12291 results for ""statistically+reactive"+taxa+in+microbial+community"

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• Molecular and phenotypic data for patients enrolled in the IMmotion150 trial

  Tumor transcriptome and whole exome sequencing data (matched tumor/normal for somatic mutation calling) along with key phenotypic information are provided for patients enrolled in the phase 2 IMmotion150 trial, assessing efficacy of atezolizumab monotherapy or combination of atezolizumab and bevacizumab versus standard of care (sunitinib) in 1L renal cell carcinoma. This data set accompanies the respective Nature Medicine publication (PMID: 29867230).

  Dataset EGAD00001004183

• RNAseq - Discovery of resistance mechanisms to the BRAF inhibitor vemurafenib in metastatic BRAF mutant melanoma

  We propose to biopsy 20 consented BRAF mutant melanoma patients at Addenbrooke's Hospital pre-treatment with vemurafenib and also upon the development of resistant disease, with the aim of using exome sequence and SNP6 data to identify novel sequence variants and copy number alterations that can be used to validate observed resistance mechanisms in our cell line models and also to use these models to inform as to likely candidate small molecule inhibitors to overcome resistance and that could be tested in the clinical trial setting.

  Dataset EGAD00001001050

• Adenoma development in familial adenomatous polyposis and MUTYH‐associated polyposis: somatic landscape and driver genes

  Familial adenomatous polyposis (FAP) and MUTYH‐associated polyposis (MAP) are inherited disorders associated with multiple colorectal adenomas that lead to a very high risk of colorectal cancer. The somatic mutations that drive adenoma development in these conditions have not been investigated comprehensively. In this study we performed analysis of paired colorectal adenoma and normal tissue DNA from individuals with FAP or MAP, sequencing 14 adenoma whole exomes (eight MAP, six FAP), 55 adenoma targeted exomes (33 MAP, 22 FAP) and germline DNA from each patient.

  Dataset EGAD00001004332

• Chordoma Sequencing Project RNAseq

  This is a continuation of the Chordoma Sequencing Project. All cancers arise due to somatically acquired abnormalities in DNA sequence. Systematic sequencing of cancer genomes allows acquisition of complete catalogues of all classes of somatic mutation present in cancer. These mutation catalogues will allow identification of the somatically mutated cancer genes that are operative and characterise patterns of somatic mutation that may reflect previous exogenous and endogenous mutagenic exposures. In this application, we aim to perform whole genome sequencing on 10 chordoma matched genome pairs. RNA Sequencing/Methylation and SNP6 and an additional sequencing of three cancer cell lines will be added to this work.

  Dataset EGAD00001000653

• Whole genome sequencing libraries from the study "Histological Transformation and Progression in Follicular Lymphoma: a Clonal Evolution Study".

  Whole genome sequencing libraries from the study "Histological Transformation and Progression in Follicular Lymphoma: a Clonal Evolution Study". These are libraries from 41 patients. Specifically: 15 transformed follicular lymphoma (TFL), 6 early progressers (PFL), and 20 non-early progressers (NPFL). For TFL and PFL patients, trios consisting of diagnostic (T1), transformed/progressed (T2) and a matching normal are available (n = 63 libaries in total). For NPFL patients, a tumor-normal pair are available (n = 40 libraries).

  Dataset EGAD00001002897

• Genome and transcriptome sequence data from a colorectal adenocarcinoma patient (Response to Angiotensin Blockade with Irbesartan in a Patient with Metastatic Colorectal Cancer)

  Genome and transcriptome sequence data from a colorectal adenocarcinoma patient, generated as part of the BC Cancer Agency's Personalized OncoGenomics (POG) study. These data are included in the manuscript entitled, "Response to Angiotensin Blockade with Irbesartan in a Patient with Metastatic Colorectal Cancer".

  Dataset EGAD00001001876

• Comprehensive copy number aberration analysis using digital Multiplex Ligation-dependent Probe Amplification (digitalMLPA) in pediatric B-cell precursor acute lymphoblastic leukemia

  In this study a next-generation sequencing based method was applied to comprehensively screen for recurrent, disease-relevant copy number aberrations in a cohort of Hungarian patients. Diagnostic bone marrow samples from 260 children with B-cell acute lymphoblastic leukemia as well as 72 control samples and were investigated by digital multiplex ligation-dependent probe amplification using the disease-specific D007 probemix. Whole chromosome gains and losses, as well as subchromosomal copy number aberrations were simultaneously profiled.

  Dataset EGAD00001010878

• RNA sequencing of CD8 T cells from melanoma patients prior to and during checkpoint immunotherapy and untreated healthy controls

  We are interested in inter-individual variation in transcriptional response to immune checkpoint blockade. We have analysed poly A purified RNA expression from CD8 T cells (297 transcriptomes in total) isolated from metastatic melanoma patients (n=106) prior to and during treatment with either single agent (Pembrolizumab) or combination (Ipilimumab/ Nivolumab) immune checkpoint blockade. We compare expression at different stages of treatment and additionally contrast this with that from healthy controls (n=68).

  Dataset EGAD00001005973

• University of Pennsylvania CAR T Cell Responding and Non-responding Patients

  The adoptive transfer of autologous T cells genetically modified to express a CD19-specific, 4-1BB/CD3zeta-signaling chimeric antigen receptor (CAR; CTL019) has shown remarkable activity in patients with B acute lymphoblastic leukemia. Similar therapy can induce long-term remissions for relapsed/refractory chronic lymphocytic leukemia (CLL) patients, but in only a small subset of subjects. The determinants of response and resistance to CTL019 therapy of CLL are not fully understood. We employed next generation sequencing of RNA (RNA-seq) to identify predictive indicators of response to CTL019 treatment. We performed RNA-seq on leukapheresis and manufactured infusion product T cells from patients with heavily pre-treated and high-risk disease. To characterize potency, we also performed RNA-seq on the cellular infusion product after CAR-specific stimulation. Our findings indicate that durable remission in CLL is associated with gene expression signatures of early memory T cell differentiation (e.g., STAT3), while T cells from poorly- or non-responding patients exhibited elevated expression of key regulators of late memory as well as effector T cell differentiation, apoptosis, aerobic glycolysis, hypoxia and exhaustion. These gene expression signatures, along with additional immunological biomarkers, may be used to identify which patients are most likely to respond to cellular therapies and suggest manufacturing modifications that might potentiate the generation of maximally efficacious infusion products. In a follow-up study, we report multiplex CRISPR-Cas9 gene editing on T cells in humans to test the hypothesis that disrupting genes encoding the endogenous T cell receptor (TCR), TCRα (TRAC) and TCRβ (TRBC), as well as PD-1 (PDCD1) would enhance the efficacy of autologous T cells engineered to express a transgenic NY-ESO TCR. We used single cell RNA-seq to comprehensively characterize the transcriptomic phenotype of this T cell product and its evolution over time in a patient with sarcoma. Notably, this patient's transferred T cells that persisted in vivo demonstrated increases in expression of genes associated with a central memory state (IL7R, TCF7). These findings may guide future trials involving administration of genetically redirected, genome -edited T cells.In this follow-up study, we investigated whether CRISPR-Cas9-mediated disruption of PDCD1 and/or CTLA-4 could restore CART dysfunction in healthy donors and/or CLL patients. We show that depletion of CTLA-4 rescues the function of T cells from leukemia patients that previously failed CART cell treatment. We performed single-cell RNA sequencing and characterized the transcriptomic landscape of CTLA-4 KO CART19 cells that showed higher proliferation and anti-tumor efficacy by permitting unopposed CD28 signaling and maintenance of CAR expression on the T cell surface under stress-test conditions of chronic antigen exposure. Our findings reveal that selective disruption of CTLA-4 invigorates dysfunctional patient T cells, providing a strategy for increasing patient responses to CART cell therapy.

  Study phs001707

• 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

• Resuscitation Outcomes Consortium (ROC) Controlled Study of the Clinical Effectiveness of Automated Real-Time Feedback on CPR Process Conducted at a Subset of ROC Sites (CPR) (ROC-CPR-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives: A substudy of the ROC PRIMED trial, the ROC CPR trial sought to investigate whether real-time audio and visual feedback during cardiopulmonary resuscitation (CPR) outside a hospital increases the proportion of participants who achieved prehospital return of spontaneous circulation.Background: Cardiopulmonary resuscitation is an essential link in the chain of survival for treating cardiac arrest. However, performance of CPR is highly variable both outside hospital and in hospital. Interruptions in chest compression, inadequate depth of chest compression, and high rates of ventilation adversely affect blood flow during chest compressions and can hinder resuscitation. Suboptimal CPR, particularly time spent without chest compressions (low chest compression fraction), can reduce survival of cardiac arrest patients.Current technology incorporated into a monitor-defibrillator can assess core components of CPR through the use of an accelerometer and impedance changes across the defibrillation electrodes. This technology can also provide real-time audiovisual feedback so that the rescuer is prompted to perform according to guideline specifications. Use of such feedback increases the likelihood of performing CPR in accordance with guidelines during training and simulation. Participants: There were 1586 participants: 771 treated without feedback and 815 with feedback.Design: CPR feedback was provided through proprietary Q-CPR software operating in the Philips MRx monitor-defibrillator. The feedback feature of the defibrillator includes audible voice prompts and visual messages on the monitor screen that are triggered when measured chest compressions or ventilation deviate from guidelines or are interrupted.The study was conducted in 21 emergency medical service (EMS) agencies at three ROC regions in the U.S. and Canada. Randomized treatment clusters, which ranged from individual emergency medical vehicles to groups of emergency agencies, were assigned to feedback-on or feedback-off treatments. Each cluster remained in its assigned mode for two to seven months, after which it switched to the opposite treatment arm. At the end of those two treatment periods, each cluster was again randomly assigned to feedback-on or feedback-off. This cycle continued for the duration of the study. Each cluster switched treatment arms at least once, and up to four times, during the study. Conclusions: Real-time visual and audible feedback during CPR altered performance to more closely conform with CPR guidelines. Clusters assigned to feedback were associated with increased proportion of time in which chest compressions were provided, increased compression depth, and decreased proportion of compressions with incomplete release. However, frequency of prehospital return of spontaneous circulation did not differ according to feedback status, nor did the presence of a pulse at hospital arrival, survival to discharge, or awake at hospital discharge (Hostler, et al., 2011, PMID: 21296838).

