second line (DLD-1) is CDX2-positive at baseline, and was infected with a series of lentivirus vectors encoding for CRISPR/Cas9 constructs designed to selectively inactivate the CDX2 gene. In both cases, infected cells were purified by fluorescence-activated cell sorting (FACS), based on the differential expression of a green fluorescent reporter (EGFP) that was also encoded by the lentivirus vectors, and transcribed in tandem with either the CDX2 cDNA (HT-29) or CRISPR/Cas9 gRNAs targeting CDX2 (DLD-1). The experiments were designed to include 3 experimental replicates per condition, and to compare the transcriptional profile of genetically engineered cells with that of autologous controls (i.e., HT-29 cells infected with an "empty" version of the same lentivirus vector used to over-express CDX2, DLD-1 cells engineered with a "non-targeting" CRISPR/Cas9 gRNA). In the specific case of DLD-1 cells engineered with CRIPSR-Cas9 constructs targeting CDX2, infected cells were sorted based on the differential expression of EGFP and then plated as single-cells, in order to sub-culture three isogenic clones, all of which were genetically sequenced to confirm bi-allelic knock-out of the CDX2 gene, and confirmed to lack CDX2 protein expression by Western blot. The results of our experiments demonstrate that, in human colon epithelial cells, CDX2 controls the expression of the ABCB1 efflux pump, by positively regulating the transcription of the corresponding gene.

  Study phs002903

• Gene Expression and Regulatory Networks in Human Leukocytes - Immunological Variation Consortium

  Profiling of gene expression with microarrays holds great potential for human health, for illuminating disease pathways or providing biomarkers to monitor disease or its resolution. Using high-throughput approaches for genotyping, immunophenotyping and gene expression analysis, the project will examine the basis for the control of gene expression in human immune cells, and how it is influenced by natural genetic variation or aging. In practice, the project will combine several cross-informative approaches: 1) Building on the established sample/data pipelines and robust protocols of the Immunological Genome (ImmGen) project, and on established cohorts of ethnically diverse healthy volunteers at hand, microarray techniques will be used to generate whole-genome expression profiles from purified naive CD4+ lymphocytes and monocytes from 600 healthy volunteers. A dense genetic map will be established for all donors. The results will elucidate how variation in the human genome affects the expression of immune genes, of key importance in understanding gene variants that bring susceptibility to immune or inflammatory disease. Computational analysis of these rich data will allow the reconstruction of regulatory connections between genes, helping to establish general modules and those specific of a given immune cell type. These data will be complemented by an orthogonal data group, generated from a restricted subset of 10 individuals, in which we will profile a larger set of 28 carefully delineated cell populations that exist in human blood. This work will also benefit from powerful interspecies comparison with similar experiments being performed in mice by ImmGen. 2) In addition, RNA from the same set of 28 defined cell populations will be probed with microarrays that explore other aspects of the transcriptome: i) microRNAs and other non-coding RNAs; ii) exon or splice junction arrays that will establish a map of differential splicing in human blood leukocyte. 3) The composition and reactivity of blood cells from the same donors will be established at the time of sample collection using high-throughput flow cytometry, correlating immune phenotypes with gene expression and genetic variation. 4) Genetic variability conditions the baseline levels of gene expression, but also the responsiveness to activating challenges. With samples from the same donors, NanoString technology for transcript counting will be used to analyze the transcriptional response of defined gene sets, representing response signatures of T or dendritic cells, for a fine-grained dissection of responses to different triggers (different bacterial ligands for dendritic cells, different cytokine environment for T cells). In keeping with the resource aspect of this project, all data and interpretations will be made publicly available rapidly upon curation, allowing public querying and browsing of the data, by using and evolving the existing web architectures of the ImmGen project, of the Broad Institute, and of international repositories. RELEVANCE: Exploration with DNA chips of the genome's expression microarrays holds great potential for human health, to better understand disease and to serve as diagnostic tools. Using a combination of high-throughput genomic techniques and computational biology, we will perform a broad exploration of gene expression in human blood cells across groups of African-American, Asian and European ancestry, asking how these profiles are affected by genetic variation or by age. These results will provide an invaluable reference benchmark for the interpretation of genetic and immunological studies. Additionally, over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, in a second study we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution. 15% of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (ATAC-QTLs). ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression, and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression. In another study we analyzed RNA-seq profiles from primary CD4+ T cells of two healthy donors at six time points from 0 to 72 hours after stimulation with bead-bound antibodies against CD3 and CD28.

  Study phs000815

• (Epi)genetic Risk Architectures of Opioid-Dependent Brain

  With nearly 20,000 overdose deaths in 2014 alone, opioid addiction (OA) has emerged as one of the most pressing public health crises in recent US history. One-fifth of individuals who try heroin develop an addiction to opioids. Genetics is a major contributor to OA with an estimated 60% heritability, only somewhat less than schizophrenia (80%) which has recently seen substantial gains in identified underlying genetics. Yet, studies to date have failed to uncover most of the genes that predispose individuals to OA, leaving the overwhelming fraction of OA heritability unexplained. The proposed study takes a novel, integrated "omics-based" strategy to investigate the molecular basis of OA and uncover both genetic and epigenetic factors associated with opioid addiction. The premise for our approach is founded on studies from our labs, and others, implicating regulatory variation in common traits and diseases, including those associated with complex brain phenotypes like addiction. We have collected the largest known cohort of postmortem brains from addicts who overdosed on opioids, along with matched control brains from non-users. From both cases and control specimens, we will isolate cells from 2 regions of the brain closely implicated in the addiction phenotype: the Prefrontal Cortex (PFC) and the Nucleus Accumbens (NAc). In Aim 1, we propose ChIP-seq studies to identify regulatory elements that distinguish cases from controls and define the opioid addiction phenotype. The regulatory differences will be connected to their gene targets through high resolution in situ Hi-C. In Aim 2, we propose QTL-based approaches to identify genetic variants that underlie the regulatory differences (hmQTLs). We also propose eQTL analyses to identify genetic variants that underlie differences in transcript levels between cases and controls. Aim 3 leverages the largest heroin addiction GWAS meta-analysis to date to test the hypothesis that SNPs in regions associated with chromatin and expression differences between cases and controls define novel loci for predisposition to OA. Each Aim has the potential for discovery independent of the others (differential HM, RNAexp, QTLs, and variant-phenotype associations) but their synergy is the most powerful component of the proposed study: identifying regulatory pathways that generate, not only phenotype associations, but hypothesized mechanisms for those associations which can be the focus of new opioid addiction prevention and treatment development.

  Study phs002724

• Whole exome and transcriptome analysis of UV-exposed epidermis and carcinoma in situ reveals early drivers of carcinogenesis

  Squamous cell carcinoma in situ (SCCIS) is a prevalent precancerous lesion that can progress to cutaneous squamous cell carcinoma (cSCC). Although SCCIS is common, its pathogenesis remains poorly understood. To better understand SCCIS development, we performed laser-captured microdissection of human SCCIS and adjacent epidermis to isolate genomic DNA and RNA for next generation sequencing. Whole exome sequencing (WES) identified UV-signature mutations in multiple genes including Notch 1-3 (GeneID:4851, GeneID:4853, GeneID:4854) in the epidermis and SCCIS and oncogenic TP53 (GeneID:7157) mutations in SCCIS. Novel gene families, including SCHLAFEN genes, contained UV/oxidative-signature disruptive (UVD) epidermal mutations that manifested positive selection in SCCIS. The frequency and distribution of NOTCH and TP53 mutations indicate that NOTCH mutations may precede TP53 mutations. RNA sequencing identified 1166 differentially expressed genes; the top 5 enriched GO biological processes included: 1) immune response, 2) epidermal development, 3) protein phosphorylation, 4) regulation of catalytic activity, and 5) cytoskeletal regulation. The NEURL1 ubiquitin ligase, which targets Notch ligands for degradation, was upregulated in SCCIS. Neuralized 1 protein was found to be elevated in SCCIS suggesting that increased levels could represent a novel mechanism for downregulating Notch during UV-induced carcinogenesis. The data from DNA and RNA sequencing of epidermis and SCCIS provide insights regarding SCCIS formation.

  Study phs002019

• Whole exome sequencing for gallbladder cancer in Xinhua Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine

  Patients with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here, we report our identification of somatic mutations of GBCs in 57 tumor-normal pairs by use of a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominative prevalence of C>T mutations at TCN sites. Genes with a significant frequency of non-silent mutations include TP53 (47.1%), KRAS (7.8%), and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21 of 57) of the GBC samples. Multivariate analyses further reveal that patients with ErbB pathway mutations have a worse outcome (P = 0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in the pathogenesis of GBCs.

  Study EGAS00001000853

• NHLBI TOPMed - NHGRI CCDG: Massachusetts General Hospital (MGH) Atrial Fibrillation Study

  The Massachusetts General Hospital (MGH) Atrial Fibrillation Study was initiated in 2001. The study has enrolled serial probands, unaffected and affected family members with atrial fibrillation. At enrollment participants undergo a structured interview to systematically capture their past medical history, AF treatments, and family history. An electrocardiogram is performed; the results of an echocardiogram are obtained; and blood samples are obtained. For the TOPMed WGS project only early-onset atrial fibrillation cases were sequenced. Early-onset atrial fibrillation was defined as an age of onset prior to 66 years of age. Comprehensive phenotypic and pedigree data for study participants are available through dbGaP phs001001.

  Study phs001062

• Multiomic snRNAseq/snATACseq of human implantation sites, placenta and decidua

  This dataset is part of a study that aims to provide a spatially resolved single-cell multiomics map of human trophoblast differentiation in early pregnancy. This dataset contains 10x multiome snRNA-seq/snATAC-seq from human implantation sites, decidual and placental samples from 8-9 PCW.

  Dataset EGAD00001010038

• scRNAseq/snucRNAseq of human implantation sites, placenta and decidua

  This dataset is part of a study that aims to provide a spatially resolved single-cell multiomics map of human trophoblast differentiation in early pregnancy. This dataset contains snucRNAseq; from three human implantation sites (between 8 and 12 post-conceptional weeks, PCW) from medical hysterectomies.

  Dataset EGAD00001010037

• Heart Failure Network - Effectiveness of Ultrafiltration in Treating People with Acute Decompensated Heart Failure and Cardiorenal Syndrome (HFN CARRESS - BioLINCC)

  ObjectiveThe CARRESS trial examined the effectiveness of ultrafiltration compared with a strategy of diuretic-based stepped pharmacologic therapy on renal function and weight loss in patients with heart failure who have worsening renal function and persistent congestion.BackgroundAcute cardiorenal syndrome is defined as worsening renal function in patients with acute decompensated heart failure. It occurs in 25 to 33% of patients and is associated with poor outcomes. Current heart failure treatments focus on removing excess fluid buildup, however administration of intravenous diuretics may contribute to worsening renal function. Venovenous ultrafiltration is one alternative therapy that may be effective in patients with acute decompensated heart failure complicated by acute cardiorenal syndrome and persistent congestionSubjectsA total of 188 patients were randomized.DesignHospitalized subjects were randomly assigned to receive either ultrafiltration therapy or pharmacologic therapy. Ultrafiltration was performed at a fluid-removal rate of 200 ml per hour and loop diuretics were discontinued for the duration of the intervention. The addition of intravenous vasodilators or positive inotropic agents was prohibited, unless they were deemed to be necessary as rescue therapy. Patients assigned to stepped pharmacologic therapy received intravenous diuretics to manage congestion and maintain a urine output of 3 to 5 liters per day. In both groups, the assigned treatment strategy was to be continued until the signs and symptoms of congestion in the patient were reduced as much as possible. The primary end points were baseline changes in serum creatinine and weight as assessed at 96 hours after treatment assignment.ConclusionsThe use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function, and there was a similar amount of weight loss between the two groups. Ultrafiltration was associated with a higher rate of adverse events (Bart, et al., 2012, PMID: 23131078).

