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• SU2C-MARK Lung Cancer Consortium - Checkpoint Blockade Response Project

  Immune checkpoint inhibitors have become a critical part of the armamentarium against advanced Non-Small Cell Lung Cancer (NSCLC). While early studies have identified Tumor Mutation Burden (TMB) and PD-L1 staining as important biomarkers of response, they remain imperfect predictors. Here we describe a multi-institutional effort as part of the SU2C-MARK Lung Cancer Consortium in which Whole Exome Sequencing (WES) - and in select cases, RNA sequencing – was performed on a large collection of NSCLC samples prior to immune checkpoint blockade therapy, along with matched clinical response data following therapy. (Profiling of a small number of on- or post-treatment samples was also performed.) We anticipate this dataset to be of high value for the development of a deep understanding of the molecular determinants of immune checkpoint blockade response as well as the discovery of novel biomarkers.

  Study phs002822

• Female Infertility: Primary Ovarian Insufficiency

  Premature ovarian failure, or primary ovarian insufficiency (POI) is a phenotype of diminished or absent ovarian function occurring in 1-2% of reproductive aged women. Most cases occur spontaneously. Evaluation of the gametes in women with POI is difficult and invasive. Practitioners must often rely on indirect biomarkers of ovarian function and oocyte health, making it difficult to identify patients who may benefit from therapies allowing them to achieve pregnancy utilizing their own oocytes. This study will generate exome sequences from POI patients in an effort to elucidate the causes of unexplained POI and to better understand the normal processes of ovarian aging. A better understanding of the genetics of ovarian function may lead to new non-invasive tools for managing women's reproductive health, and direct better use of existing biomarkers in diagnosis, screening and predicting clinical outcomes.

  Study phs001174

• Detection and phasing of single base de novo mutations in biopsies from human in vitro fertilized embryos by advanced whole-genome sequencing

  Current methods available for pre-implantation genetic diagnosis (PGD) of in vitro fertilized (IVF) embryos do not detect de novo. Detection of these types of mutations requires whole genome sequencing (WGS). In this study advanced massively parallel WGS was performed on three 5-10 cell biopsies from two blastocyst-stage embryos. Overall, greater than 95% of each genome was called and experimentally derived haplotypes and barcoded read data were used to detect and phase up to 82% of de novo single base mutations with a false positive rate of ~1 error per Gb. These results suggest that phased WGS using barcoded DNA could be used in the future as part of the PGD process to maximize comprehensiveness in detecting disease causing mutations and reduce the incidence of genetic diseases.

  Study phs000858

• Accurate Immune Repertoire Sequencing Reveals Malaria Infection Driven Antibody Lineage Diversification in Young Children

  This study describes a novel Immune Repertoire Sequencing technique, termed Molecular Identifier Clustering-based Immune Repertoire Sequencing (MIDCIRS), to reduce sequencing error while maintaining extremely high coverage and applies this technique to investigate the differential immune response to malaria between infants and toddlers. Despite a lower somatic hypermutation load, we found an unexpectedly high level of competency within the infant antibody repertoire, particularly the ability to diversify B cell clonal lineages upon acute infection. Detailed clonal lineage analysis encompassing lineages containing sequences from both pre- and acute malaria timepoints revealed an increase in somatic hypermutations upon acute infection. Further analysis on pre-malaria memory B cell containing lineages in toddlers who had previously been exposed to malaria provides evidence for the capacity of memory B cells to continue to mutate and isotype switch.

  Study phs001209

• Genomic Correlates of Response and Resistance to Immune Checkpoint Blockade in Solid Tumors

  Immune checkpoint inhibitors yield clinical benefit in many cancer types, but molecular predictors of response have not yet been robustly characterized. In this study, we pursued whole exome sequencing (WES) of pre-treatment tumors from patients treated with immune checkpoint therapies - including monoclonal antibodies targeting programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). Using these data, we aim to apply computational pipelines for mutation-calling, neoantigen prediction, and other analyses to validate pre-existing hypotheses regarding response to immune checkpoint therapies and discover new relationships with greater power. Further, by pursuing genomic characterization of tumors from patients with a variety of cancer types, we hope to describe molecular features of intrinsically sensitive or resistant tumors that are both context-specific and shared across cancer types.