  Study phs003818

• Women's Health Study Accelerometry Dataset

  Background The Women's Health Study (WHS) was a randomized trial testing low-dose aspirin and vitamin E for preventing cancer and CVD among 39,876 women aged ≥45 years throughout the US from 1992-2004. When the trial ended as planned, women who were willing to participate continued in an observational follow-up study. Participants in Accelerometer Study From 2011-2015, an ancillary study collected data on physical activity and sedentary behavior using accelerometers. Women were mailed a triaxial accelerometer (ActiGraph GT3X+, ActiGraph Corp) with a wear log, and asked to wear this on their hip for seven consecutive days, removing it only during sleep and water-based activities. Further details have previously been published (PMID: 30666321). A total of 17,708 women wore and returned their devices, and data were downloaded from the devices of 17,466 women; no data were available from the other 242 (device failure). By convention, a "valid day" of wear has data on at least 10 hours (PMID: 22698174). Among these 17,466 women, 17,062 had at least one valid day of wear. The data are provided for all 17,062 women. Additionally, "compliant wear" is conventionally defined for participants wearing the device for at least 10 hours, on at least 4 days (PMID: 22698174). Of the 17,062 women, 16,741 had compliant wear (PMID: 29109088). Self-reported Physical Activity and Sedentary Behavior After we received the accelerometer from a WHS participant, she was sent a questionnaire asking her to report the time she spent in different physical activities during the week that the accelerometer was worn (see questionnaire below). A total of 15,514 women (91% of participants in the Accelerometer Study) returned their physical activity questionnaires. In addition, beginning in October 2012, we included questions on sedentary behavior; a total of 9,430 women returned questionnaires that included questions on both physical activity and sedentary behavior.

  Study phs001964

• Population Architecture using Genomics and Epidemiology (PAGE): Multiethnic Cohort (MEC)

  The Multiethnic Cohort (MEC) has established a large biorepository of blood and urine (N=67,000) and cryopreserved lymphocytes (N=15,000) linked to extensive, prospectively collected risk factors (e.g., diet, smoking, physical activity), biomarkers and clinical data for five racial/ethnic groups. This cohort study of over 215,000 men and women in Hawaii and California is unique in that it is population-based and includes large representations of older adults (45-75 yrs at baseline) for five US racial/ethnic groups (Japanese Americans, African Americans, European Americans, Latinos and Native Hawaiians) at varying risks of chronic diseases. Within the PAGE investigation, the MEC proposes to study: 1) diseases for which we have DNA available for large numbers of cases and controls (breast, prostate, and colorectal cancer, diabetes, and obesity); 2) important cancers that are less common (e.g., lung, pancreas, endometrial cancers, NHL) but for which we propose to pool our data with other funded groups; 3) common traits that are risk factors for these diseases (e.g., body mass index/weight, waist-to-hip ratio, height) and 4) relevant disease-associated biomarkers (e.g., fasting insulin and lipids, steroid hormones). The specific aims are: 1) To determine the population-based epidemiologic profile (allele frequency, main effect, heterogeneity by disease characteristics) of putative causal variants in the five racial/ethnic groups in the MEC; 2) for variants displaying effect heterogeneity across ethnic/racial groups, we will utilize differences in LD to identify a more complete spectrum of associated variants at these loci; 3) investigate gene x gene and gene x environment interactions to identify modifiers; 4) examine the associations of putative causal variants with already measured intermediate phenotypes (e.g., plasma insulin, lipids, steroid hormones); and 5) for variants that do not fall within known genes, start to investigate their relationships with gene expression and epigenetic patterns in small genomic studies. This study is part of the Population Architecture using Genomics and Epidemiology (PAGE) study phs000356.

  Study phs000220

• Charles R. Bronfman Institute for Personalized Medicine (IPM) BioBank Genome Wide Association Study of Cardiovascular, Renal and Metabolic Phenotypes

  The Institute for Personalized Medicine (IPM) Biobank Project is a consented, EMR-linked medical care setting biorepository of the Mount Sinai Medical Center (MSMC) drawing from a population of over 70,000 inpatients and 800,000 outpatient visits annually. MSMC serves diverse local communities of upper Manhattan, including Central Harlem (86% African American), East Harlem (88% Hispanic Latino), and Upper East Side (88% Caucasian/white) with broad health disparities. IPM Biobank populations include 28% African American (AA), 38% Hispanic Latino (HL) predominantly of Caribbean origin, 23% Caucasian/White (CW). IPM Biobank disease burden is reflective of health disparities with broad public health impact: average body mass index of 28.9 and frequencies of hypertension (55%), hypercholesterolemia (32%), diabetes (30%), coronary artery disease (25%), chronic kidney disease (23%), among others. Biobank operations are fully integrated in clinical care processes, including direct recruitment from clinical sites, waiting areas and phlebotomy stations by dedicated Biobank recruiters independent of clinical care providers, prior to or following a clinician standard of care visit. Recruitment currently occurs at a broad spectrum of over 30 clinical care sites. Minorities are strikingly underrepresented in GWAS, including Coronary Artery Disease (CAD) and Chronic Kidney Disease; multigenic genetic risk scores for CAD have been recently validated in European ancestry populations, but not in AA or HL populations. Several important opportunities exist for extending additional GWAS to minority populations with a shared risk spectrum of CAD and CKD. For example, progressive CKD is a major and independent risk factor for CVD with an inverse relationship between estimated GFR (eGFR), and risk for mortality and cardiovascular events. This increased risk is only partially explained by the prevalence of cardiovascular risk factors among these patients. We conducted a GWAS of CAD and CKD related phenotypes in IPM Biobank with the primary objective to explore the genetics of overlapping CAD and CKD predominantly in minority populations characterized by increased risk.

  Study phs000388

• National Institute of Neurological Disorders and Stroke (NINDS), Family Study of Essential Tremor (FASET), Identification of Susceptibility Genes for Essential Tremor

  The Familial Study of Essential Tremor (FASET) was designed to identify susceptibility genes for Essential Tremor. ET is among the most common neurological diseases with a prevalence (age > 40 years) estimated to be 4.0% and prevalence in advanced age (> 90 years) exceeding 20%. ET, often referred to as "familial tremor", is generally regarded as a highly genetic disorder with families, with affected members over multiple generations, and twin studies show high concordance among monozygotic twins. Probands (affected with ET) and relatives were enrolled in a family study of ET at Columbia University, New York between 2011 - 2014. The study was approved by the Institutional Review Board at Columbia University and written informed consent was obtained from all enrollees. The criteria for enrollment were: 1) the proband had early-onset ET with age at onset < 50 years, 2) the proband had a diagnosis of definite or probable ET, 3) in addition to the proband, there were at least two affected relatives in the family, 4) additional affected and unaffected family members were willing to participate in the study, and 5) the families contained more than two affected individuals in different generations. Blood samples were also collected for genetic research. For the genetic analyses, we excluded enrollees that we or others had diagnosed with Parkinson's disease (PD) or dystonia. The final sample includes 52 families (52 probands [affected with ET]) and 155 relatives). The number of affected individuals enrolled per family ranged from 3 - 7 (mean = 4.1). Genetic samples from FASET were analyzed with whole genome SNP genotyping (for linkage analyses) and whole exome sequencing. It is hoped that this resource will better help researchers to understand the genetic causes of ET and underlying disease pathogenesis.

  Study phs000966

• Small RNA Contents of Extracellular Vesicles from Patients with Cognitive Decline

  In this proposal, we examined samples from living neurologically normal individuals (n=72), cognitively normal Parkinson's disease (PD; n=21), PD with mild cognitive impairment (PD-MCI; n=18), PD with dementia (PDD; n=23), and dementia with Lewy-bodies (DLB; n=18), Alzheimer’s disease (AD; n=33) and mild cognitive impairment (MCI, n=38). The main goal for this study was to assess the diagnostic utility of small RNA contents from extracellular vesicles (EVs) for the prediction of cognitive decline. Plasma samples were collected and the RNA from extracellular vesicles (EVs) was isolated using the Qiagen exoRNeasy kit, and the small RNA contents were sequenced using the PerkinElmer NextFlex kit (v2). While PD is typically thought of as a motor disorder, there are significant non-motor symptoms that can be devastating. One of the most common non-motor symptoms of PD is dementia (PDD). While PD subjects that develop dementia all have Lewy bodies, there is often co-pathology with tau and β-amyloid found at autopsy or by PET amyloid imaging; thus, subjects diagnosed with AD were also included in the study. The development of the category, mild cognitive impairment (MCI) in AD, and in PD, provides an opportunity to identify and examine a transitional state between normal aging and dementia; this is a patient population ideally suited for therapeutic intervention. Progress in the detection, validation, and standardization of molecular biomarkers from biofluids, such as extracellular RNAs (exRNAs), would be efficient and cost-effective aids in the assessment of disease progression, cognitive decline, and response to therapeutics. We have provided the raw fastq files for the sequencing data from each sample. We are also providing demographic information, as complete as we have for each person; including age, diagnosis, sex, and cognitive assessments.

  Study phs003300

• A Genome-Wide Association Study of Lung Cancer Risk

  Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types genotyping 515,922 single nucleotide polymorphisms (SNPs) in 5,739 incident lung cancer cases and 5,848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from 10 additional studies for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication resulting in 3,333 adenocarcinomas (AD), 2,589 squamous cell carcinomas (SQ), and 1,418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT) on chromosome 5p15.33, was associated with risk of adenocarcinoma (OR=1.23, 95%CI=1.13-1.33, P=3.02x10-7), but not other histologic types (OR=1.01, P=0.84, and OR=1.00, P=0.93, for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR=1.24, 95%CI=1.17-1.31, P=3.74x10-14 for AD and OR=0.99, P=0.69 and OR=0.97, P=0.48, for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma. Note: The lung study dataset to be released to dbGaP and caBIG excludes 47 individuals from the PLCO cohort who consented to participate only in cancer research projects and 22 individuals because of updated QC. Thus, the released dataset is derived from 11517 subjects, 5699 cases and 5818 controls. After the updated QC, the dataset to be released to dbGaP and caBIG includes 506062 SNPs.