  Study phs003510

• Genetic analysis of Hirschsprung disease

  Hirschsprung disease (HSCR) is a birth defect resulting from the absence of nerve (ganglion) cells in the gastrointestinal tract. Hirschsprung disease has a population incidence of 1/5,000 live births and most often occurs as an isolated condition. However, approximately 30% of HSCR cases are associated with other birth defects such as Down syndrome, deafness, hypopigmentation, and Congenital Central Hypoventilation syndrome (CCHS). Hirschsprung disease is a genetic condition with autosomal dominant, autosomal recessive, and multigenic patterns of inheritance described. The goal of the research study is to identify genes harboring causative HSCR mutations and to better understand the complex inheritance of HSCR in families using whole genome mapping and sequencing studies with functional follow-up of candidate genes and variants. We intend to ascertain the frequency with which mutations in any human gene lead to familial and isolated forms of HSCR. Clinical information is collected to allow investigation of possible genotype - phenotype correlations. The subject population consists of individuals diagnosed with HSCR and their unaffected relatives. Individuals/families are ascertained through support groups, web-based listings of research studies and genetic testing services, an educational study website, and referrals from genetic counselors and physicians. Blood, or tissue, samples are requested from affected individuals and their unaffected relatives.

  Study phs000497

• ATAC-seq in hiPSC-derived neurons after BDNF and KCl stimulations

  Brain-Derived Neurotrophic Factor (BDNF) is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. Molecular mechanisms of BDNF promoting cellular survival and synaptic plasticity have been intensely studied, yet its role in genome regulation is obscure. Using human induced pluripotent stem cell (hiPSC)-derived neurons via lentiviral delivery of the neuronal transcription factor Ngn2, we performed a temporal profiling (1h, 6h and 10h) of chromatin accessibility upon BDNF treatment or depolarization (KCl) to identify BDNF-specific chromatin-to-gene expression programs.

  Dataset EGAD00001009100

• RNA and ChIP Sequencing datasets from the study Kalirin-RAC controls nucleokinetic migration in ADRN-type neuroblastoma

  This dataset contains the RNA and ChIP Sequencing data from the study Kalirin-RAC controls nucleokinetic migration in ADRN-type neuroblastoma. The data is organized in 7 experiments which are divided by both sequencing technology or the application of siRNA or drug interventions (or lack thereof) on neuroblastoma cell lines. The experiment names and the file names have been chosen in each respective experiment to guide future users of the data to replicate the analyses in the manuscript.

  Dataset EGAD00001006964

• Genomic analysis of pancreatic neuroendocrine tumour with MEN1, ATRX, or DAXX mutations

  This dataset includes 52 samples from 19 individuals with pancreatic neuroendocrine tumours. These samples were analyzed using RNA-sequencing, whole-exome sequencing, shallow (~0.3x) whole-genome sequencing, and a 21-gene panel targeted capture sequencing. Everything was sequenced using the Illumina HiSeq and is provided in BAM or FASTQ format.

  Dataset EGAD00001006001

• Sleep Heart Health Study (SHHS-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.Related StudiesParent cohort phenotype data can be accessed through ARIC-BioLINCC, Framingham-BioLINCC, and CHS-BioLINCC. Objectives To determine the cardiovascular and other consequences of sleep-disordered breathing and to test whether sleep-disordered breathing is associated with an increased risk of coronary heart disease, stroke, all-cause mortality and hypertension by examining subjects from well-characterized and established epidemiologic cohorts. Background Obstructive sleep apnea syndrome (OSA) is a potentially debilitating condition characterized by repetitive episodes of apnea while asleep, nocturnal oxygen desaturation, excessive daytime sleepiness, and loud disruptive snoring. Epidemiologic data from middle-aged adults indicate that OSA is common, with prevalence rates of 4% in men and 2% in women. Prior studies implicated OSA as a risk factor for the development of hypertension, ischemic heart disease, congestive heart failure, stroke and consequently premature death. Questions arose as to whether an increased propensity for cardiovascular and cerebrovascular diseases was limited to only those with frank OSA or whether more subtle forms of sleep-disordered breathing (SDB) would also confer elevated risk. Further evidence was also needed to clarify whether, SDB, including OSA, is an independent risk factor for the development of cardiovascular or cerebrovascular disease. Known cardiovascular and cerebrovascular disease risk factors such as obesity and smoking are commonly present in those with SDB; therefore, apparent associations between SDB and cardiovascular and cerebrovascular diseases may have resulted from the effects of these concomitant risk factors. Moreover, there was no understanding as to whether such factors as race, age, gender, and prevalent cardiovascular or cerebrovascular disease might interact with SDB to alter future cardiovascular and cerebrovascular disease risk. Mechanisms underlying any propensity to develop cardiovascular or cerebrovascular disease with SDB had not been firmly established (Quan, et al., 1997, PMID: 9493915). Participants Participants in SHHS were recruited from nine existing NHLBI epidemiological studies in which data on cardiovascular risk factors had been collected previously. The “parent” cohorts included: Two sites of the Atherosclerosis Risk in Communities Study (ARIC) Three sites of the Cardiovascular Health Study (CHS) The Framingham Offspring Cohort The Strong Heart Study (SHS) sites in South Dakota, Oklahoma, and Arizona The New York Hypertension Cohorts The Tucson Epidemiologic Study of Airways Obstructive Diseases and the Health and Environment Study From these parent cohorts, a sample of participants who met the inclusion criteria (age 40 years or older; no history of treatment of sleep apnea; no tracheostomy; no current home oxygen therapy) was invited to participate in the baseline examination of the SHHS, which included an initial polysomnogram (SHHS-1). Several cohorts over-sampled snorers in order to increase the study-wide prevalence of sleep-disordered breathing. In all, 6441 individuals were enrolled between November 1, 1995 and January 31, 1998. During exam cycle 3 (January 2001-June 2003), a second polysomnogram (SHHS-2) was obtained in 3295 of the participants. Due to sovereignty issues, Strong Heart Study participants are not included in the shared SHHS data. Data from a total of 5839 participants (1920 ARIC, 1249 CHS, 997 Framingham Offspring and OMNI 1, and 1673 from other studies), consenting to share data are available. Design The Sleep Heart Health Study added in-home polysomnography to the data collected in each of the parent studies at a baseline SHHS exam and a follow-up approximately 4 years later. Using the Compumedics PS polysomnograph, sleep studies were obtained in an unattended setting, usually in the homes of the participants, by trained and certified technicians. The recording montage consisted of: C3/A2 and C4/A1 EEGs, sampled at 125 Hz right and left electrooculograms (EOGs), sampled at 50 Hz a bipolar submental electromyogram (EMG), sampled at 125 Hz thoracic and abdominal excursions (THOR and ABDO), recorded by inductive plethysmography bands and sampled at 10 Hz "airflow" detected by a nasal-oral thermocouple (Protec, Woodinville, WA), sampled at 10 Hz finger-tip pulse oximetry (Nonin, Minneapolis, MN) sampled at 1 Hz ECG from a bipolar lead, sampled at 125 Hz for most SHHS-1 studies and 250 Hz for SHHS-2 studies Heart rate (PR) derived from the ECG and sampled at 1 Hz body position (using a mercury gauge sensor) ambient light (on/off, by a light sensor secured to the recording garment)This montage provides data on the occurrence of sleep-disordered breathing, sleep stages, heart rate, oximetry and on arousals. Each participant in the parent studies was also asked to complete the Sleep Habits Questionnaire which covers usual sleep pattern, snoring, and sleepiness.

  Study phs003637

• Combined Targeting of CDK4/6 and HER2 Signaling in Orthotopic Patient-Derived Xenografts of HER2-Positive Breast Cancer Brain Metastases

  Patients with metastatic HER2-positive (HER2+) breast cancer will frequently develop brain metastases (BCBMs). Here, we report that p16INK4A, a tumor suppressor, is deficient in the majority of HER2+ BCBMs. Furthermore, p16INK4A deficiency, as measured by protein immunohistochemistry, can be a predictive marker associated with response to combined treatment with tucatinib and abemaciclib in our orthotopic patient-derived xenografts (PDXs) models of HER2+ BCBMs. Our findings provide the rationale for a biomarker-driven clinical trial of combined treatment with CDK4/6- and HER2-targeted agents for patients with HER2+ BCBM.  

  Study phs002482

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

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

  Study phs003160

• DONSON encodes a novel replication fork protection factor mutated in microcephalic dwarfism.

  To ensure efficient genome duplication, cells have evolved a multitude of factors that promote unperturbed DNA replication, and protect, repair and restart damaged forks. Here we identify DONSON as a novel fork protection factor, and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a component of the replisome that stabilises forks during normal genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype. In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

  Study EGAS00001002224

• CTCF/cohesin-binding sites are frequently mutated in cancer

  Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin frequently colocalizes with CTCF (CCCTC-binding factor), affecting genomic stability, expression and epigenetic homeostasis. Cohesin subunits are mutated in cancer, but CTCF/cohesin-binding sites (CBSs) in DNA have not been examined for mutations. Here we report frequent mutations at CBSs in cancers displaying a mutational signature where mutations in A•T base pairs predominate. Integration of whole-genome sequencing data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data identified frequent point mutations at CBSs. In contrast, CRCs showing an ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase ɛ (POLE) displayed significantly fewer mutations at and adjacent to CBSs. Analysis of public data showed that multiple cancer types accumulate CBS mutations. CBSs are a major mutational hotspot in the noncoding cancer genome.

  Study EGAS00001003010

• Combined gene expression and digital pathology identifies molecular mediators of T cell exclusion and immune suppression in ovarian cancer

  Close proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what determines the spatial distribution of T cells in the tumour microenvironment is not well understood. Coupling digital pathology and transcriptome analysis on a large ovarian tumour cohort, we develop a machine learning approach to molecularly classify and characterize tumour-immune phenotypes. Our study identifies two important hallmarks characterizing T cell excluded tumours: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFb and activated stroma. Furthermore, we identify TGFb as a key mediator of T cell exclusion. TGFb reduces MHC-I expression in ovarian cancer cells in vitro; TGFb also activates fibroblasts and induced extracellular matrix (ECM) production as a potential physical barrier to hinder T cell infiltration. Our findings indicate that targeting TGFb may represent a promising strategy to overcome T cell exclusion and improve clinical benefits of cancer immunotherapy.