  Study phs000336

• Adult Eosinophilic Esophagitis Registry Atlas

  Eosinophilic esophagitis (EoE) arises in the setting of type 2 cytokine-driven inflammation, is characterized by the infiltration of eosinophils in the esophageal mucosa, and is associated with dysphagia and fibrostenotic complications. Disease development and progression involve complex interactions between epithelial cells, stromal cells and immune cells. Indeed, increased epithelial permeability is consistently found in EoE, potentially leading to increased antigen exposure and inflammation. Persistent inflammation can in turn lead to fibroblast activation and fibrosis, which, together with the mediators produced by eosinophils and mast cells, leads to dysmotility. To decipher the interactions between these cell types across distinct disease states, we obtained biopsies from 7 healthy controls and 15 EoE subjects, including both active disease and clinical remission, to perform single cell RNA-sequencing (scRNA-seq).Each biopsy sample was enzymatically digested within 3 hours of collection with collagenase/dispase to generate a single cell suspension. Suspensions were then loaded on a 10x Chromium controller, and libraries were generated with the 3' Chemistry pipeline (v2 or v3) before sequencing on an Illumina sequencer. The resulting sequence data was demultiplexed and analyzed with the CellRanger pipeline to generate raw fastq files and processed gene-count matrices for each sample. Altogether, our study generated transcriptomic profiles from 421,312 individual cells after quality control and filtering.Our analyses reveal 60 cell subsets and functional alterations in cell states, compositions, and interactions that highlight previously unknown features of EoE. Active disease displayed enrichment of ALOX15+ macrophages, novel PRDM16+ dendritic cells expressing the EoE risk gene ATP10A, and cycling mast cells, with concomitant reduction of TH17 cells. Receptor–ligand expression uncovered eosinophil recruitment programs, increased fibroblast interactions in disease, and IL-9+IL-4+IL-13+TH2 and endothelial cells as potential mast cell interactors. Resolution of inflammation-associated signatures included mast and CD4+ Tissue-resident memory T (TRM) cell contraction and cell type-specific downregulation of eosinophil chemoattractant, growth, and survival factors.

  Study phs003574

• Genomic features of Helicobacter pylori-na��ve diffuse-type gastric cancer.

  Helicobacter pylori (HP) is a major etiologic driver of diffuse-type gastric cancer (DGC). However, improvements in hygiene have led to an increase in the prevalence of HP-na��ve DGC; that is, DGC that occurs independent of HP. Although multiple genomic cohort studies for gastric cancer have been conducted, including studies for DGC, distinctive genomic differences between HP-exposed and HP-na��ve DGC remain largely unknown. Here, we employed exome and RNA sequencing with immunohistochemical analyses to perform binary comparisons between 36 HP-exposed and 27 HP-na��ve DGCs from sporadic, early-stage, and intramucosal or submucosal tumor samples. Among the samples, 33 HP-exposed and 17 HP-na��ve samples had been preserved as fresh-frozen samples. HP infection status was determined using stringent criteria. HP-exposed DGCs exhibited an increased single nucleotide variant burden (HP- exposed DGCs; 1.97 [0.48���7.19] and HP-na��ve DGCs; 1.09 [0.38���3.68] per megabase; p=0.0003) and a higher prevalence of chromosome arm-level aneuploidies (p<0.0001). CDH1 was mutated at similar frequencies in both groups, whereas RHOA���ARHGAP pathway misregulation was exclusive to HP-exposed DGCs (p=0.0167). HP-exposed DGCs showed gains in chromosome arms 8p/8q (p<0.0001), 7p (p=0.0035) and 7q (p=0.0354), and losses in 16q (p=0.0167). Immunohistochemical analyses revealed a higher expression of intestinal markers such as CD10 (p<0.0001) and CDX2 (p=0.0002) and a lower expression of the gastric marker, MUC5AC (p=0.0305) among HP-exposed DGCs. HP-na��ve DGCs, on the other hand, had a purely gastric marker phenotype. This work reveals that HP-na��ve and HP-exposed DGCs develop along different molecular pathways, which provide a basis for early detection strategies in high incidence settings.

  Study JGAS000575

• Nala GSI GSAv3 PGx Study

  Background: Microarrays are a well-established and widely adopted technology capable of interrogating hundreds of thousands of loci across the human genome. Combined with imputation to cover common variants not included in the chip design, they offer a cost-effective solution for large-scale genetic studies. Beyond research applications, this technology can be applied for testing pharmacogenomics, nutrigenetics, and complex disease risk prediction. However, establishing clinical reporting workflows requires a thorough evaluation of the assay's performance, which is achieved through validation studies. In this study, we performed pre-clinical validation of a genetic testing workflow based on the Illumina Global Screening Array for 25 pharmacogenomic-related genes. Methods: To evaluate the accuracy of our workflow, we conducted multiple pre-clinical validation studies. Here, we present the results of accuracy and precision assessments, involving a total of 73 cell lines. These assessments encompass reference materials from the Genome-In-A-Bottle (GIAB), the Genetic Testing Reference Material Coordination Program (GeT-RM) projects, as well as additional samples from the 1000 Genomes project (1KGP). We conducted an accuracy assessment of genotype calls for target loci in each indication against established truth sets. Results: In our per-sample analysis, we observed a mean analytical sensitivity of 99.39% and specificity 99.98%. We further assessed the accuracy of star-allele calls by relying on established diplotypes in the GeT-RM catalogue or calls made based on 1KGP genotyping. On average, we detected a diplotype concordance rate of 96.47% across 14 pharmacogenomic-related genes with star allele-calls. Lastly, we evaluated the reproducibility of our findings across replicates and observed 99.48% diplotype and 100 % phenotype inter-run concordance. Conclusion: Our comprehensive validation study demonstrates the robustness and reliability of the developed workflow, supporting its readiness for further development for applied testing.

  Study EGAS00001007710

• Genomic profiling of paediatric high grade gliomas from the HERBY clinical trial

  The HERBY trial was a phase-II open-label, randomised, multicentre trial evaluating bevacizumab in patients with newly-diagnosed non-brainstem high grade glioma (HGG) between the ages of 3-18yrs. 121 patients were randomised with 1yr event-free survival as the primary end-point. Confirmation of HGG diagnosis by reference pathology was mandatory before randomisation, followed by review with five independent expert neuropathologists. We collected specimens from 89 patients consenting to translational research, and performed Sanger sequencing for H3F3A, Illumina 450K BeadArray methylation profiling, and whole exome sequencing and RNA sequencing where possible. 7/89 patients (8%) harboured H3F3A G34R/V mutations, whilst 24/89 (27%) harboured H3F3A K27M, the latter reflecting a high proportion of the novel entity recognised in the 2016 WHO classification of diffuse midline glioma with H3K27M mutation. Both histone mutations conferred a significantly shorter progression-free (p=0.0104) and overall survival (p=0.00159). 450K methylation subtyping additionally identified a number of subgroups in histone wild-type cases. These included infrequent (4/86, 4.6%) cases with IDH1 mutation in older children, further categorised into astrocytic ATRX-mutant (n=3) or 1p19q co-deleted with TERT promoter mutation (n=1). 9/74, (12%) of cases were classified as biologically resembling pleomorphic xanthoastrocytoma (PXA) by methylation profiling, with 5/9 harbouring BRAF V600E mutations and epithelioid histology, and 3/9 NF1 mutation and giant cell features. Three cases had methylation profiles more closely resembling low grade gliomas, though were morphologically high grade, and harboured MAPK dysregulation in two cases, with the third part of an additional infant (<3yrs) cohort. Finally, four cases had a mutational burden several orders of magnitude higher than the rest, with (2197-5332) somatic coding variants/sample reflecting a hypermutator phenotype. These data provide an important insight into the wide biological diversity of ‘HGG’ found in the paediatric age group and allow for a profound refinement of clinical trial interpretation.

  Study EGAS00001002328

• Raw bulk TCRseq data fromTIL and non-TIL expanded TRACERx samples in the manuscript Bulk TCRseq from TRACERx samples from 'Subclonal immune evasion in non-small cell lung cancer'

  Immune checkpoint blockade in non-small cell lung cancer (NSCLC) rarely leads to complete tumour remission, suggesting that tumours harbour subpopulations of cancer cells that can escape immune predation. However, while tumours consist of multiple genetically distinct clones, the extent to which separate tumour subclones differ intrinsically in their functional capacity for immune evasion remains largely unexplored. This has been challenging to address due to an inability to isolate and propagate individual tumour subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived platform that allows the functional analysis of immune escape at single clone resolution. We generated libraries of >20 separate NSCLC organoid lines per patient by isolating individual (clonal) organoids established from multiple spatially separated tumour regions. Each organoid subline was co-cultured with autologous tumour infiltrating lymphocytes (TIL) to evaluate their capacity to elicit a T cell response. Organoid lines derived from separate tumour regions, or from single clones within individual regions, differ vastly in their capacity to elicit a T cell response, showing the coexistence of intrinsically immune evading (‘cold) and non-evading (‘hot) clones in the same primary tumour. Organoid lines escaping T cell recognition represent genetically and transcriptionally unique subclones with a distinct evolutionary history, showing that evolutionary sculpting of subclonal diversity can have functional consequences for anti-tumour immunity. Notably, the identification of immune-evasive subclones would not have been possible using computational approaches alone, highlighting the unique value of functional co-culture platforms. This patient-derived functional co-culture platform reveals that tumour evolution can give rise to distinct cancer clones with intrinsic differences in immune evasion capacity and provides an approach to prospectively identify, isolate and characterise immune evading subclones from patients with cancer.

  Study EGAS00001008118

• UK10K_NEURO_ASD_FI

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.These samples are a subset of a nationwide collection of Finnish autism spectrum disorder (ASD) samples. The samples have been collected from Central Hospitals across Finland in collaboration with the University of Helsinki. The samples consist of 93 individuals with a diagnosis of autistic disorder or Asperger syndrome from 36 families with at least two affected individuals. Of these individuals, 16 can be genealogically connected to form two large pedigrees originating from Central Finland, suggesting possible genetic risk factors shared identical by descent within the pedigrees. All diagnoses are based on ICD-10 and DSM-IV diagnostic criteria for ASDs. Additional phenotypic data is available for a subset of the individuals.For further information with regard to this cohort please contact Aarno Palotie (Aarno.palotie@helsinki.fi).

  Study EGAS00001000110

• ctDNA to predict risk of progression and death after trifluridin/tipiracil therapy

  Background. Late-line treatment in metastatic colorectal cancer (mCRC) can improve the prognosis. However, not every patient has a benefit and may experience severe side effects. Thus, predictive/prognostic biomarkers are urgently needed. Despite many promising results, the role of circulating tumor DNA (ctDNA) analysis in trifluridin/tipiracil (FTD/TPI) treated mCRC patients is so far still elusive. Study design. This prospective non-interventional translational biomarker phase II study enrolled 30 metastatic CRC patients treated with FTD/TPI. The primary study aim was to identify a molecular biomarker to predict overall survival (OS) benefit upon FTD/TPI treatment. Methods. mCRC patients (60% male, 40% female) with FTD/TPI therapy were included. Molecular profiling in cell-free DNA from plasma was performed prior to treatment and on average 4, 8 and 12 weeks after FTD/TPI initiation. Tumor levels were assessed as the highest variant allele frequency (hVAF) and correlated with OS. Uni- and multivariate analyses for survival were performed with clinical variables. Multivariate analyses for survival and treatment efficacy were adjusted to age, gender and ECOG performance status. Results. Compared to previous data, our disease control rate of 30% was lower with a median OS of 8.1 months and a median PFS of 3.2 months. At baseline (BL) and the first two follow-ups (FU), a hVAF cut-off of 7.5% was most discriminative (BL HR 0.39 95% CI 0.16 - 0.98 P=0.0212, FU1 HR 0.30 95% CI 0.12 -0.77 P=0.0021, FU2 HR 0.23 95% CI 0.08-0.70 P=0.0004) whereas at the last follow-up the stratification was most pronounced at a 15% cut-off. An elevated hVAF trajectory over time was associated with a higher risk of death. Conclusion. ctDNA is detectable in a high proportion of mCRC patients. Changes in ctDNA levels are associated with survival among FTD/TPI therapy and may identify patients who benefit most from treatment in these late-stage disease.

  Study EGAS00001006883

• Whole genome and whole exome sequencing of serial biopsies of relapsed/refractory diffuse large B-cell lymphoma.

  Purpose: Diffuse large B-cell lymphoma (DLBCL) is cured in more than 60% of patients, but outcomes remain poor for patients experiencing disease progression or relapse (refractory or relapsed DLBCL [rrDLBCL]), particularly if these events occur early. Although previous studies examining cohorts of rrDLBCL have identified features that are enriched at relapse, few have directly compared serial biopsies to uncover biological and evolutionary dynamics driving rrDLBCL. Here, we sought to confirm the relationship between relapse timing and outcomes after second-line (immuno)chemotherapy and determine the evolutionary dynamics that underpin that relationship. Patients and methods: Outcomes were examined in a population-based cohort of 221 patients with DLBCL who experienced progression/relapse after frontline treatment and were treated with second-line (immuno)chemotherapy with an intention-to-treat with autologous stem-cell transplantation (ASCT). Serial DLBCL biopsies from a partially overlapping cohort of 129 patients underwent molecular characterization, including whole-genome or whole-exome sequencing in 73 patients. Results: Outcomes to second-line therapy and ASCT are superior for late relapse (>2 years postdiagnosis) versus primary refractory (<9 months) or early relapse (9-24 months). Diagnostic and relapse biopsies were mostly concordant for cell-of-origin classification and genetics-based subgroup. Despite this concordance, the number of mutations exclusive to each biopsy increased with time since diagnosis, and late relapses shared few mutations with their diagnostic counterpart, demonstrating a branching evolution pattern. In patients with highly divergent tumors, many of the same genes acquired new mutations independently in each tumor, suggesting that the earliest mutations in a shared precursor cell constrain tumor evolution toward the same genetics-based subgroups at both diagnosis and relapse. Conclusion: These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naïve disease and have implications for optimal patient management.

  Study EGAS00001007053

• Single cell TCRseq data fromTIL and non-TIL expanded TRACERx samples in the manuscript Bulk TCRseq from TRACERx samples from 'Subclonal immune evasion in non-small cell lung cancer'

  Immune checkpoint blockade in non-small cell lung cancer (NSCLC) rarely leads to complete tumour remission, suggesting that tumours harbour subpopulations of cancer cells that can escape immune predation. However, while tumours consist of multiple genetically distinct clones, the extent to which separate tumour subclones differ intrinsically in their functional capacity for immune evasion remains largely unexplored. This has been challenging to address due to an inability to isolate and propagate individual tumour subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived platform that allows the functional analysis of immune escape at single clone resolution. We generated libraries of >20 separate NSCLC organoid lines per patient by isolating individual (clonal) organoids established from multiple spatially separated tumour regions. Each organoid subline was co-cultured with autologous tumour infiltrating lymphocytes (TIL) to evaluate their capacity to elicit a T cell response. Organoid lines derived from separate tumour regions, or from single clones within individual regions, differ vastly in their capacity to elicit a T cell response, showing the coexistence of intrinsically immune evading (‘cold) and non-evading (‘hot) clones in the same primary tumour. Organoid lines escaping T cell recognition represent genetically and transcriptionally unique subclones with a distinct evolutionary history, showing that evolutionary sculpting of subclonal diversity can have functional consequences for anti-tumour immunity. Notably, the identification of immune-evasive subclones would not have been possible using computational approaches alone, highlighting the unique value of functional co-culture platforms. This patient-derived functional co-culture platform reveals that tumour evolution can give rise to distinct cancer clones with intrinsic differences in immune evasion capacity and provides an approach to prospectively identify, isolate and characterise immune evading subclones from patients with cancer.

  Study EGAS00001008161

• Small‑scale mutations are infrequent as mechanisms of resistance in post‑PARP inhibitor tumour samples in high grade serous ovarian cancer

  Targeted DNA sequencing of high-grade serous ovarian cancer (HGSC) tumour and normal samples from 26 patients. Following target hybrid capture of 63 genes involved in DNA repair and response to treatment with an Agilent SureSelect XT panel, sequencing libraries were generated using the SureSelect XT Low Input Target Enrichment System (Agilent) as per the manufacturer's protocol. Libraries were sequenced on an Illumina NextSeq 500 at the Peter MacCallum Cancer Centre (Melbourne, Australia).

  Study EGAS50000000146

• Long read transcriptome of DM1 patients whole blood

  DM1 is characterized by dysregulation of alternative mRNA splicing, to an quantitative as well as qualitative extend that is heterogenous between clinically similar patients. Hundreds of transcripts have been identified that can be misspliced in DM1, and for many of these it is still unclear whether they generate stable proteins in DM1 patients. We generated long-read transcriptome data of DM1 patients whole blood after hemoglobin depletion. Each sample is a mix of 5 patients of varying age.

  Study EGAS50000000196

• Whole Exome Sequencing for Colorectal Cancer

  This project was designed to use next generation sequencing technology to screen the protein coding regions of the genome for low frequency variants in a panel of high-risk colorectal adenocarcinoma cases. Blood and cell-line DNA for colorectal cancer patients and a subset of quality control samples that had existing whole exome sequence data were analyzed using Illumina HiSeq sequencers. Samples from this project were from participants in the Women's Health Initiative (WHI) and the Diet, Activity, and Lifestyle Study (DALS).

  Study phs000410

• Molecular Signatures of DCIS to Invasive Progression for Basal-Like Breast Cancers: An Integrated Mouse Model and Human Tumor Study

  We studied the genomic signatures of progression in breast ductal carcinoma in situ (DCIS) as it progresses towards triple negative invasive breast cancer (TNBC). Single cell RNA sequencing (scRNAseq) was performed on the C3Tag genetically engineered mouse model that forms human breast-like DCIS and TNBC. Bulk RNA sequencing was performed on RNA harvested from archival formalin-fixed, paraffin embedded (FFPE) pairs comprising of estrogen receptor (ER) positive (ER+) and negative (ER-) subsets of DCIS. 

  Study phs002443

• DNA and RNA Profiling Using Simultaneous Sequencing (Simul-seq)

  Paired DNA and RNA profiling is increasingly employed in genomics research to uncover molecular mechanisms of disease and to explore personal genotype and phenotype correlations. We developed a novel simultaneous DNA and RNA sequencing approach (Simul-seq) that enables comprehensive genomic and transcriptomic profiles from small quantities of cells or tissues. In this study, Simul-seq was performed on patient-derived fibroblast cells as well as an esophageal adenocarcinoma tumor sample and compared with standard DNA and RNA-sequencing approaches.

  Study phs001214

• A National Translational Science Network of Precision-Based Immunotherapy for Primary Liver Cancer (PLC)

  The primary objective of the NCI-CLARITY study is to establish a biospecimen repository for genomic, genetic and epigenetic analysis to study the biology of primary liver cancer (PLC) development and progression. Secondary objectives include predicting overall and progression-free survival following immunotherapy. In the retrospective phase, anonymous archival tissue from PLC patients was obtained from five participating sites. Whole exome and transcriptome sequencing was generated and used to predict overall survival in response to immunotherapy.

  Study phs003074

• The Nephrotic Syndrome Study Network (NEPTUNE)

  The Nephrotic Syndrome Study Network (NEPTUNE) is a collaborative investigational infrastructure of 40 North American sites for conducting clinical and translational research in Focal Segmental Glomerulosclerosis (FSGS), Membranous Nephropathy (MN), and Minimal Change Disease (MCD). NEPTUNE provides prospective, un-blinded, standardized evaluation of clinical and molecular outcomes in two cohorts: A) adults and children with incident or prevalent, biopsy-proven FSGS, MN, or MCD, recruited at the time of first biopsy, and B) children with incident Nephrotic Syndrome without a diagnostic kidney biopsy.