  Study EGAS00001003487

• Small_molecule_inhibitors_in_melanoma___Kenski___Kong___WES

  Small-molecule inhibitors targeting the most commonly activated pathway in melanoma, MAPK pathway (either alone or in combination) are already given to melanoma patients for few years, and initially reduce tumour burden dramatically, eventually melanomas become resistant and tumours progress while on treatment. Resistance to this treatment occurs by acquisition of additional mutations or other alterations that affect the mitogen-activated protein kinase (MAPK) pathway by either direct or indirect signalling. Many resistance mechanisms somehow lead to reactivation of extracellular signal-regulated kinase (ERK), thereby restoring signalling of the oncogenic BRAF/MEK/ERK pathway. In addition, PI3K pathway activation contributes to resistance to BRAF inhibition. Less frequent but equally important to the phenomenon of targeted drug resistance is the observation that B15–20% of BRAF mutant melanoma patients fail to respond to BRAF inhibition already early on treatment, owing to intrinsic resistance. These patients have little therapeutic options, unless immunotherapy can be given. To better understand the resistance mechanisms in MAPK inhibitor-treated melanoma patients and melanoma biology, our lab generated a big panel of MAPK inhibitor resistant melanoma cell lines by continuous drug exposure. The understanding of the genetic landscape and gene expression as well as cross resistance to other treatment regimens, and other aspects of melanoma biology such as phenotype switch, will allow us to better exploit new therapeutic strategies for melanoma patients.

  Study EGAS00001002863

• Comprehensive Genomic Characterization of Translocation Renal Cell Carcinoma

  Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the TFE3 gene on chromosome Xp11.2 and a partner gene on either chrX or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics uniquely constrains somatic chrX alterations and underlies cancer sex differences.This version of the dbGaP study provides a comprehensive set of whole genome data and tables with clinical information collected for the 16 patients (15 pateints as tRCC and 1 patient as ccRCC) in the study cohort. The data also contains 12 RNA-seq samples used in the study and analyses. We anticipate that this data will considerably advance our molecular and genetic understanding of oncogenic translocations in TFE3-tRCC involving inactive chromosome X and its role in cancer sex bias.

  Study phs003008

• Whole genome sequencing (bam files) of 5 samples of myxofibrosarcoma and 5 matched pairs

  Myxofibrosarcoma (MFS) is a rare subtype of sarcomas in the elderly, whose genetic basis is poorly understood. To elucidate it, the whole genome sequence was performed.

  Dataset EGAD00001007825

• Single cell transcriptomic analysis of the immune cell compartment in the human small intestine and in Celiac disease

  Celiac disease is an autoimmune disorder in which ingestion of dietary gluten triggers an immune reaction in the small intestine leading to destruction of the lining epithelium. Current treatment focusses on lifelong adherence to a gluten-free diet. Gluten-specific CD4+ T cells and cytotoxic intraepithelial CD8+ T cells have been proposed to be central in disease pathogenesis. Here we use unbiased single-cell RNA-sequencing and explore the heterogeneity of CD45+ immune cells in the human small intestine. We show altered myeloid cell transcriptomes present in active celiac lesions. CD4+ and CD8+ T cells transcriptomes show extensive changes and we define a natural intraepithelial lymphocyte population that is reduced in celiac disease. We show that the immune landscape in Celiac patients on a gluten-free diet is only partially restored compared to control samples. Altogether, we provide a single cell transcriptome resource that can inform the immune landscape of the small intestine during Celiac disease.

  Study EGAS00001003751

• Genomic Psychiatry Cohort (GPC) Whole Genome Sequencing and Genotyping Study

  The Center for Genomic Psychiatry at the University of Southern California (USC), SUNY Downstate and an extensive network of academic medical centers have created the Genomic Psychiatry Cohort (GPC). The GPC consists of a large clinical cohort of patients with schizophrenia, bipolar disorder, and healthy controls. The data generation of genotyping and whole genome sequencing of the GPC has been done in collaboration with the USC and the Broad Institute of MIT and Harvard. Genome-wide association studies are being performed with the samples to identify genetic risks for psychiatric disease. Genotyping is also being used to determine ancestry informative markers and replication of candidate genes. Whole genome sequencing identifies functional variants associated with disease risk.

  Study phs001020

• Tissue Site

  Tissue site for RNAsequencing data. Tissue site is associated with the clinical biomarker data and be linked to the biomarker data using the SAMPLE and PAT identifiers.

  Dataset EGAD50000000931

• CYPTAM - PacBio SMRT sequencing

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

  Dataset EGAD00001005972

• Single-cell analysis for metastatic gastric adenocarcinoma

  Intra-tumoral heterogeneity (ITH) is the fundamental property of cancer, however, the origins of ITH remain poorly understood. Here we performed single-cell RNA sequencing of peritoneal carcinomatosis (PC) from patients with advanced gastric adenocarcinoma (GAC), constructed a transcriptome map of 45,048 PC cells, profiled the transcriptome states of diverse tumor cell lineages and types, incisively explored ITH of PC tumor cells, and identified significant correlates with patient survival.

  Study EGAS00001004443

• Whole genome sequencing with linked reads of pediatric glioblastoma samples

  Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand mechanisms of tumor evolution in this cancer, we performed whole genome sequencing with linked reads on longitudinally resected pGBM samples. Our analyses showed that all diagnostic and recurrent samples were collections of genetically diverse subclones. Clonal composition rapidly evolved at recurrence, with less than 8% of non-synonymous single nucleotide variants being shared in diagnostic-recurrent pairs. In order to track the origins of the mutational events we observed in pGBM, we generated whole genome datasets for two patients and their parents. These trios showed that genetic variants could be (i) somatic, (ii) inherited from a healthy parent, or (iii) arose de novo in the germlines of pGBM patients. Analysis of variant allele frequencies supported a model of tumor growth involving slow-cycling cancer stem cells that give rise to fast-proliferating progenitor-like cells and to non-dividing cells. Interestingly, radiation and anti-mitotic chemotherapeutics did not increase overall tumor burden upon recurrence. These findings support an important role for slow-cycling stem cell populations in contributing to recurrences, since slow-cycling cell populations are expected to be less prone to genotoxic stress induced by these treatments and to accumulate few mutations. Our results highlight the need for new targeted treatments that account for the complex functional hierarchies and genomic heterogeneity of pGBM.

  Study EGAS00001003432

• Atypical 3q26/MECOM rearrangements genocopy inv(3)/t(3;3) in acute myeloid leukemia

  Acute myeloid leukemia (AML) with inv(3)/t(3;3)(q21q26) is a distinct WHO recognized entity, characterized by its aggressive course and poor prognosis. In this subtype of AML, the translocation of a GATA2 enhancer (3q21) to MECOM (3q26) results in overexpression of the MECOM isoform EVI1 and monoallelic expression of GATA2 from the unaffected allele. The full-length MECOM transcript, MDS1-EVI1, is not expressed as the result of the 3q26 rearrangement. Besides the classical inv(3)/t(3;3), a number of other 3q26/MECOM rearrangements with poor treatment response have been reported in AML. Here we demonstrate, in a group of 33 AML patients with atypical 3q26 rearrangements, MECOM involvement with EVI1 overexpression, but no or low MDS1-EVI1 levels. Moreover, the 3q26 translocations in these AML patients often involve super-enhancers of genes active in myeloid development (e.g. CD164, PROM1, CDK6 or MYC). In more than 50% of these cases allele specific GATA2 expression was observed, either by copy number loss or by an unexplained allelic imbalance. Altogether, atypical 3q26 recapitulate the main leukemic mechanism of inv(3)/t(3;3) AML, namely EVI1 overexpression driven by enhancer hijacking, absent MDS1-EVI1 expression and potential GATA2 involvement. Therefore, we conclude that both atypical 3q26/MECOM and inv(3)/t(3;3) can be classified as a single entity of 3q26-rearranged AMLs. Routine analyses determining MECOM rearrangements, EVI1 and MDS1-EVI1 expression are required to recognize 3q-rearranged AML cases.

  Study EGAS00001004325

• Genetic Basis of Developmental Disabilities

  Developmental disabilities are birth defects that cause lifelong problems with how a body part or system works. Developmental disabilities include nervous system insults affecting how the brain, spinal cord and nervous system function; they cause intellectual disability, including Down syndrome and fragile X syndrome; and they also cause learning and behavioral disorders, such as autism spectrum disorders. At the Kennedy Krieger Institute, approximately 450 inpatients and 13,000 outpatients are seen per year (involving 114,000 visits). For most of these disorders, the underlying molecular cause has not been identified. Some, such as chromosomal disorders, have a strongly genetic basis while others, such as traumatic brain injury, are caused by environmental insults but are nonetheless influenced by the genetic background. The purpose of the present study is to identify chromosomal abnormalities underlying a variety of developmental disabilities. The approach is to obtain blood and saliva from children, and from one or both biological parents (and in some cases from siblings and/or additional relatives). Genomic DNA is purified and assayed on single nucleotide polymorphism (SNP) microarrays and/or by sequencing, including whole genome sequencing. These technologies provide high resolution information about chromosomal changes, and the information provided by the parental (and other relatives') DNA allows an interpretation of whether changes in a child are inherited or occur de novo. The study design includes multiple data analysis procedures to interpret the biological significance of findings of chromosomal changes relative to a child's parents, relative to children with similar diagnoses, relative to children with other chromosomal anomalies, and (in some cases) relative to the chromosomal status of siblings. We will further interpret the significance of the findings relative to the general (apparently normal) population by obtaining publicly available data from apparently normal individuals.

  Study phs000337

• Germline Genomic Analyses of Breast Cancer in Latinas

  In this case-control study of breast cancer among Hispanic/Latina (H/L) women, the goals were to identify breast cancer susceptibility genes and genetic variants for risk of developing breast cancer in H/L women. There were two phases with whole exome sequencing (WES) done in a discovery phase and targeted sequencing of candidate genes in the replication phase. The candidate genes selected for replication came from the first phase and from genes known to affect breast cancer risk in prior studies. Cases and controls were drawn from several studies. Breast cancer cases for discovery phase included women from the City of Hope (COH) Clinical Cancer Genomics Community Research Network (CCGCRN), UCSF Cancer Genetics Clinic and USC Cancer Genetics clinic. Controls for discovery phase included women who did not have breast and were recruited through City of Hope community fairs. A separate group of controls included women from the California Teachers Study. Additional controls for discovery were obtained from WES already generated by the Multi-ethnic cohort (MEC) study. The discovery/WES results of known breast cancer genes were published (PMID 31206626). In the replication phase, we included cases and controls from the Cancer de Mama (CAMA) study which is a case-control study of breast cancer in Mexico, MEC for those not included in the discovery dataset, the San Francisco Bay Area Cancer study (phs000912), the Northern California Breast Cancer Registry, and the California Pacific Medical Center Research Institute Women's Cohort (phs000395). Cases from the PATHWAYS study who were recruited from Northern California Kaiser Permanente were also included. Results from the combined discovery and replication analyses are reported in PMID 36747679.