  Study phs003210

• Small Genomic Insertions Form Enhancers that Misregulate Oncogenes

  ChIP-Seq data from 102 cell lines were processed to identify insertions relative to the human reference genome. To confirm the ability of a computational pipeline to identify insertions that are actually present in these genomes, we PCR-amplified and deeply sequenced regions where insertions were predicted to exist in MOLT4 T-cell acute lymphoblastic leukemia cells. The current study release makes available sequences of amplicons from a tumor cell genome (MOLT4) where a computational pipeline predicted small insertions from orthogonal data.

  Study phs001242

• NCT03343197: Clinical Biomarker Data

  Patients with IDH1-mutated low-grade glioma were treated with AG-120 (ivosidenib), AG-881 (vorasidenib), or Placebo for 28 days before surgical resection. A portion of the surgical sample was submitted for exome capture-based transcriptome sequencing (Personalis ACE Whole Transcriptome). Following surgery, subjects had the option to continue (or initiate) treatment with AG-120 or AG-881.This dataset comprises next-generation sequencing data from biopsies obtained in the clinical trial: NCT03343197 (Study of AG-120 and AG-881 in Subjects with Low Grade Glioma).

  Study phs003148

• GUARDIAN: The Insulin Resistance Atherosclerosis Family Study (IRASFS)

  TThe IRAS Family Study was a family study designed to examine the genetic and epidemiologic basis of glucose homeostasis traits and abdominal adiposity. Briefly, self-reported Mexican pedigrees were recruited in San Antonio, TX and San Luis Valley, CO. Probands with large families were recruited from the initial non-family-based IRAS Study, which was modestly enriched for impaired glucose tolerance and T2D. GUARDIAN includes 1,024 individuals in 88 pedigrees from the IRAS Family Study. Insulin sensitivity was obtained by FSIGT.

  Study phs001008

• NHLBI TOPMed: Children's Health Study (CHS) Integrative Genomics and Environmental Research of Asthma (IGERA)

  The Integrative Genomics and Environmental Research of Asthma (IGERA) Study was proposed to collect immortalized cell lines, RNA, cDNA and DNA from 400 well-characterized subjects who participated in the southern California Children's Health Study (CHS) and to develop an accompanying database for these samples consisting of extensive phenotype, exposure, genome-wide genotype, gene expression, and methylation data. A subset of Hispanic-White participants (n=160) were included in the TOPMed project, including 77 asthma cases and 83 controls.

  Study phs001603

• Pulmonary Fibrosis and Telomerase Dysfunction

  This study was used to perform an exome-limited analysis of whole genome sequencing data of patients with idiopathic pulmonary fibrosis (IPF) or familial pulmonary fibrosis. Case cohorts were derived from local centers at University of Southwestern or Columbia University, and subjects were from the IPFnet cohort of clinical trial. Rare damaging mutations in the coding regions of cases were compared to healthy controls, and gene burden analysis was performed to identify enrichment of novel risk genes in the development of pulmonary fibrosis. 

  Study phs002692

• Whole exome sequencing and methylation profiling of uveal melanoma

  Uveal melanoma (UM) is the most common primary cancer of the eye and frequently leads to metastatic death. Metastatic risk can be stratified into low, intermediate and high based on the presence of mutually exclusive mutations in EIF1AX, SF3B1 and BAP1, respectively. The purpose of this study was to comprehensively profile the genetic aberrations in a set of primary uveal melanomas using whole exome sequencing, as well as DNA methylation profiling of selected samples, to improve understanding of its pathogenesis.

  Study phs001421

• Segmental Overgrowth/Vascular Anomalies/Dermatologic Disorders

  This study was designed to determine the molecular etiology of disorders characterized by segmental overgrowth, vascular anomalies, or dermatologic conditions that are part of the diagnostic criteria for Proteus syndrome or PIK3CA-related overgrowth spectrum (PROS). Somatic variants in AKT1 or PIK3CA have been identified as causative for Proteus syndrome and PROS respectively, and this study aimed to determine the extent of allelic and genetic heterogeneity in individuals who fully met the diagnostic criteria, had some aspects of, or had isolated manifestations of either syndrome.

  Study phs002006

• Myocardial Infarction Genetics Exome Sequencing Consortium: BioImage Study

  The BioImage Study (BioImage Study: A Clinical Study of Burden of Atherosclerotic Disease in an At-Risk Population, NCT00738725), is a prospective, observational study aimed at characterizing subclinical atherosclerosis in U.S. adults (55 to 80 years old) at risk for clinical atherosclerotic cardiovascular disease (PMID: 25790876). All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Illumina's ICE Capture reagent and sequencing was performed on an Illumina HiSeq 2000 or 2500.

  Study phs001058

• Pharmacogenomics of Rheumatoid Arthritis Therapy

  Rheumatoid arthritis (RA) is the most common autoimmune inflammatory arthritis worldwide and affects 1.3 million adults in the USA. It has previously been studied using phenotype algorithms to identify electronic health records (EHR) case cohorts. Early genetic studies of EHR-linked cohorts of RA patients have been replicated in known associations. Further development of collections of EHR-linked cohorts for RA and other phenotypes may enable not only enhanced understanding of disease risks but also the investigation of outcomes and treatment responses.

  Study phs000983

• UW TAN Study of Metastatic Urothelial Carcinoma

  Patients with metastatic urothelial carcinoma treated at our institution, who elected to undergo rapid autopsy at the time of death, are included in this study. These patients agreed to submit their tissue (normal samples for germline analysis [kidney or liver] as well as primary and metastatic tumor sites [urothelial carcinoma]) and the time of autopsy. Each patient signed consent to allow study of these tissues including histologic, sequencing (DNA/RNA), and implantation in to animals as able for future study.

  Study phs001797

• Single Suture Craniosynostosis: Gene and Pathway Discovery

  Craniosynostosis is the premature fusion of one or more of the calvarial sutures. In this work, we used genomics and network modeling to reveal genetic and developmental pathways which, when disrupted, result in premature calvarial fusion. Calvarial bone explants were obtained from children undergoing surgery for single suture craniosynostosis. Primary osteoblast cell lines were established from calvarial explants and used as an RNA source.  The data available includes subject sex, affected suture, RNA sequence variants and counts.

  Study phs002684

• Longitudinal Assessment of Methylmercury and Gut Microbes During Pregnancy

  Methylmercury is a potent neurotoxin, and the fetal period is the most vulnerable exposure period. There is significant variability in methylmercury metabolism, which has been attributed to differences in the structure and function of the gut microbiome. Our main objective was to better understand the interplay between gut microorganisms and methylmercury metabolism during pregnancy. To address this aim, associations were investigated between maternal biomarkers (blood, hair, stool) for prenatal methylmercury exposure and maternal gut microbiota during early and late gestation.

  Study phs001768

• Genomic Characterization of African-American Prostate Cancer

  African-American men have the highest incidence and mortality rate from prostate cancer. This study represents a whole exome sequencing study of prostate cancer samples from African-American men. We performed exome sequencing and analysis of prostate tumors and matched normal tissues to identify somatic mutations and insertion/deletions across this cohort. All sequencing was performed at the Broad Institute. This study has the potential to identify novel recurrently mutated genes in prostate cancer and improve our understanding of prostate cancer in African-Americans.

  Study phs000945

• Luminal Androgen Receptor-Enriched Triple Negative Breast Cancer

  This is a study to determine the efficacy of androgen receptor (AR) inhibitors in LAR (luminal androgen receptor)-enriched triple-negative breast cancer (TNBC) in the neoadjuvant setting. Twenty-four patients were treated with neoadjuvant AR inhibitor enzalutamide and paclitaxel for 12 weeks. Whole exome sequencing and RNA-sequencing was performed prior to treatment. The data for only two patients are consented for release through dbGaP. The remaining data are available under a Materials Transfer Agreement with the University of Texas MD Anderson Cancer Center.

  Study phs003586

• Paired Analysis of Host and Pathogen Genomes Identifies Determinants of Human Tuberculosis

  The outcome of infectious diseases may depend on the interaction between human and pathogen genomic variations. This study was designed to explore and validate this relationship in tuberculosis (TB) by conducting a genome-to-genome study of paired genomes from human hosts and the infectious agent Mycobacterium tuberculosis.Blood samples were collected from 699 TB patients in Lima, Peru, as part of a 2020 cohort study during the COVID-19 pandemic. Genotyping data for these individuals are available through dbGaP.

  Study phs003718

• Transcriptome HCCO Hypoxia and Doxorubicin resistance

  We hypothesized that HCCO-intrinsic determinants of response to hypoxia or doxorubicin could be reflected in the gene expression profiles of the HCCOs. Therefore, we selected for comparative transcriptomic analysis two sets of 4 HCCO lines that were severely (hypoxia-sensitive) or barely affected (hypoxia-resistant) by hypoxia in an ATP-based proliferation assay or two sets of 4 HCCO lines whose doxorubicin response curves were clearly separated both under normoxic and hypoxic culture conditions for comparative transcriptomic analysis.

  Study EGAS50000000042

• Whole Genome Sequencing of HER2-Positive Metastatic Extramammary Paget’s Disease: A Case Report

  Extramammary Paget’s disease (EMPD) is a rare cancer that occurs within the epithelium of the skin. Whole genome sequencing of the tumor and matched blood was performed. Whole genome sequencing revealed the underlying copy number variation landscape in HER2-positive metastatic EMPD. The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributed to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen.

  Study EGAS50000000243

• WES of breast cancer patients and controls

  This study assessed the variant profiles of 408 samples from 126 breast cancer patients with various survival outcomes, including paired uninvolved mammary gland samples collected at proximal distances from primary lesions. As a reference, control samples from 15 mammoplasty individuals without cancer history were studied. Whole exome sequencing was performed to identify post-zygotic and germline variants present in the studied samples. Variant annotation in known databases, interpretation, and statistical analyses followed to discern the clinical relevance of called variants.

  Study EGAS50000000539

• Patient-Derived Breast Cancer Organoid Study

  This study uses normal and tumor tissues from breast cancer patients to derive 3D cell culture models called organoids. Organoid technology is an innovative platform that can be used to study a patient's tumor in a dish ex-vivo. As part of this study we have comprehensively characterized these models using next-generation sequencing for: 1) pathogenic SNVs in a targeted gene panel 2) copy number alterations 3) transcriptome analysis using RNA sequencing and 4) single-cell RNA sequencing

  Study phs002722

• Ballett

  TSO500 study: The project, called "BALLETT" (Belgian Approach of Local Laboratory Extensive Tumor Testing), has a double goal: (1) show the relevance of broad molecular profiling to improve oncological patients care, (2) demonstrate that broad molecular testing can be performed in a decentralized setting by local diagnostics laboratories in a fully standardized and uniform way while complying with the highest quality standards. NCT05058937 The publication number is: Your manuscript ID is bcr-2023-256124. Title: CUP and BRAF V600E meeting the BEACON combination.

  Study EGAS50000000478

• Human dorsal root ganglia after plexus injury - RNA-fragment sequencing from histological slices

  Human dorsal root ganglia from patients with brachial plexus injury and from subjects from forensic autopsy were extracted and fixed with paraformaldehyde. The cellular composition of these DRG was analysed in histopathological slices. From some of the slices, total RNA was extracted and total RNAseq was performed. The RNA sequencing data represent DRG with neuronal preservation (n=6) or neuronal loss (n=2) versus control (n=6). Details can be found in the corresponding publication and supplement to this publication.

  Study EGAS50000000682

• BE_screens_of_WRN_gene_in_MSI_models

  We will take advantage of a base-editing screening strategy to engineer mutations in the WRN gene by deep mutagenesis. Two MSI-H cell lines sensitive to WRNi will be genetically modified to express doxycycline-inducible ABE and CBE base editors through a knock-in strategy. Moreover, we will design a pooled library of ~4000 gRNAs targeting the WRN gene plus appropriate controls gRNAs. Library-transduced cells will be selected with WRNi to identify WRN mutations able to interfere with the activity of WRNi.

  Study EGAS00001006872

• A Large-Scale, Consortium-Based Genomewide Association Study of Asthma

  We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma.

  Study EGAS00000000077

• The Genetic Landscape of Familial Pulmonary Fibrosis

  This dataset was collected from a study that was designed to identify disease-causing rare genetic variants in individuals with Familial Interstitial Pneumonia (FIP). Subjects were identified from our ongoing FIP Registry (IRB #020343), where FIP is defined as idiopathic interstitial lung disease (ILD) in two or more family members with at least one affected individual diagnosed with idiopathic pulmonary fibrosis (IPF). Whole exome sequencing was performed on ~600 affected members from 525 kindreds using genomic DNA isolated from peripheral blood.

  Study phs003750

• Kids First: Whole Genome Sequencing Studies of Multiplex Nonsyndromic Cleft Lip/Palate Families

  Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect that affects approximately 135,000 newborns worldwide, and imposes significant medical, psychosocial and financial burdens to affected individuals and their families. Genetic variation in numerous genes has been associated with NSCLP, however the exact mechanisms by which they contribute to the condition remain largely unknown. Here, we will use whole genome sequencing and robust analytical approaches to systematically evaluate the causes of NSCLP in 923 individuals from large multigenerational families.

  Study phs002626

• Longitudinal single-cell transcriptomic study in patient-derived xenografts of pediatric T-ALL

  In this study, we conducted single cell full length total RNA sequencing (VASA-seq) on 13 matched pediatric T-ALL PDX samples at initial diagnosis and relapse, along with 5 non-relapsing PDX samples collected at initial diagnosis. We identified a subpopulation of T-ALL cells with stem-like cell features that expands substantially at relapse indicating resistance to first-line therapy. Chemotherapy resistance was further validated through functional testing: Two samples were subjected to in-vitro drug testing, treated with Cytarabine for three days, followed by single-cell transcriptomic analysis using 10x Genomics. Additionally, in-vivo drug testing was conducted on one sample, involving re-engraftment into mice and treatment with a combination of Vincristine, Doxorubicin, and Dexamethasone. Single-cell transcriptomic analysis using 10x Genomics was performed after 0, 15 and 30 days of treatment.

  Dataset EGAD50000000831

• Genomic analysis of HGSOC using long read sequencing

  High-grade serous ovarian cancer (HGSOC) is characterized by widespread genomic instability, but genomic and epigenomic alterations within repetitive regions remain poorly understood. This study aims to investigate genomic and epigenomic variations in HGSOC using Oxford Nanopore long-read sequencing technology. High-molecular-weight DNA was extracted from cryopreserved, pre-treatment tumor samples and matched blood specimens. The objectives include developing a robust long-read sequencing analysis pipeline, identifying novel genomic and epigenomic variations, and exploring potential applications in future clinical and basic research.

  Study EGAS50000001036

• Allogeneic induced pluripotent stem (iPS) cell-derived cartilage transplantation for articular cartilage damage in knee joints: a phase I, first-in-human study

  Damaged articular cartilage seldom heals due to a limited capacity for self-repair, frequently leading to osteoarthritis. Regenerative interventions are expected to heal the damage. We have recently established a method to produce cartilage from induced pluripotent stem cells (iPSCs) in a clinically applicable process. The primary aim of this study was to evaluate the safety including tumorigenesis and the subsequence efficacy of allogeneic iPSC-derived cartilage transplantation into damaged areas of knee articular cartilage.

  Study EGAS50000001167

• Identification of therapeutic target molecules for prostate cancer by using next generation sequencer

  Comprehensive transcriptional characterization of cancer tissues can reveal important molecular signatures associated with the disease progression. Long non-coding RNA (LncRNA) has a diversity of functions such as transcription, epigenetic and gene regulation in cancer cells including prostate cancer cells. Here, we performed directional RNA-sequence (RNA-seq) on clinical samples obtained from prostate cancer (PC) and lethal castration-resistant PC (CRPC) patients to identify novel molecular signatures including protein coding genes and non-coding RNAs induced in CRPC tissues.

  Study JGAS000198

• Elucidation of genomic pathology of a patient with concurrent acute myeloid leukemia and mediastinal germ cell tumor

  The occurrence of a mediastinal germ cell tumor (GCT) and hematological malignancy in the same patient is very rare. Whole exome sequencing was performed for concurrent acute myeloid leukemia (acute megakaryoblastic leukemia) and mediastinal germ cell tumor. Somatic mutations, such as TP53 or PTEN, were commonly identified in both acute myeloid leukemia and mediastinal germ cell tumor, suggesting the common founder clone. Normal buccal cells were used as a control. Illumina NextSeq 500 platform were used.

  Study JGAS000211

• WES sequencing of metastatic colorectal cancer patient-derived xenografts with known response to irinotecan.

  Chemotherapy is the standard-of-care treatment for metastatic colorectal cancer (mCRC) and benefits some patients, but what distinguishes responders from non-responders is unclear. In this study, we expand a pre-existing collection (https://doi.org/10.1158/2159-8290.CD-24-0556) of molecularly annotated patient-derived xenografts to uncover functional predictors of response to 5-FU and irinotecan combination therapy (FOLFIRI) in mCRC. We complemented previous mutational profiles with whole exome sequencing for 46 xenografts with known response to irinotecan.

  Study EGAS50000001484

• Bulk RNA sequencing of metastatic colorectal cancer patient-derived xenografts with known response to irinotecan

  Chemotherapy is the standard-of-care treatment for metastatic colorectal cancer (mCRC) and benefits some patients, but what distinguishes responders from non-responders is unclear. In this study, we expand a pre-existing collection (https://doi.org/10.1158/2159-8290.CD-24-0556) of molecularly annotated patient-derived xenografts to uncover functional predictors of response to 5-FU and irinotecan combination therapy (FOLFIRI) in mCRC. We complemented previous expression profiles with bulk RNAseq for 38 xenografts with known response to irinotecan.

  Study EGAS50000001485

• Single-cell and bulk RNA-sequencing of nivolumab-treated glioblastoma

  Glioblastoma is a highly aggressive type of brain tumour for which there is no curative treatment available. Immunotherapies have shown limited responses in unselected glioblastoma patients, and it is currently not well understood what separates the few responders from the non-responders at the cellular and molecular level. Here we investigate the phenotypic and transcriptional evolutionary dynamics at single-cell resolution during nivolumab immune checkpoint treatment of eight glioblastoma patients enrolled in a translational phase I/II clinical trial.

  Study EGAS00001007110

• cfDNAme allows early prediction of PE

  Preeclampsia (PE) is a leading cause for peripartal morbidity, especially if developing early in gestation. To enable prophylaxis to prevent PE, it is essential that pregnancies at risk of PE are identified early, in the first trimester. To identify patients at risk, we profiled methylomes of plasma-derived cell-free DNA (cfDNA) from pregnant women. We detected DNA methylation differences between control and PE pregnancies that enable risk stratification of patients, at PE diagnosis but also presymptomatically, around 12 weeks of gestation.

  Study EGAS00001007071

• Mutational spectrum of highly differentiated, fusion-negative rhabdomyosarcoma (set 1).

  Pediatric PAX-FOXO1 fusion-negative rhabdomyosarcoma represents a diverse spectrum of tumors. In this study, the mutational spectrum of 22 fusion-negative rhabdomyosarcomas with high, rhabdomyoma-like levels of differentiation was evaluated using OncoPanel v.2 (OPv2), an Agilent SureSelect custom designed bait set consisting of the coding regions of 504 cancer-relevant genes. Corresponding normal tissue was not available. Discarded normal human skeletal muscle, obtained from 7 donors without tumor history, were also included in the sequencing run.

  Study EGAS00001002630

• Whole_genome_sequence_of__third_generation_family_member__SFHS_

  Previously we performed deep WGS on 6 parents and 13 children from 3 large families from the Scottish Family Health Study to identify de novo mutations. This prelim is cover the additional sequencing of one grandchild from one of these three families. The inclusion of a third generation individual will provide additional experimental validation for the de novo mutations found in the initial trio. As in the previous study, the DNA will be WGS to a depth of approximately 25X to achieve this purpose.