  Study phs003144

• Mutational signature in colorectal cancer induced by genotoxic pks+ E. coli

  Various species of the intestinal microbiota have been associated with the development of colorectal cancer (CRC), yet a direct role of bacteria in the occurrence of oncogenic mutations has not been established. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin. This compound alkylates DNA on adenine residues and induces double strand breaks in cultured cells. Here, we exposed human intestinal organoids to genotoxic pks+ Escherichia coli by repeated luminal injection over a period of 5 months. Whole genome sequencing (WGS) of clonal organoids before and after this exposure reveals a distinct mutational signature, absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature is detected in a subset of 3668 human metastatic cancer genomes, predominantly in a subset of CRC cases. Our study describes a distinct mutational signature in CRC and implies that the underlying mutational process directly results from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.

  Study EGAS00001003934

• Whole Genome Sequencing Consortium on Frontotemporal Dementia With Underlying TDP-43 Pathology

  Frontotemporal lobar degeneration (FTLD) is one of the leading causes of dementia in individuals younger than 65 years. The FTLD symptoms of most patients are not yet explained by mutations in the known FTLD genes (C9orf72, GRN, MAPT). Identifying genetic risk associated with the disease is key for developing disease models and new therapeutic avenues. We performed short-read whole-genome sequencing (WGS) on 19 neuropathologically normal individuals and 560 patients with FTLD, including 171 pathologically confirmed FTLD patients, 352 clinically diagnosed FTLD patients, and 37 autosomal dominant FTLD patients. Pathologically confirmed FTLD patients include FTLD with TDP43 inclusions (FTLD-TDP) and FTLD with FUS inclusions (FTLD-FUS), autosomal dominant FTLD patients include GRN (FTLD-TDP GRN) and C9ORF72 (FTLD-TDP C9ORF72) mutation carriers, clinically diagnosed patients include behavioral variant of frontotemporal dementia (bvFTD), frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS), frontotemporal dementia with corticobasal syndrome (FTD-CBS), semantic variant of primary progressive aphasia (svPPA), and non-fluent variant of primary progressive aphasia (nfvPPA).

  Study phs003309

• Upper cortical layer-driven network impairment in schizophrenia

  Schizophrenia is one of the most wide-spread and complex mental disorders. To characterize the impact of schizophrenia, we performed single nucleus RNA sequencing (snRNA-seq) of >220,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls. Additionally, >115,000 neurons were analyzed topographically by immunohistochemistry. Compositional analysis of snRNA-seq data revealed a reduction in abundance of GABAergic neurons and a concomitant increase in principal neurons, most pronounced for upper cortical layer subtypes, which was substantiated by histological analysis. Many neuronal subtypes showed extensive transcriptomic changes, the most dramatic - in upper layer GABAergic neurons, including downregulation in energy metabolism and upregulation in neurotransmission. Transcription factor network analysis demonstrated a developmental origin of transcriptomic changes. Finally, Visium spatial transcriptomics further corroborated upper layer neuron vulnerability in schizophrenia. Overall, our results point towards general network impairment within upper cortical layers as a core substrate associated with schizophrenia symptomatology. Study is available on bioRxiv (https://doi.org/10.1101/2020.11.17.386458) and in upcoming publication.

  Study EGAS00001006495

• Sant Joan de Déu Research Institute (IRSJD)

  Sant Joan de Déu Research Institute (IRSJD) institutional Data Access Committee. The objective of the DAC is to manage, review and assess datasets access requests. The DAC is managed by the Knowledge Management Unit, and an adhoc committee per dataset will be formed to take into consideration each access request. Contact the Knowledge Management Unit at gestio.coneixement@sjd.es

  Dac EGAC50000000253

• Comparison of the performance of two commercial genome-wide association study genotyping platforms in Han Chinese Samples

  Affymetrix 6.0, Illumina OMNIExpress, and llumina Immunochip genotype data for Han Chinese population including rheumatoid arthritis cases and controls. Data is in PLINK binary format. Illumina genotype clustering was performed using Illumina’s BeadStudio software. SNPs were reclustered using the study samples, low quality subjects were removed, and a subset of clustering results were manually inspected and verified. All SNPs with GenCall scores less than 0.15 were excluded. For Affymetrix chips, clustering was performed using the program Birdseed version 2, as implemented using Affymetrix Genotyper Console v4.0, using the default quality control (QC) thresholds.

  Study EGAS00000000131

• Blood plasma and paired genomic DNA from neuroblastoma patients

  The dataset is comprised of 3 blood plasma samples (Patient 1-3_plasma_cfDNA) paired with genomic DNA (Patient 1-3_tumor gDNA) from the corresponding primary neuroblastoma from three patients. For all these samples whole-exome sequencing (WES) data have been generated.

  Dataset EGAD00001006012

• Quantitative analysis of a novel DNA hypermethylation panel using bronchial specimen for lung cancer diagnosis

  The dataset includes IDAT raw files for 10 samples and the analyzed DMP file which describes the differential methylation positions based on Illumina Infinium MethylationEPIC BeadChip. All samples (5 lung cancer cases vs. 5 benign lung disease controls) were obtained from bronchial washings at the site of the lesion under bronchoscopy manipulation. The histological type of the five lung cancer cases is adenocarcinoma and squamous cell carcinoma.

  Dataset EGAD00010002465

• Validation of a Haloplex platform for targeted re-sequencing of the exons of 25 genes

  We recently used the Agilent SureSelect platform to re-sequence a set of genes known to be mutated in human AML. The results from 10 AML DNA samples were very satisfactory, but the effort required was significant. Thus, we decided to re-sequence the same genes using the Haloplax system for target enrichment in 48 AML samples. We planned to do this using MiSeq and have data from a pilot of 3 samples. The data is promising but coverage appears pathcy so far. However, in order to get a better understanding of the data we will need deeper sequencing. We will need two lanes of HiSeq to get the same degree coverage as Sureselect. his 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 EGAD00001000603

• Whole Genome Sequencing of Neuroblastoma

  Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour1. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%)2-5. Here we present a whole genome sequence analysis of 87 neuroblastoma of all stages. Only few recurrent amino-acid changing mutations were found. In contrast, analysis of structural defects identified in 18% of high stage neuroblastoma a local shredding of chromosomes, known as chromothripsis6. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization7-9. In addition, ATRX, TIAM1 and a series of regulators of the Rac Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumors with defects in these genes were aggressive high stage neuroblastoma, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromotripsis and neuritogenesis gene alterations, which frequently occur in high risk tumors.

  Study EGAS00001000222

• NeoPAL study - RNAseq and Targeted DNA sequencing data

  This dataset is composed of 159 RNAseq data (fastq, bam and count tables) and 35 targeted DNAseq data (fastq).

  Dataset EGAD50000001490

• MGA-NUTM1 fusion in high grade spindle cell sarcoma Data

  There is a total of 4 sample data (2 WGS and 2 RNAseq) belong to 2 patient deposited in this study.

  Dataset EGAD00001004479

• Phylogenetic development of childhood tumours

  The aim of this study is to reconstruct the phylogenetic development of childhood tumours

  Dataset EGAD00001005770

• Clonality of circulating tumor cells in breast cancer brain metastases patients

  The incidence of brain metastases in breast cancer (BCBM) patients is increasing. These patients have a very poor prognosis and therefore identification of blood-based biomarkers, such as circulating tumor cells (CTCs) and understanding the genomic heterogeneity could help to personalize treatment options. In this study, DNA from individual CTCs as well as corresponding primary tumors and brain metastases were analyzed by next generation sequencing (NGS) in order to evaluate copy number aberrations and single nucleotide variations (SNVs).

  Dataset EGAD00001005020

• Development of the prevention and therapy of CRC using patient derived culture tissues.

  Tumor tissues consist of functionally heterogeneous cells including those with high clonogenic potential called cancer stem cells (CSCs) which produce differentiated non-tumorigenic progenies. Transplantation assays have been performed to identify cell surface markers in solid tumors including colorectal cancers, which identified several CSC markers such as CD133 and CD44. In addition to the transplantation, the lineage tracing of genetically labelling cells in animal models of cancer qhas been employed to explore the cellular heterogeneity of tumors by identifying the CSCs and its progenies. This approach is particularly useful to investigate solid tumors, where cellular proliferation and differentiation are controlled by niche factors and cell-cell contact with adjacent cells. Lineage tracing of mouse model of cancer unravel the mode of growth of autochthonous tumor in their native environment. In this study, we used patient derived organoids (PDO) established from surgically resected CRC patients to identify the CSC. Single cell RNA-seq analysis identified potential CRC markers, which may exhibit self-renewal activity and produce progenitors

  Study JGAS000139

• Genomic and transcriptomic landscape of T-cell lymphoblastic lymphoma compared to T-cell acute lymphoblastic leukemia: similar subtypes and different fusions

  Due to the lower incidence of T-LBL and difficulties in obtaining diagnostic T-LBL material, extensive research on T-LBL has been hampered whereas genetic aberrations in T-ALL are thoroughly characterized. Given the similarities and differences between T-LBL and T-ALL, the question has been raised whether T-LBL and T-ALL represent two different diseases or different manifestations of the same disease. This study aims to identify the genomic and transcriptomic landscape of T-LBL and compare the findings to what is found T-ALL. Comparison of the molecular aberrations between T-LBL and T-ALL can provide insights into the overlap and differences in malignant development between the two entities, which could lead to improved risk stratification in T-LBL in order to eventually adapt T-LBL treatment protocols based on molecular-genetic prognostic factors.

  Study EGAS00001007767

• Single cell transcriptomic and genomic profiling of carcinogenesis in patients with familial adenomatous polyposis

  Familial Adenomatous Polyposis (FAP) is characterized by hundreds to thousands of adenocarcinomas at different evolutional stages in the colon and rectum. Much effort has been made to illuminate the key genomic alterations that facilitate the transition from adenoma to carcinoma. However, the strong heterogeneity of the tumors may hamper these efforts. Here, by sequencing matched adjacent normal tissues, adenomas at different stages and carcinomas from the same patient, we precisely traced the process of colorectal carcinogenesis. Our study offers an accurate genomic landscape during the initiation and progression of carcinogenesis, especially for the transition between adenomas and carcinomas.

  Study EGAS00001003598

• SardiNIA Medical Sequencing Discovery Project

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

  Study phs000313

• 'Targeted High Throughput Sequencing in Clinical Cancer Settings: Formaldehyde fixed-paraffin embedded (FFPE) tumor tissues, input amount and tumor heterogeneity'

  "Background: Massively parallel sequencing technologies have brought an enormous increase in sequencing throughput. However, these technologies need to be further improved with regard to reproducibility and applicability to clinical samples and settings. Methods: Using identification of genetic variations in prostate cancer as an example we address three crucial challenges in the field of targeted re-sequencing: Small nucleotide variation (SNV) detection in samples of formalin-fixed paraffin embedded (FFPE) tissue material, minimal amount of input sample and sampling in view of tissue heterogeneity.Results: We show that FFPE tissue material can supplement for fresh frozen tissues for the detection of SNVs and that solution-based enrichment experiments can be accomplished with small amounts of DNA with only minimal effects on enrichment uniformity and data variance. Finally, we address the question whether the heterogeneity of a tumor is reflected by different genetic alterations, e.g. different foci of a tumor display different genomic patterns. We show that the tumor heterogeneity plays an important role for the detection of copy number variations, but is of minor importance for the detection of somatic variations.Conclusions: The application of high throughput sequencing technologies in cancer genomics opens up a new dimension for the identification of disease mechanisms. In particular the ability to use small amounts of FFPE samples available from surgical tumor resections and histopathological examinations facilitates the collection of precious tissue materials. However, care needs to be taken in regard to the locations of the biopsies taken, which can have an influence on the prediction of copy number variations. Bearing these technological challenges in mind will significantly improve many large-scale sequencing studies and will - on a long-range - result in a more reliable prediction of individual cancer therapies."