  Study EGAS00001000429

• Comprehensive single-cell genome analysis at nucleotide resolution using the PTA Analysis Toolbox

  We developed a comprehensive bioinformatic workflow, called the PTA Analysis Toolbox (PTATO), to accurately detect single base substitutions, insertions-deletions (indels) and structural variants in PTA-based WGS data. PTATO includes a machine learning approach and filtering based on recurrency to distinguish PTA-artefacts from true mutations with high sensitivity (up to 90%), outperforming existing bioinformatic approaches. Our results show that PTATO enables studying somatic mutagenesis in the genomes of single cells with unprecedented sensitivity and accuracy.

  Study EGAS00001007288

• RNAseq___Discovery_of_resistance_mechanisms_to_the_BRAF_inhibitor_vemurafenib_in_metastatic_BRAF_mutant_melanoma

  We propose to biopsy 20 consented BRAF mutant melanoma patients at Addenbrooke's Hospital pre-treatment with vemurafenib and also upon the development of resistant disease, with the aim of using exome sequence and SNP6 data to identify novel sequence variants and copy number alterations that can be used to validate observed resistance mechanisms in our cell line models and also to use these models to inform as to likely candidate small molecule inhibitors to overcome resistance and that could be tested in the clinical trial setting.

  Study EGAS00001000813

• Discovery_of_resistance_mechanisms_to_the_BRAF_inhibitor_vemurafenib_in_metastatic_BRAF_mutant_melanoma

  We propose to biopsy 20 consented BRAF mutant melanoma patients at Addenbrooke's Hospital pre-treatment with vemurafenib and also upon the development of resistant disease, with the aim of using exome sequence and SNP6 data to identify novel sequence variants and copy number alterations that can be used to validate observed resistance mechanisms in our cell line models and also to use these models to inform as to likely candidate small molecule inhibitors to overcome resistance and that could be tested in the clinical trial setting.

  Study EGAS00001000812

• Colorectal adenomas and carcinomas NKI-AvL TGO series Gut2009

  Colorectal cancer (CRC) develops from normal epithelium, through a benign precursor lesion called adenoma, by accumulation of genetic alterations affecting oncogenes and tumour suppressor genes. These CRC-related genomic alterations often result in specific RNA-expression patterns. RNA isolated from fresh frozen specimen of 32 adenomas and 29 CRCs was obtained from the previously published study (Carvalho et al. 2009) and RNA-sequencing was performed with the aim to examine RNA expression changes in colorectal adenoma-to-carcinoma progression.

  Study EGAS00001002758

• Mutational spectrum of highly differentiated, fusion-negative rhabdomyosarcoma (set 2).

  Pediatric PAX-FOXO1 fusion-negative rhabdomyosarcoma represents a diverse spectrum of tumors. In this study, the mutational spectrum of 22 fusion-negative rhabdomyosarcomas with high, rhabdomyoma-like levels of differentiation was evaluated using OncoPanel v.2 (OPv2), an Agilent SureSelect custom designed bait set consisting of the coding regions of 504 cancer-relevant genes. Corresponding normal tissue was not available. Discarded normal human skeletal muscle, obtained from 7 donors without tumor history, were also included in the sequencing run.

  Study EGAS00001002771

• Aneurysmal Subarachnoid Hemorrhage patients with or without vasospasm

  Cerebellar vasospasm is a severe complication of aneurysmal subarachnoid hemorrhage (aSAH) occurring for 30% of aSAH patients. To date, no biomarker of vasospasm occurrence exists and thus all aSAH patients undergo a preventive and dangerous treatment. In this study, we explored the miRNome of aSAH patients to detect potential expression differences between the patients developing a vasospasm (VSP+) or not (VSP-). The shared data include raw and normalized count miRNA data in aneurysmal subarachnoid hemorrhage patients with or without vasospasm.

  Study EGAS00001003092

• Genomic_landscape_of_liver_cirrhosis

  We are interested in the genomic landscape of liver cirrhosis and its potential manifestations for liver physiology and risk for hepatocellular carcinoma. Previous work in CASM has shown that there is a strong element of clonality within cirrhotic nodules and that some recurring mutations have been identified. However how this relates to the overall liver is not known and therefore by taking geographically disparate biospies, we aim to correlate our findings and make conclusions as to the characteristics of the overall genomic landscape.

  Study EGAS00001004329

• Bulk RNAseq gene expression of baseline tumors from metastatic urothelial bladder cancer patients (IMvigor210) and metastatic renal cell carcinoma (IMmotion150)

  We examined tumors from a large cohort of patients with metastatic urothelial bladder cancer (mUC) and metastatic renal cell carcinoma (mRCC) treated with an anti-PD-L1 agent (atezolizumab) and found that high tumor IL8 gene expression was associated with worse overall survival (OS). We further identified the tumoral immune presence based on Teff signature. We found that high tumor IL8 expression continued to be associated with worse OS even in inflamed tumors in mUC and mRCC.

  Study EGAS00001004386

• Whole Exome Sequencing of 15 Tumor/Normal pairs of inflammatory hepatocellular adenomas

  The French ICGC project on liver tumors is coordinated by Pr Jessica Zucman-Rossi and funded by Inca (French Institute for Cancer). The aim of the present project is to identify the catalog of somatic and germline mutations in liver tumors. The present series corresponds to 15 Tumor/Normal pairs of Whole Exome Sequencing (WES) of IHCA samples. Aligned bam files can be both in hg19 (CHC750T/CHC750N; CHC2189T/CHC2189N; CHC2615T/CHC2614N) or hg38 (other samples).

  Study EGAS00001003686

• A_compendium_of_mutational_signatures_due_to_environmental_exposures

  Analysis of mutational signatures caused by exposure to known mutagens in human induced pluripotent stem (iPS) cells. A reference human iPS cell-line will be exposed to 100 chemicals known or proposed to be mutagenic. Following exposure to mutagen, cells will undergo a period of recovery before sub clones are generated and sequenced. The progenitor “parental” IPS cell-line will be used to generate reference sequence data, in order to determine the mutational signatures acquired as a result of exposure to different mutagens.

  Study EGAS00001002060

• Mutational Landscape of Plasmablastic Lymphoma

  Plasmablastic lymphoma (PBL) represents a clinically heterogeneous subtype of aggressive B-cell non-Hodgkin lymphoma. Although targeted sequencing studies and a single center whole exome sequencing (WES) study in HIV+ patients recently revealed several genes, associated with PBL pathogenesis, the global mutational landscape and transcriptional profile of PBL remain elusive. To inform on disease-associated mutational drivers, mutational patterns and perturbed pathways in HIV+ and HIV- PBL we performed WES and RNA-sequencing (RNA-seq) of 34 PBL tumors.

  Study EGAS00001004906

• High-grade serous ovarian cancer refined with single-cell RNA-sequencing

  We performed single-cell RNA-sequencing of 18,403 cells unbiasedly collected from 7 treatment-naive HGSOC tumours. For each phenotypic cluster of tumour or stromal cells, we identified specific transcriptomic markers. Next, we explored which phenotypic clusters correlate with overall survival based on expression of these transcriptomic markers in 1467 bulk RNA-seq tumours. By evaluating molecular subtype signatures in single cells, we assessed to what extent a phenotypic cluster of tumour or stromal cells contributes to each molecular subtype.

  Study EGAS00001004987

• The distinct DNA methylome of acute lymphoblastic leukemia

  Here, using whole genome bisulfite sequencing (WGBS) data of over one hundred patients from multiple subtypes of acute lymphoblastic leukemia (ALL), controls samples and ALL cell lines, we show that in contrast to the prevailing paradigm, ALL samples exhibit CpG island hypermethylation but little to no global loss of methylation. The subtype-specific CpG island hypermethylation levels in T cell ALL span a broad range of methylation levels rather than previous binary classifications and are influenced by multiple factors, including TET2 expression.

  Study EGAS00001005203

• Sequencing of an adolescent patient with germline RET mutant alveolar rhabdomyosarcoma

  An adolescent patient presented with an alveolar rhabdomyosarcoma made more unique by the presence of a germline RET mutation ordinarily associated with and a known driver of multiple endocrine neoplasia type 2A (MEN2A) cancer. To better understand the role of this germline RET mutation in the genetics and phenotypic response of this unique alveolar rhabdomyosarcoma, we performed DNA and RNA sequencing of the patients in addition to functional studies on patient-derived cultures and genetically similar similar cell models.

  Study EGAS00001004359

• Defining structural variation associated with breast cancer susceptibility by long-read genome sequencing

  Germline structural variants (SVs) are challenging to identify by conventional genetic testing assays. Long-read sequencing has improved the global characterization of SVs, but its sensitivity at genetic loci associated with high- and moderate-penetrance cancer susceptibility has not been reported. This study used long-read genome sequencing performed on the Oxford Nanopore Technologies' PromethION to resolve variants underlying breast cancer susceptibility in sixteen individuals with pathogenic germline SVs in BRCA1, BRCA2, CHEK2 or PALB2.

  Study EGAS00001005872

• Single cell RNAseq of lung adenocarcinoma

  Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing as well as single-cell BCR sequencing of cells from 16 LUADs and 47 multi-region normal lung tissues of defined spatial proximities from the tumors. Our multi-region single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecological evolution LUAD from the lung that comprise high-potential targets for early interception.

  Study EGAS00001005021

• Multiomic profiling of pleomorphic rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) describes rare soft-tissue tumors that exhibit features of skeletal muscle differentiation. The most common subtypes in children are alveolar and embryonal rhabdomyosarcoma, with the alveolar subtype characterized by PAX3/7 fusions. A lesser known and rarer subtype, pleomorphic rhabdomyosarcoma (PRMS), occurs most frequently in adults vetween the ages of 40 and 50. This pleomorphic subtype is often misdiagnosed and little is known about its molecular characterization. Here, we conducted comprehensive genomic, transcriptomic, and methylation profiling of these tumors.