  Study EGAS00001000136

• Single cell and spatial transcriptomics of adult human adrenal glands

  The data set is composed of single cell transcriptomics data for adrenal glands from 11 deceased organ donors (10x 3') and spatial transcriptomic data for adrenal glands from 4 deceased organ donors (10x Visium).

  Dataset EGAD50000000394

• Ribosome profiling shows variable sensitivity to detect open reading frames for conventional and different types of cryptic T cell antigens

  The aim of the study was to explore the sensitivity of ribosomal profiling to detect ORFs for cryptic antigens targeted by T cells in immune responses. Ribosomal profiling was performed for six EBV-LCLs. Detection of conventional and cryptic MiHA-encoding ORFs was compared. The data showed that open reading frames (ORFs) for conventional MiHAs as well as cryptic MiHAs in upstream ORFs were frequently detected with similar sensitivity. However, only a limited number of MiHAs in in reading frames alternative to protein-coding sequences and no ORFs derived from long non-coding RNAs were detected. In conclusion, Ribo-seq for identification of antigen-encoding ORFs is useful to screen for cryptic antigens in upstream ORFs as potential targets for immunotherapy.

  Study EGAS50000000322

• Molecular biomarkers in progression from refractory celiac disease to the lethal cancer variety enteropathy associated T cell lymphoma (EATL)

  Enteropathy associated T cell lymphoma (EATL) is frequently preceded by a state of refractoriness to the gluten-free diet, called “refractory celiac disease” or RCD. We aim to study which mutations and copy number aberrations are already manifest in RCD and to identify differences between RCD patients that do, and do not, develop EATL. We have applied whole exome sequencing to detect mutations and copy number aberration predictive for progression from RCD to EATL.

  Study EGAS00001006669

• Comparison of transcriptional response of induced pluripotent stem (iPS) cell-derived and monocyte-derived macrophages to bacterial lipopolysaccharide stimulation

  In the first part of this project, we will differentiate IPS cells from 5 human donors into macrophages, and extract RNA from unstimulated and LPS stimulated macrophages to perform RNA sequencing. We will also extract RNA before and after stimulation in blood- derived macrophages from 5 additional, unrelated healthy samples. In the second part of the project, RNA-seq data will be analysed to compare LPS response of these two macrophage populations. In summary, we will perform 75bp PE RNA-seq on 20 samples (10 pre and post stimulus), on the HiSeq 2500 platform. Samples will be multiplexed at 5 samples / lane, so we will require 4 flow cells in total.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 EGAD00001001106

• MutaSeq data for A.10-12

  MutaSeq was applied to CD34+ cells from patient samples A.10, A.11 and A.12 of the study. The protocol followed is described in https://doi.org/10.1038/s41467-021-21650-1 and in the methods of the manuscript

  Dataset EGAD00001010189

• Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial

  The IMagyn050 trial (NCT03038100), which evaluated the efficacy of Atezo vs placebo (Pla) with carboplatin, paclitaxel and bevacizumab (CPB) in front line ovarian cancer patient (pts), did not meet its co-primary endpoints of PFS in ITT or PD-L1+ (Moore et al. JCO 2021). The aim of this exploratory study was to evaluate whether patients with BRCA1/2-mutated or homologous recombination-deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial. Methods: Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. PD-L1 status of tumor-infiltrating immune cells was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious BRCA1/2 alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay. HRD was defined as gLOH ≥16%, regardless of BRCA1/2 mutation status. Potential associations between progression-free survival (PFS) and genomic biomarkers were evaluated using standard correlation analyses and log-rank of Kaplan-Meier estimates. Results Among biomarker-evaluable samples, 22% (234/1050) harbored BRCA1/2 mutations and 46% (446/980) were HRD. Median TMB was low irrespective of BRCA1/2 or HRD. Only 3% (29/1024) had TMB ≥10 mut/Mb and 0.3% (3/1022) were MSI-high. PFS was better in BRCA2-mutated versus BRCA2-non-mutated tumors and in HRD versus proficient tumors. PD-L1 positivity (≥1% expression on immune cells) was associated with HRD but not BRCA1/2 mutations. PFS was not improved by adding atezolizumab in BRCA2-mutated or HRD tumors; there was a trend toward enhanced PFS with atezolizumab in BRCA1-mutated tumors. Conclusion Most ovarian tumors have low TMB despite BRCA1/2 mutations or HRD. Neither BRCA1/2 mutation nor HRD predicted enhanced benefit from atezolizumab. This is the first randomized double-blind trial in ovarian cancer demonstrating that genomic instability triggered by BRCA1/2 mutation or HRD is not associated with improved sensitivity to immune checkpoint inhibitors.

  Study EGAS00001006838

• Androgen activity in the normal male embryonic hindbrain drives lethal PFA ependymoma

  PFA ependymoma is an unusual infantile brain tumor with few somatic mutations, thought to be driven by epigenetic mechanisms. PFA ependymomas have a markedly higher incidence, and a worse prognosis in males as compared to female infants. Here we show that the cellular hierarchy of male PFA is less differentiated than female PFA. Androgen supplementation promotes the growth of PFA ependymoma. We conclude that androgen signaling in both the normal developing hindbrain, and PFA ependymoma are both necessary and sufficient to promote growth and delay differentiation.

  Study EGAS50000000507

• Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

  Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

  Study EGAS00001000942

• Resolution and methylation patterns of supernumerary marker chromosomes

  Herein we study the structure of ring and marker chromosomes in 10 carriers. The aim is to gain understanding of the formation and function of ring and marker chromosomes.

  Study EGAS50000001466

• Adipose tissue macrophage dysfunction is associated with a breach of vascular integrity in NASH

  Our study describes for the first time the myeloid cell landscape in human visceral adipose tissue at single-cell level within a cohort of well-characterized patients with non-alcoholic fatty liver disease.

  Study EGAS50000000424

• Investigation of a method for generating cells for regenerative medicine using comprehensive nucleic acid analysis of iPS cell-derived cardiomyocytes.

  Regenerative medicine for heart failure is expected to restore cardiac function by using human iPS cells (hiPSCs). In our laboratory, it was shown that transplantation of cardiomyocytes (CMs) derived from hiPSCs into a pig model of myocardial infarction improves the disease condition. However, the instability of differentiation efficiency and tumorigenicity after transplantation are still issues to be resolved. We attempt to identify and analyze the genes and DNA methylation associated with the induction of differentiation of hiPSCs into CMs with the aim of achieving stable induction of CMs differentiation. Furthermore, we aim to analyze genes involved in tumorigenesis in CMs, and to develop a predictive marker for tumorigenesis to ensure the safety of cells before transplantation.

  Study JGAS000665

• APOBEC Mutagenesis, Kataegis, Chromothripsis in EGFR-Mutant Osimertinib-Resistant Lung Adenocarcinomas

  Expanding on studies investigating apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis in histological transformation of epidermal growth factor receptor (EGFR)-mutant lung cancers, it has been hypothesized that mutational signature analysis may help better understand acquired resistance to targeted therapies. Using mutational signature analysis in Receptor Tyrosine Kinase (RTK) driven lung adenocarcinomas, more specifically EGFR mutant lung cancer, APOBEC dominant mutational signatures were noted more frequently in subclonal post Tyrosine Kinase Inhibitor (TKI) treatment biospecimen samples and in the presence of large-scale genomic rearrangements. This is hypothesized to be due to the pressure of treatment with TKIs; a fact that should be further explored and can be potentially manipulated in order to overcome drug resistance.

  Study phs003812

• Mapping Genotypes to Chromatin Accessibility Profiles in Single Cells

  In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1–3. Therefore, somatic mutations likely alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. To chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed Genotyping of Targeted loci with single-cell Chromatin Accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution, across thousands of cells within a single assay. We applied GoT-ChA to CD34+ cells from myeloproliferative neoplasm (MPN) patients with JAK2V617F-mutated hematopoiesis.

  Study EGAS50000000164

• Population Architecture using Genomics and Epidemiology (PAGE)

  PAGE II (2013-2017) seeks to expand understanding gained during PAGE I and similar studies of how ancestry-specific differences in allele frequencies and LD may explain differences in risks of common traits and conditions. Recent studies have identified rare genetic variants that are likely to contribute to common diseases and traits and observed that rare variants likely to be functional, such as those in coding and regulatory regions, tend to be population-specific. PAGE II has genotyped over 50,000 samples using MEGA, an Illumina high density custom exomechip array. The MEGA data is being imputed in PAGE to the 1000 Genomes panel. PAGE also sequenced 1,000 samples representative of 21 populations from the Americas. PAGE has harmonized phenotype data for ~300 trait variables. These datasets will be analyzed to continue emphasis on characterizing population-level disease risks in non-European-descent individuals. Cohorts in PAGE II are: CALiCo (Causal Variants Across the Life Course, a consortium of ARIC, CARDIA, HCHS/SOL, Strong Heart Studies), ISMMS (Mount Sinai BioMe Biobank), MEC (Multiethnic Cohort), WHI (Women's Health Initiative), and Stanford University (PAGE Global Reference Panel). Genotyping services were provided by the Center for Inherited Disease Research (CIDR) and sequence data were provided by the McDonnell Genome Institute at Washington University School of Medicine. PAGE I (2008-2013): The first phase of PAGE examined putative causal genetic variants across approximately 100,000 African Americans, Asian Americans, American Indians, European Americans, Hispanic Americans, and Native Hawaiians from four groups representing nine large U.S.-based cohorts. Two genotyping approaches were employed - targeted genotyping of selected SNPs identified in genome-wide association studies of common disease, and a large-scale effort focused on the Metabochip array, which facilitated trans-ethnic fine mapping of several diseases of public health importance. Cohorts in PAGE I were: CALiCo (Causal Variants Across the Life Course, a consortium of ARIC, CARDIA, CHS, HCHS/SOL, Strong Heart Cohort Study, Strong Heart Family Study), EAGLE (Epidemiologic Architecture for Genes Linked to Environment, based on 3 National Health and Nutrition Examination Surveys (NHANES)), MEC (Multiethnic Cohort) and WHI (Women's Health Initiative). Logistical and scientific support is provided by the PAGE Coordinating Center and the NHGRI Division of Genomic Medicine. PAGE II is funded by the NHGRI and the NIMHD. To access PAGE studies currently available in dbGaP, please click on the links below.Please note that some PAGE studies belong to larger cohorts and have been included as PAGE substudies. For those studies, there is an additional link to the parent study. phs000223 PAGE-ARIC and phs000280 ARIC Cohort phs000236 PAGE-CARDIA and phs000285 CARDIA Cohort phs000301 PAGE-CHS and phs000287 CHS Cohort phs000559 PAGE-EAGLE-BioVu phs000208 PAGE-EAGLE-NHANES phs000555 PAGE-HCHS/SOL and phs000810 HCHS/SOL Cohort phs000220 PAGE-MEC phs000580 PAGE-SHS and SHFS phs001033 PAGE Global Reference Panel phs000227 PAGE-WHI and phs000200 WHI Cohort

  Study phs000356

• Comparison Across Multiple Types of Sleep Deprivation

  This study is designed to assess neurobehavioral performance, as well as molecular and physiological changes associated with variations in timing and quantity of sleep. Gene expression changes associated with neurobehavioral (cognitive) performance were assessed in a time-series among individuals randomly assigned to four separate sleep conditions during a 10-day inpatient study: a well-rested control, sleep restriction with nighttime sleep, sleep restriction with daytime sleep to roughly simulate shiftwork schedules, and total (acute) sleep deprivation.

  Study phs003924

• Bulk and RIP-seq transcriptome datasets from skin fibroblasts in PTBP1- and PTBP2-related disorders

  PTBP1- and PTBP2-related disorders are rare human conditions that cause variable neurodevelopmental phenotypes, including intellectual disability and behavioral problems such as autism spectrum disorder, anxiety, aggressiveness, and attention disorders, with or without hyperactivity. PTBP1-related disorder is also associated with skeletal dysplasia. In this study, we generated bulk RNA sequencing and RNA immunoprecipitation sequencing (RIP-seq) data from skin fibroblasts obtained from patients and healthy controls.

  Study EGAS50000001210

• Single-cell RNA sequencing of 6 follicular lymphoma tumors

  Follicular lymphoma (FL) is an indolent cancer of mature B-cells but carries increased risk of transformation to a more aggressive histology over time. We present here comprehensive profiling both tumor and immune compartments in 6 diagnostic FL biopsies by single-cell RNA sequencing. This confirmed results from 155 FL tumors characterized by mass cytometry (CyTOF) which revealed two distinct evolutionary trajectories with disparate risk of transformation and alternate biologies.

  Study EGAS00001005257

• RNA sequencing of Korean ER positive breast cancer females aged under 35 years old.

  Corresponding data set is composed of RNA sequencing of Korean ER positive breast cancer under 35 years old. This set provides 50 alignment files of 50 tumor samples. This is a part of total project data set.

  Dataset EGAD00001003243

• Regions of common inter-individual DNA methylation differences in human monocytes.

  Based on whole genome bisulfite sequencing of five human monocytes from unrelated individuals, we have identified regions of common inter-individual DNA methylation differences, where methylation is inversely correlated with active histone marks, but not with the expression of the associated genes. Genome-wide association studies in 1128 individuals show that allelic DNA methylation is caused by genetic variation in cis. At some loci, DNA methylation appears to be affected also by genetic variation in trans.

  Study EGAS00001002265

• Epigenetic profiling of human CD4+ memory T cells reveals their proliferative history and argues in favor of a progressive differentiation model driven by epigenetically controlled master regulators.

  A key element of adaptive immunity is the development of long-lived memory cells, which protect against recurring infection by providing a highly enriched pool of antigen-specific cells ready to react to the pathogen. Different classes of memory T cells occur upon primary activation of naive T cells, however, their detailed differentiation pathway is not entirely clear. As part of the IHEC consortium, we generated genome-wide epigenetic maps of a number of CD4+ T cell memory (Tmem) stages including rare subsets such as terminally differentiated (TEMRA) and bone marrow-resident Tmem. We found that CD4+ T cells show progressive global DNA demethylation with differentiation into memory stages, which reflects their proliferative history and likely indicates their decline in differentiation and proliferation potential. Furthermore, transcriptomic profiling combined with co-regulation network analyses arranged different Tmem subsets into a successive differentiation pathway. In addition, we identified a number of epigenetically controlled candidate master regulators for Tmem formation, of which we functionally validated a new methylation-sensitive promoter for the known 'naive-keeper' transcription factor Foxp1. Our study highlights the power of epigenomic datasets in the elucidation of the cellular history but also of the functional potential of T cell populations including the identification of epigenetically controlled master regulators.

  Study EGAS00001001624

• Identification of RNA biomarkers in Parkinson's disease patients

  Parkinson?s disease (PD) is an age-related, chronic and progressive neurodegenerative disorder characterized by a loss of dopaminergic neurons and subsequent motor symptoms. These overt motor symptoms are often preceded by prodromal non-motor symptoms. Though a number of genetic and environmental factors have been identified to play a role in PD, more exact methods for both diagnosing and assessing prognosis are yet to be discovered. By analyzing the transcriptome of early-stage PD patients, this study aims to identify genes (including important non-coding RNAs) and pathways altered at disease onset that may be used as novel biomarkers for PD diagnosis as well as potential new drug targets. The study consists of three main sources of data: first year blood transcriptomes, second year blood transcriptome and matched neural stem cell (NSC)/neuron transcriptomes. All transcriptome libraries were synthesized and sequenced using no-amplification non-tagging cap analysis of gene expression (nAnT-iCAGE) on the Illumina HiSeq 2500 platform. Resulting data was mapped to the human genome annotation (hg38), processed CAGE tags were clustered ready for differential expression analyses. First year blood sequencing consisted of 22 PD patients and 10 healthy controls across four lanes. In the second year, a further four lanes were sequenced containing 17 PD patients (12 patients from the first year and 5 new patients) along with 10 healthy controls and 5 first year blood samples matching the new second year patients.

  Study JGAS000119

• Whole Exome Sequencing of Congenital Diaphragmatic Hernia Patients and Trios

  Congenital diaphragmatic hernia (CDH) is a common and severe birth defect characterized by structural defects of the diaphragm and by pulmonary hypoplasia. Congenital diaphragmatic hernia patient may present either as an isolated phenotype or together with other congenital anomalies in a complex phenotype. Despite the clinical significance of CDH, the underlying genetic and developmental pathways are incompletely understood. In order to establish a catalog of human genetic variation for this condition, we performed whole exome sequencing (WES) on 275 carefully phenotyped individuals with CDH in the Pediatric Surgical Research Laboratories at the Massachusetts General Hospital (Boston, MA, USA) and Boston Children's Hospital (Boston, MA, USA). The exome data generated are valuable for comparison of candidate genes derived from WES of other CDH cohorts or affected kindreds, and to provide ideal candidates for further functional studies with the ultimate goal of enhancing our understanding of the heterogeneous and, possibly, oligogenic molecular etiology of CDH. While familial clustering has been reported in rare kindreds, the majority of probands with CDH have no family history of CDH leading to the hypothesis that de novo variants are an important and relatively frequent etiological mechanism. In the second version of the study, we performed WES analysis on 87 trios, to assess the contribution of de novo mutations in the etiology of diaphragmatic and pulmonary defects and to identify previously unknown candidate genes. This dbGaP submission includes WES data on: (a) 20 new probands, (b) 9 probands also reported in the previous version (dbGaP accession no. phs000783.v1.p1), (c) 174 unaffected parents, including the parents of 67 previously reported probands. Combined analysis with other available cohorts of congenital diaphragmatic hernia revealed a genome-wide enrichment of likely gene-disrupting de novo variants (i.e., nonsense, frameshift or splice site), and missense de novo variants predicted in silico to be damaging.

  Study phs000783

• Analysis of copy number variation landscape of glioma by shallow coverage whole genome sequencing

  We reported shallow coverage whole genome sequencing (WGS) is an economic method for identification of whole genome somatic copy number variation (SCNV). Combining with a Taqman low density array (TLDA) designed for molecular subtyping of glioma, it enabled classification of glioma into biological entities with different cellular origin and genomic alterations. Further, we also showed shallow-coverage WGS enabled systematic identification of clonal and subclonal SCNV in glioma genomes and the burden and pattern of SCNV can serve as an objective marker of tumor progression and predict risk and relapse.

  Study EGAS00001003690

• Metabolic and molecular consequences of the TBC1D4 p.Arg684Ter variant in human skeletal muscle

  Skeletal muscle of Inuit homozygous carriers of the common Greenlandic TBC1D4 p.Arg684Ter variant is severely insulin resistant but have normal metabolic responses during exercise,

  Study EGAS50000000040

• Exome sequencing of synchronous colorectal cancers

  Approximately 4% of colorectal cancer (CRC) patients have at least two simultaneous cancers in the colon. Due to the shared environment, these synchronous CRCs (SCRCs) provide a unique setting to study colorectal carcinogenesis. Understanding whether these tumors are genetically similar or distinct is essential when designing therapeutic approaches. We performed exome sequencing of 47 primary cancers and corresponding normal samples from 23 patients. Additionally, we carried out a comprehensive mutational signature analysis to assess whether tumors had undergone similar mutational processes and the first immune cell score analysis (IS) of SCRC to analyze the interplay between immune cell invasion and mutation profile in both lesions of an individual. The tumor pairs shared only few mutations, favoring different mutations in known CRC genes and signaling pathways, and displayed variation in their signature content. Two tumor pairs had discordant mismatch repair statuses. In majority of the pairs, IS varied between primaries. Differences were not explained by any clinicopathological variable or mutation burden.

  Study EGAS00001003474

• Mind Body Study: A Sub-Study on Psychosocial Factors and Microbiomes of Nurses in the Nurse's Health Study II

  The Mind-Body Study is a sub-study of the Nurses' Health Study II (NHSII) which investigated associations between biomarkers and psychosocial factors. The prevalences of clinically meaningful depressive symptoms, mild-to-severe anxiety symptoms, experiencing major-life discrimination, and food addiction were 19%, 21%, 30%, and 5% respectively. These participants were more likely to have experienced childhood abuse and take psychotropic medications but less likely to have chronic conditions such as diabetes and hypertension than participants in the larger NHSII cohort. Participants (n = 213, mean age = 60.6) provided one or two separate stool samples for microbiome profiling between 2013 and 2014, and completed two online psychosocial assessments 10 months apart. The participants also completed two 30-day FFQs around the two microbiome collections. There was excellent reproducibility of psychosocial factors over 1 year. Moderate-to-strong positive correlations were observed between markers of distress and between positive psychosocial factors such as mindfulness and optimism. Here, the subjects' metadata including phenotypic and diet covariates have been provided. Microbial DNA sequence data from the stool microbiome collections is provided via Sequence Read Archive (SRA).

  Study phs003786

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

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

  Study EGAS00001004327

• Wellcome Trust Sanger Institute

  Access to individual-level genotype data is available by application to the MalariaGEN Independent Data Access Committee. Access to data will be granted to qualified investigators for appropriate use. For further information information on data release policy and data access application form, please follow the link below.

  Dac EGAC00000000002

• Human tumour ChIP-seq.

  We profiled 16 patient tumour samples by ChIP-seq. H3K27ac and Input are provided for 16 samples and H3K27me3 is provided for 14 samples. Among the 16 samples, 9 are G34WT and 7 are G34R/V. The raw fastq or bam files are provided.