  Study EGAS00001007230

• Conserved interferon-gamma signaling and decreased immune exclusion programs in responses to immune checkpoint blockade therapy_CM38-DNA

  We analyzed baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). Analysis of whole transcriptome data showed that T cell infiltration and interferon-gamma signaling signatures corresponded most highly with clinical response to therapy, with a reciprocal decrease in cell cycle and WNT signaling pathways in responding biopsies. Clinical outcome differences were likely not due to differential melanoma cell responses to interferon-gamma, as 57 human melanoma cell lines exposed in vitro to this cytokine showed a conserved interferon-gamma transcriptome response unless they had mutations that precluded signaling from the interferon-gamma receptor. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream interferon-gamma signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.

  Dataset EGAD00001006284

• The mutational landscape of human somatic and germline cells

  During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

  Dataset EGAD00001006643

• The mutational landscape of human somatic and germline cells

  During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

  Dataset EGAD00001006642

• Combinatorial CRISPR screen identifies fitness effects of paralogues FAM50A and FAM50B

  Genetic redundancy has evolved as a way for human cells to survive the loss of genes that are single copy and essential in other organisms, but also allows tumours to survive despite having highly rearranged genomes. In this study we CRISPR screen 1,191 gene pairs, including paralogues and known and predicted synthetic lethal interactions to identify 105 gene combinations whose co-disruption results in a loss of cellular fitness. 27 pairs influence fitness across multiple cell lines including the paralogues FAM50A/FAM50B, two genes of unknown function. Silencing of FAM50B occurs across a range of tumour types and in this context disruption of FAM50A reduces cellular fitness whilst promoting micronucleus formation and extensive perturbation of transcriptional programmes. This dataset includes CRISPR screening of cancer cell lines, RNA sequencing studies of cancer cell lines and also data from the sequencing of tumour xenografts collected from mice.

  Dataset EGAD00001006649

• Profiling molecular heterogeneity in human primary microglia

  In the brain the cells that control inflammation are called a type of white blood cell called microglia. Microglia are located throughout the brain and spinal cord and account for 10–15% of all cells found within the brain. As the resident white blood cells, they are the main active immune defence in the central nervous system (CNS). Microglia are part of an important class of cells known as macrophages that have two main states: M1 and M2. M1 cells are pro- inflammatory, leading to more inflammation, while M2 are anti-inflammatory, and drive wound healing. In this study, we will collect primary microglia from surgical biospies of 100 individuals. 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 EGAD00001005736

• BAM files of total RNA-Seq data of POPS control samples (GRCh37)

  Placental biopsies (n = 64 female placentas, n = 67 male placentas) were selected from healthy pregnancies from the POPs cohort. A quality control process was also applied for the RNA-Seq datasets: reads were trimmed with Trim Galore!, which uses cutadapt internally and were mapped to the same version of human genome reference (hg19). TopHat2, a splice-aware mapper built on top of Bowtie2 short-read aligner, was used in the mapping process in which so-called two-pass (or two-scan) alignment protocol was applied to rescue unmapped reads from the initial mapping step. In the second mapping, previously unmapped reads were re-aligned to the exon-intron junctions detected in the first-mapping by TopHat2 and were combined across all 131 placenta samples. The initial and second mapped reads were merged by samtools

  Dataset EGAD00001003462

• Assessment of genetic and epigenetic variation in human IPS cells-RNA

  In order to progress human induced pluripotent stem cells (hiPSCs) towards the clinic, several outstanding questions must be addressed. It is possible to reprogram different somatic cell types into hiPSCs and from studies in the mouse, it appears that an epigenetic memory of the starting cell type is carried over to hiPSCs. However a comprehensive comparative study of the characteristics of these hiPSCs has been missing from the literature. Importantly studies which aimed to address these aspects of hiPSCs have used cells from different patients. In order to avoid this important confounding variable and to keep the genetic background constant, tissue samples were procured from the patients and reprogrammed to iPS cells. The transcriptomes of these iPS cells will be compared. Protocol: primary cultures of cells were reprogrammed to iPS cells. RNA was extracted using a standard column extraction kit.

  Dataset EGAD00001000604

• Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation

  Presurgical studies allow study of the relationship between mutations and response of estrogen receptor positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in Phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 Controls). In poor responders (based on Ki67 change) we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores   occur in approximately 30% of tumours. In Phase II we combine targeted sequencing on another 28 treated patients with Phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.

  Dataset EGAD00001002651

• H3Africa - Consortium WGS

  To address gaps in sequence data for some of the African populations being studied in H3Africa projects, additional sequencing has been carried out through various projects and the data are being made available. The first dataset includes a high coverage whole genome sequence dataset generated at the Baylor College of Medicine with samples provided by H3Africa PIs and collaborators, funded by the National Institutes of Health. The sequence data files are accompanied by minimal metadata, including country, ethnic group (where available) and sex.

  Study EGAS00001005972

• Conserved interferon-gamma signaling and decreased immune exclusion programs in responses to immune checkpoint blockade therapy_CM38-RNA

  We analyzed baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). Analysis of whole transcriptome data showed that T cell infiltration and interferon-gamma signaling signatures corresponded most highly with clinical response to therapy, with a reciprocal decrease in cell cycle and WNT signaling pathways in responding biopsies. Clinical outcome differences were likely not due to differential melanoma cell responses to interferon-gamma, as 57 human melanoma cell lines exposed in vitro to this cytokine showed a conserved interferon-gamma transcriptome response unless they had mutations that precluded signaling from the interferon-gamma receptor. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream interferon-gamma signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.

  Dataset EGAD00001006282

• Detection of rare mutations, copy number variation, and DNA methylation in the same template DNA molecules

  The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy number are the most sensitive ways to detect the presence of cancer. To further increase the sensitivity of such assays with limited amounts of sample, it would be useful to be able to evaluate the same template molecules for all these changes. Here we report an approach, called MethylSaferSeqS, that achieves this goal, and can be applied to any standard library preparation method suitable for massively parallel sequencing. The innovative step was to copy both strands of each DNA-barcoded molecule with a primer that allows the subsequent separation of the original strands (retaining their 5-methylcytosine residues) from the copied strands (in which the 5-methylcytosine residues are replaced with unmodified cytosine residues). The epigenetic and genetic alterations present in the DNA molecules can then be obtained from the original and copied strands, respectively. We applied this approach to plasma from 265 individuals, including 198 with cancers of the pancreas, ovary, lung and colon, and found the expected patterns of mutations, copy number alterations, and methylation. Furthermore, we could determine which original template DNA molecules were methylated and/or mutated. MethylSaferSeqS should be useful for addressing a variety of questions relating genetics and epigenetics in the future.

  Study EGAS00001006839

• Memorial Sloan Kettering (MSKCC) Single Cell Mutational Profiling in Myeloid Malignancies

  Myeloid malignancies have previously been characterized by large scale bulk molecular profiling studies on patient samples. These studies, while clinically informative, are unable to delineate mutation order as well as clonal architecture and complexity. To investigate the clonal framework of myeloid malignancies, the Single Cell Mutational Profiling in Myeloid Malignancies study was designed. This study performed sequencing of 148 samples from 117 adult patients diagnosed with clonal hematopoiesis (n = 21), myeloproliferative neoplasms (MPN; n = 14), and acute myeloid leukemia (AML; n = 82) between 20 and 87 years of age. Sequencing of all samples was performed using the Tapestri single cell DNA sequencing platform from Mission Bio, Inc. The platform utilizes a custom amplicon panel covering 109 amplicons across 31 genes frequently mutated in myeloid malignancies (CH, MPN, AML). Using the single cell DNA sequencing data, we were capable of elucidating clonal architecture and clonal complexity in each sample. In a subset of samples, we also performed simultaneous single cell DNA sequencing and cell surface protein expression analysis using the Tapestri DNA + Protein platform. This study allowed us to determine the expression of 7 cell surface proteins (CD3, CD11b, CD19, CD34, CD38, CD45RA, and CD90) at single cell resolution. We performed DNA+ Protein sequencing on samples from CH patients (n = 7) as well as AML patients (n = 17).

  Study phs002049

• Evolution of Core Archetypal Phenotypes in High-Grade Serous Ovarian Cancer (HGSOC)

  The evolution of resistance in high-grade serous ovarian cancer (HGSOC) cells in response to chemotherapy is only partially understood. To uncover phenotypic changes associated with chemotherapy resistance, we performed single-cell RNA-sequencing (scRNA-seq) or whole-genome sequencing of 23 total patients, with longitudinal samples collected from 9, treatment-naïve samples from 8 patients, and post-treatment samples from 6 patients. Our study revealed that the HGSOC transcriptome could be described using three core archetypal phenotypes, defined as oncogenic tasks that describe majority of the transcriptional data. We implemented a multi-task learning approach to identify the biological tasks of each archetype and identified metabolism and proliferation, cellular defense response, and DNA repair signaling. The “metabolism and proliferation” archetype evolved during treatment and was enriched in cancer cells from patients that received multiple-lines of treatment and had elevated tumor burden indicated by CA-125 levels. The emergence of archetypes was not consistently linked to specific whole-genome driver mutations. However, archetypes were closely associated with sub-clonal clusters at the single-cell level, indicating that cancer cell sub-populations specialize in particular biological tasks. Our study reveals a defining principle of ovarian tumor evolution using temporal scRNA-seq profiles, identifies the key phenotypic features across patients and links metabolic shifts with a response to chemotherapy.

  Study phs002294

• Gabriella Miller Kids First Pediatric Research Program: An Integrated Clinical and Genomic Analysis of Treatment Failure in Pediatric Osteosarcoma

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in childhood cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Although the survival of children with relapsed osteosarcoma is very poor, little is known about the etiology of treatment failure in this disease. The purpose of this project is to perform whole genome sequencing on serial samples from patients with osteosarcoma obtained before treatment, after treatment, and at relapse/metastasis in order to identify the mutations and pathways that are drivers of drug resistance. If successful, our results may help identify patients at high risk for treatment failure and may yield new treatments for children who cannot currently be cured.

  Study phs001714