  Dataset EGAD00001006100

• Analysis of T-cell receptor clonotypes in tumor micro-environment identifies shared cancer type-specific signatures

  Despite the conventional view that a truly random V(D)J recombination process should generate a highly diverse immune repertoire, emerging reports suggest that there is a certain bias towards the generation of shared/public immune receptor chains. These studies were performed in viral diseases where public T-cell receptors (TCR) appear to confer better protective responses. Selective pressures generating common TCR clonotypes are currently not well understood but it is believed that they confer a growth advantage. As very little is known about public TCR clonotypes in cancer, here we set out to determine the extent of shared TCR clonotypes in the intra-tumor microenvironments of virus- and non-virus- driven head and neck cancers using TCR sequencing. We report that tumor-infiltrating T-cell clonotypes were indeed shared across individuals with the same cancer type, where the majority of shared sequences were specific to the cancer type (ie viral versus non-viral). These shared clonotypes were not particularly enriched in EBV-associated nasopharynx cancer, but in both cancers, exhibited distinct characteristics, namely shorter CDR3 lengths, restricted V- and J-gene usages and also demonstrated convergent V(D)J recombination. Many of these shared TCRs were expressed in patients with a shared HLA background. Pattern recognition of CDR3 amino acid sequences revealed strong convergence to specific motifs that were unique to each cancer type, suggesting they may be enriched for specificity to common antigens found in the tumor microenvironment. The identification of shared TCRs in infiltrating tumor T-cells not only adds to our understanding of the tumor adaptive immune recognition but could also serve as disease-specific biomarkers and guide the development of future immunotherapies.

  Study EGAS00001005480

• Reference exome data for Australian Aboriginal populations from Western Australia and the Northern Territory

  Here we provide a catalogue of variants called after sequencing the exomes of 50 Aboriginal individuals from the Northern Territory (NT) of Australia and compare these to 72 previously published exomes from a Western Australian (WA) population of Martu origin. Sequence data for both NT and WA samples were processed using an ‘intersect-then-combine’ (ITC) approach, using GATK and SAMtools to call variants. The data is provided as 2 VCF files, one for the WA population and one for the NT population.

  Dataset EGAD00001005189

• Small Intestine Neuroendocrine Tumors (Carcinoid Tumors)

  The diagnosed incidence of small bowel neuroendocrine tumors (NETs) is increasing. While patients with localized disease can be treated surgically, those with metastatic disease currently have few treatment options. The success of biologically targeted therapies in other malignancies has led to interest in the molecular alterations underlying the pathogenesis of these NETs. To identify genetic aberrations in small intestine NETs, we generated copy number profiles from 31 primary and metastatic tumors and performed whole-exome sequencing on a subset of 29 primary small intestine NETs and 24 metastatic NETs in parallel with normal blood DNA. Whole-genome sequencing data was generated on 15 tumor/normal pairs and 5 primary/metastasis/normal trios. The global genetic landscape of small bowel NETs is relatively quiet. Consistent with previous studies, the overwhelming majority of tumors were characterized by loss of chromosome 18 and, to a lesser extent, other chromosome arm gains and losses. In stark contrast to arm-level alterations, recurrent high-level focal amplifications and deletions were much less prevalent in these tumors. High-throughput mutation screening and exome sequencing revealed similarly low rates of somatic mutation in NETs (median of 0.77 non-silent mutations per megabase (Mb) of coding DNA) compared to other recent cancer exome sequencing efforts. Our analysis of this cohort identified only a single, statistically significant recurrent somatic mutation targeting the cyclin-dependent kinase inhibitor gene, CDKN1B, encoding p27.

  Study phs000579

• Whole Genome and Exon Capture Sequencing of Bladder Cancers

  One primary bladder cancer and paired peripheral blood sample were subjected to whole genome sequencing on an Illumina HiSeq 2000 platform. This technology was utilized to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations found was a loss-of-function mutation in TSC1 (Tuberous Sclerosis Complex 1), a regulator of mTOR pathway activation. Targeted sequencing using an exon capture and sequencing assay was performed on 13 tumors derived from patients on the same everolimus trial as the index patient and the sequencing data from these tumors is included. TSC1 mutation status was correlated with response to everolimus. The index patient responder tumor and peripheral blood DNA were also subjected to exon capture and sequencing.

  Study phs000535

• Sequence data to study genomic CNVs that drive apoptotic resistance and relapses on immune checkpoint inhibitors

  This project investigates the genomic mechanisms underlying acquired resistance to immune checkpoint inhibitors (ICIs) across tumor types, addressing the critical clinical problem of treatment relapses where the molecular basis remains poorly understood. Through integrative genomic analyses of longitudinal clinical melanomas, functional CRISPR-Cas9 screens, and human and murine melanoma models, the study demonstrates that copy-number variant (CNV)-driven subclonal evolution is a primary driver of clinical relapses. The research identifies resistance-driver genes targeted by CNVs, including pro-apoptotic gene deletions and anti-apoptotic gene amplifications, which collectively downregulate apoptotic priming in resistant cells. The findings establish that modulating the apoptotic threshold can prevent or reverse ICI resistance, positioning CNV evolution as a key driver of acquired resistance and identifying apoptotic regulation as a therapeutic target to combat resistance evolution.

  Study EGAS50000001055

• BLUEPRINT DNA Methylation 450K data of mantle cell lymphoma

  We have applied an analytic strategy to decipher the DNA methylome of 86 mantle cell lymphomas (MCL) in light of the methylome of the entire B-cell lineage. In this way, we first identified two MCL subgroups that respectively carry epigenetic imprints of pre- and post-germinal center B cells. Secondly, we observed that pure tumor-specific changes are rare, as most (89-99%) DNA methylation alterations in MCL are within or in close proximity of those regions showing dynamic methylation in normal B cells. Several thousand of these differentially methylated regions in MCL show concurrent changes in enhancer-associated histone modifications, including a region located 650 Kb away from the MCL oncogene SOX11. At the clinical level, epigenetic and genetic changes co-evolve during MCL progression and the magnitude of epigenetic changes is associated with overall survival of the patients.

  Study EGAS00001001637

• POPCOL: population-based colonoscopy.

  PopCol is a cohort study in Stockholm, Sweden that includes a data-rich set of individuals with data available from bowel symptoms questionnaires, gastroenterology visits and biospecimens (genotype and 16S sequencing from blood and stool samples, respectively). Genotyping was carried out using the Illumina HumanOmniExpressExome-8v1 arrays at the SciLifeLab NGI facility in Uppsala, Sweden. Fecal DNA was extracted from samples kept at -80°C using Qiagen 5 QIAamp DNA Stool Mini Kits and analyzed using 16S rRNA gene amplicon sequencing (in the V1-V2 hypervariable region). This was performed on the Illumina MiSeq platform at the Institute of Clinical Molecular Biology (IKMB) in Kiel, Germany. Of these, six PopCol participants were PPI users and 12 used antibiotics. The study was approved by the local Committee of Research Ethics (Forskningskommitté Syd) at Karolinska Institutet, Stockholm, in November 2001. Written informed consent was obtained from all participants

  Study EGAS00001004869

• Women's Health Initiative Clinical Trial and Observational Study

  The Women's Health Initiative (WHI) is a long-term national health study that has focused on strategies for preventing heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women. The original WHI study included 161,808 postmenopausal women enrolled between 1993 and 1998. The Fred Hutchinson Cancer Research Center in Seattle, WA serves as the WHI Clinical Coordinating Center for data collection, management, and analysis of the WHI. The WHI has two major parts: a partial factorial randomized Clinical Trial (CT) and an Observational Study (OS); both were conducted at 40 Clinical Centers nationwide. The CT enrolled 68,132 postmenopausal women between the ages of 50-79 into trials testing three prevention strategies. If eligible, women could choose to enroll in one, two, or all three of the trial components. The components are: Hormone Therapy Trials (HT): This double-blind component examined the effects of combined hormones or estrogen alone on the prevention of coronary heart disease and osteoporotic fractures, and associated risk for breast cancer. Women participating in this component with an intact uterus were randomized to estrogen plus progestin (conjugated equine estrogens [CEE], 0.625 mg/d plus medroxyprogesterone acetate [MPA] 2.5 mg/d] or a matching placebo. Women with prior hysterectomy were randomized to CEE or placebo. Both trials were stopped early, in July 2002 and March 2004, respectively, based on adverse effects. All HT participants continued to be followed without intervention until close-out. Dietary Modification Trial (DM): The Dietary Modification component evaluated the effect of a low-fat and high fruit, vegetable and grain diet on the prevention of breast and colorectal cancers and coronary heart disease. Study participants were randomized to either their usual eating pattern or a low-fat dietary pattern. Calcium/Vitamin D Trial (CaD): This double-blind component began 1 to 2 years after a woman joined one or both of the other clinical trial components. It evaluated the effect of calcium and vitamin D supplementation on the prevention of osteoporotic fractures and colorectal cancer. Women in this component were randomized to calcium (1000 mg/d) and vitamin D (400 IU/d) supplements or a matching placebo. The Observational Study (OS) examines the relationship between lifestyle, environmental, medical and molecular risk factors and specific measures of health or disease outcomes. This component involves tracking the medical history and health habits of 93,676 women not participating in the CT. Recruitment for the observational study was completed in 1998 and participants were followed annually for 8 to 12 years. Extension Studies: The original protocol allowed for follow-up until March 2005, after which participants were invited to enroll in the first WHI Extension Study for follow-up through 2010. Participants were invited again to participate in the second WHI Extension Study with continued follow up from 2010 to at least 2015. As of March 31, 2011 there were 93,122 women enrolled in the second extension. In Extension Study 2, the overall WHI study population was divided into two new subsamples, the Medical Records Cohort (MRC) and the Self-Report Cohort (SRC). The MRC consists of all former hormone trial participants and all African American and Hispanic participants from all study components. The SRC consists of the remaining participants. The extent of outcome information collected differs between the two cohorts, with more extensive outcomes information collection on the MRC. As part of Extension Study 2, selected older WHI participants were invited to participate in an In Person Visit (a.k.a., Long Life Study) at their homes during which additional blood samples were collected and various measurements were taken (such as blood pressure, height, weight, waist circumference, grip strength, etc.). In October 2015, Extension Study 2 was renewed with continued follow-up planned through October 2020, pending annual contract review and renewal. Additional Information: The WHI website, https://www.whi.org/about/SitePages/About%20WHI.aspx has much more information about the study. For WHI data collection forms used over the years, please see https://www.whi.org/researchers/studydoc/SitePages/Forms.aspx. For additional dataset documentation, see https://www.whi.org/researchers/data/Pages/Available%20Data.aspx. For data preparation and use, please refer to 'WHI dbGaP Cohort Data Release Data Preparation Guide May 2018' for additional details about the WHI data. The WHI Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" box located on the right hand side of this top-level study page phs000200 WHI Cohort. phs000386 WHI SHARe phs000281 GO-ESP WHISP phs000315 WHI GARNET phs000503 WHISE phs000227 PAGE WHI phs000675 WHIMS+ phs000746 WHI Harmonized and Imputed GWAS phs001334 WHI Metabolomics of CHD phs001335 WHI BA23 phs001614 WHI LLS Phase III GWAS

  Study phs000200

• Multimodal plasma and urinary cell-free DNA profiling improves risk stratification in newly diagnosed prostate cancer

  Prostate cancer (PCa) is a heterogeneous disease, impeding early detection and risk stratification. Liquid biopsies (LBx) enable minimally invasive tumor profiling, but circulating tumor-derived DNA (ctDNA) detection remains difficult, particularly in early-stage PCa. We developed a multimodal LBx approach combining genomic and epigenomic cell-free DNA (cfDNA) features in plasma and urine from newly diagnosed PCa patients to improve early characterization of PCa and risk stratification of aggressive disease. Plasma and urine samples from 55 localized PCa (lPCa) patients, 18 advanced PCa (aPCa) patients, and 36 cancer-free controls were subjected to low-coverage whole-genome sequencing and methylated DNA immunoprecipitation sequencing to assess fragmentation, chromosomal instability, and methylation in cfDNA. This complementary approach yielded a 45% ctDNA detection rate in newly diagnosed PCa. Major differences were observed between aPCa and controls, reflecting increasing signals with tumor progression. Epigenomic cfDNA features differentiated lPCa from aPCa, and ctDNA was detected in 46% of PCa patients with prostate-specific antigen <10 ng/ml, suggesting potential for risk stratification. This study highlights the value of multimodal LBx approaches for early characterization of primary PCa and identification of aggressive disease at initial diagnosis. Integration into clinical workflows could complement diagnostics and support personalized decision-making tailored to patients’ PCa risk profiles. 

  Study EGAS00001008195

• High Altitude Pulmonary Hypertension

  The Central Asian Kyrgyz highland population provides a unique opportunity to address genetic diversity and understand the genetic mechanisms underlying hypoxia-induced high altitude pulmonary hypertension (HAPH). While a significant fraction of the population is unaffected, there are susceptible individuals who display HAPH in the absence of any lung, cardiac or hematologic disease. We report herein the analysis of the whole genome sequencing of healthy individuals compared with HAPH patients and other controls. In this study, 34 male individuals from Central Asian Kyrgyz highland are sequenced with Illumina HiSeq 2000 with mean-coverage of 30X.

  Dataset EGAD00001004308

• An isoform quantitative trait locus in SBNO2 links genetic susceptibility to Crohn’s disease with defective antimicrobial activity

  Despite major advances in linking single genetic variants to single causal genes, the significance of genetic variation on transcript-level regulation of expression, transcript-specific functions, and relevance to human disease has been poorly investigated. Strawberry notch homolog 2 (SBNO2) is a candidate gene in a susceptibility locus with different variants associated with Crohn’s disease and bone mineral density. The SBNO2 locus is also differentially methylated in Crohn’s disease but the functional mechanisms are unknown. Here we show that the isoforms of SBNO2 are differentially regulated by lipopolysaccharide and IL-10. We identify Crohn’s disease associated isoform quantitative trait loci that negatively regulate the expression of the noncanonical isoform 2 corresponding with the methylation signals at the isoform 2 promoter in IBD and CD. The two isoforms of SBNO2 drive differential gene networks with isoform 2 dominantly impacting antimicrobial activity in macrophages. Our data highlight the role of isoform quantitative trait loci to understand disease susceptibility and resolve underlying mechanisms of disease. This dataset contains RNAseq raw data from CD14+ monocyte-derived macrophages and siRNA-mediated knockdown experiments, as well as RNAseq raw data from THP-1 monocytes-derived macrophages following ectopic expression of SBNO2 isoforms.

  Dataset EGAD50000000264

• Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and is Associated with Worse Outcomes

  Small-cell lung cancer (SCLC) is a very aggressive neuroendocrine lung cancer often associated with oncogenic MYC amplifications, which are known to drive SCLC heterogeneity marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states. The genetic mechanisms of MYC amplification and phenotypic plasticity between cell states is not known. Using data from cell-lines and a few patient-derived samples along with integrated whole-genome sequencing, long-range optical mapping, single-cell DNA sequencing, and fluorescence in situ hybridization, we have attempted to successfully characterize extrachromosomal DNA (ecDNA) as the primary source of MYC amplifications and driver fusions in SCLC.

  Study phs003190

• Whole genome sequencing data from paired tumor and normal tissue in a cohort of NSCLC patients.

  WGS data for paired tumor and normal tissue from 260 patients in the TRACERx ctDNA study. The patient cohort is comprised of NSCLC patients undergoing surgical resection of their tumour. The patients were then followed up for a median of ~5 years after surgery, and serial blood samples were collected. The WGS data here was generated to inform the manufacture of custom ctDNA panels.

  Dataset EGAD50000001693

• GenomeDenmark Phase 2 - whole genome variants called using BayesTyper

  Variants and genotypes called in 50 danish parent-offspring trios from 80x Illumina sequencing data using BayesTyper. Data was produced using different insert size libraries of the sizes 180, 500, 800, 2000, 5000, 10000 and 20000 bp. The sample IDs for the fathers and mothers are TrioID-01 and TrioID-02, respectively, and the IDs for the children are TrioID-0x, where x is a number between 3 and 7

  Dataset EGAD00001003188

• Indexing Genes Impacted by Copy Number Variation in Developmental Disorders

  A challenge in clinical genomics is to predict whether copy number variation (CNV) affecting a gene or multiple genes will manifest as disease. Increasing recognition of gene dosage effects in neurodevelopmental disorders prompted us to develop a computational approach based on critical-exon (highly expressed in brain, highly conserved) examination for potential etiologic effects. Using a large CNV dataset, our updated analyses revealed significant (P < 1.64 x 10-15) enrichment of critical-exons within rare CNVs in cases compared to controls. Separately, we used a weighted gene co-expression network analysis (WGCNA) to construct an unbiased protein module from prenatal and adult tissues and found it significantly enriched for critical exons in prenatal (P < 1.15 x 10-50, OR = 2.11) and adult (P < 6.03 x 10-18, OR = 1.55) development. WGCNA yielded 1,206 proteins for which we prioritized the corresponding genes as likely to have a role in neurodevelopmental disorders. We compared the gene lists obtained from critical-exon and WGCNA analysis and found 438 candidate genes associated with CNVs annotated as pathogenic, or variants of uncertain significance (VOUS), from among 10,619 developmental delay cases. We identified genes containing CNVs previously considered to be VOUS, to be new candidate genes for neurodevelopmental disorders (GIT1, MVB12B and PPP1R9A) demonstrating the utility of this strategy to index the clinical effects of CNVs. Reprinted from Uddin et al, 2016, with permission from Scientific Reports.

  Study phs001154

• WES of probands in KLB project

  These are the vcf files of exome sequencing of the two probands who were found to harbor mutations in KLB. Sample: EGAN00001564799 is the proband 1; Sample: EGAN00001564800 is the proband 11 in the KLB paper. Exome capture was performed using the SureSelect All Exon capture (Agilent Technologies, Santa Clara, CA USA) and sequenced on the HiSeq2500 (Illumina, San Diego CA USA).

  Dataset EGAD00001003463

• Whole-Exome Sequencing and Targeted DNA Sequencing of Matched Ocular Melanocytosis and Uveal Melanoma

  Ocular melanocytosis is the most important predisposing condition for the eye cancer uveal melanoma (UM). Here we used whole-exome and deep targeted sequencing to identify for the first time a clonal Gq pathway mutation in ocular melanocytosis, which gave rise to UM. Additionally, we elucidated the order in which canonical genetic aberrations were acquired during tumor evolution. These findings provide a mechanistic explanation for the well-known clinical association of ocular melanocytosis with UM, and they provide new insights into UM tumor evolution. Reprinted from: Durante MA, Field MG, Sanchez MI, Covington KR, Decatur CL, Dubovy SR, Harbour JW. Genomic evolution of uveal melanoma arising in ocular melanocytosis, with permission from Cold Spring Harbor Molecular Case Studies.

  Study phs001835

• Analysis of the B cell receptor repertoire in six immune-mediated diseases

  Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn’s disease, Behçet’s disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and—in particular—isotype use. An increase in clonality in systemic lupus erythematosus and Crohn’s disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune- mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.

  Dataset EGAD00001005431

• Quantification of chromosomal copy number aberrations by shallow whole-genome sequencing

  Detection of DNA copy number aberrations by shallow whole-genome sequencing (WGS) faces many challenges including lack of completion and errors in the human reference genome, repetitive sequences, polymorphisms, variable sample quality, and biases in the sequencing procedures.Formalin-fixed paraffin-embedded (FFPE) archival material, the analysis of which is important for studies of cancer, presents particular analytical difficulties due to degradation of the DNA and frequent lack of matched reference samples. We present a robust, cost-effective WGS method for DNA copy number analysis that addresses these challenges more successfully than currently available procedures. In practice very useful profiles can be obtained with 0.1 fold genome coverage. We improve on previous methods by; first, implementing a combined correction for sequence mappability and GC content, and second, applying this procedure to sequence data from the 1000 Genomes Project in order to develop a blacklist of problematic genome regions. A small subset of these blacklisted regions were previously identified by ENCODE, but the vast majority are novel unappreciated problematic regions. Our procedures are implemented in a pipeline called QDNAseq. We have analyzed over 1,000 samples, most of which were obtained from the fixed tissue archives of over 25 institutions.We demonstrate that for most samples our sequencing and analysis procedures yield genome profiles with noise levels near the statistical limit imposed by read counting. The described procedures also provide better correction of artifacts introduced by low DNA quality than prior approaches, and better copy number data than high-resolution microarrays at substantially lower cost.

  Study EGAS00001000642

• Cryptic Splice Mutation in the Fumarate Hydratase Gene in Patients With Clinical Manifestations of Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)

  Four patients with hysterectomy were evaluated for biochemical and molecular evidence of autosomal dominant Fumarate Hydratase (FH) alterations causing Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). HLRCC is an autosomal dominant condition characterized by the development of cutaneous and uterine leiomyomas, and risk for development of an aggressive form of papillary renal cell cancer. Enzyme assay, western blot analyses, direct nanopore RNA sequencing, and whole genome sequencing (WGS) were utilized. The study identified a cryptic splice mutation in intron 9 of the FH gene that results in retention of 57 base pairs of intronic sequence in the affected allele of the mature FH mRNA.

  Study phs003381

• RNA-Seq of human longitudinal whole blood samples from PCR-positive and PCR-negative recent household contacts of COVID-19 index cases.

  Little is known about the transcriptomic profile of individuals who are exposed to SARS-CoV-2 yet resist becoming PCR positive. To investigate this, longitudinal whole-blood samples were taken (0, 7, 14, and 28 days after enrolment) from PCR positive and PCR negative SARS-CoV-2-naïve household contacts who were recently exposed to a COVID-19 index. Samples were also taken from pre- and post-pandemic unexposed controls. Total RNA was extracted from PAXgene tubes before undergoing poly(A) selection followed by globin and rRNA depletion. DNA libraries were constructed using the NEBNext® Ultra™ II Directional RNA Library Prep Kit for Illumina. All samples were then sequenced across 2 flowcells of an Illumina HiSeq 4000.

  Dataset EGAD50000000684

• Full blood mRNA sequencing of myotonic dystrophy type 1 patients after cognitive behavioural therapy

  This dataset consists of 60 mRNA sequencing runs from full blood of 31 myotonic dystrophy type 1 patients, of which for 27 patients reliable data is available before and after 10 months of cognitive behavioural therapy. >30 million 150 bp paired end reads were obtained with UMI-labeled adapters to facilitate filtering of PCR duplicates. Via UMI-analysis we found samples with the aliases sample_01 and sample_02 to contain a very high number of PCR duplicates and recommend the use of these samples only with highest caution or not at all.

  Dataset EGAD00001008383