  Study phs001565

• International Collaboration of Incident HIV and HCV in Injecting Cohorts (InC3)

  This study represents a merged international multi-cohort project of pooled biological and behavioral data from ten prospective cohorts of injection drug users (Grebely J, Morris MD, Rice TM, Bruneau J, Cox AL, Kim AY, et al., 2012, PMID: 23203695). Of the 10 cohorts, six provided data and samples for the genome wide association study (GWAS) entitled “Genetic Analysis of Opioid Addiction in People Who Inject Drugs”. The InC3 cohorts included in the GWAS were: i) Australian Trial in Acute Hepatitis C (ATAHC-I, Sydney); ii) Hepatitis C Incidence and Transmission Study in Prison (HITS-p) (Sydney); iii) Hepatitis C Incidence and Transmission Study in Community (HITS-c) (Sydney); iv) HepCo Study (Montreal); v) SuperMIX Study (combining the Networks II & MIX studies, Melbourne); and vi) the UFO Study (San Francisco).

  Study phs002310

• Profiles of Extracellular RNA in Cerebrospinal Fluid and Plasma from Subarachnoid Hemorrhage Patients

  Brain injury resulting from hemorrhagic stroke is clinically challenging to manage and results in high rates of morbidity and mortality. The pathophysiology of brain damage resulting from aneurysmal subarachnoid hemorrhage (aSAH) is largely unknown, and methods to treat and monitor patients are variable with no meaningful correlations to patient outcome. Prediction of patient risk for serious neurological complications is currently a significant clinical obstacle. An extracellular RNA (exRNA) biomarker to predict onset and severity of brain damage would improve patient outcomes. We sequenced plasma and CSF samples from adult patients with SAH. Samples were collected from post bleed day 1 to day 7. Total exRNA was isolated from each sample. In addition, we prepared a subset of 140 CSF samples, isolating the RNA contained within extracellular vesicles and vesicle-depleted biofluid.

  Study phs001759

• National Cancer Institute - Population Structure and Natural Selection in the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) study in Uganda

  A genome-wide analysis of genetic structure, gene flow, and natural selection was conducted in populations in the endemic Burkitt lymphoma (eBL) belt in Ghana and Northern Uganda, both subject to a high incidence of falciparum malaria and eBL. These populations have different ethnolinguistic ancestries and are located 2400 miles apart in sub-Saharan Africa. We characterized genetic composition of these populations in the context of 22 additional African populations and present evidence for gene flow events that occurred in the last 3000 years, possibly related to regional migrations in Western Africa and major migrations involving Nilotic, Cushitic, and Bantu groups. The Ugandan population was comprised of 758 children (mean age ~7 years) from 17 Western Nilo-Saharan tribes. The current dataset includes 561 healthy children and 197 children with eBL from northern Uganda.

  Study phs001705

• National Human Genome Research Institute Tumor Sequencing Project (TSP) - Lung Adenocarcinoma

  The Tumor Sequencing Project (TSP) Consortium is a collaboration among participants at the Baylor College of Medicine Human Genome Sequencing Center, the Broad Institute Genome Sequencing Platform, the Dana Farber Cancer Institute, the Memorial Sloan-Kettering Cancer Center, the Genome Sequencing Center and Siteman Cancer Center at Washington University, the M.D. Anderson Cancer Center and the University of Michigan Medical Center. The TSP Part A will pilot approaches to large-scale identification of genomic changes in tumors by sequencing the exonic regions of 623 genes in 188 specimens of adenocarcinoma of the lung, as well as using high density SNP genotyping arrays for high resolution identification of changes in chromosomal copy number. The TSP Part B will pilot approaches to tumor characterization of lung adenocarcinoma samples using next-generation sequencing technologies and benchmark those results against Part A data generated with ABI3730 instruments.

  Study phs000144

• Pancreatic Cancer Case Control Association Study

  Pancreatic cancer is the fourth leading cause of cancer death in the United States. This is in large part due to the rapidly fatal course of this disease, as the vast majority of patients die within months of diagnosis and the five-year survival rate is less than 5. We have brought together over 8000 participants from 9 studies of pancreatic cancer, to conduct a GWAS of pancreatic cancer. The studies were drawn from the Pancreatic Cancer Case-Control consortium and include case-control studies from the United States, Europe and Australia. Sites include: Johns Hopkins National Familial Pancreas Tumor Registry, Mayo Clinic Biospecimen Resource for Pancreas Research, Ontario Pancreas Cancer Study (OPCS), Yale University, MD Anderson Case Control Study, Queensland Pancreatic Cancer Study, University of California San Francisco Molecular Epidemiology of Pancreatic Cancer Study, International Agency of Cancer Research and Memorial Sloan Kettering Cancer Center.

  Study phs000648

• Emory University African American Vaginal, Oral, and Gut Microbiome in Pregnancy Cohort Study

  The Emory University African American Microbiome in Pregnancy Cohort Study prospectively enrolls African American women between 18-40 years of age without chronic medical conditions into a longitudinal follow-up study that involves completing microbiome sampling and data collection at two time points in pregnancy (8-14 weeks gestation and 24-30 weeks gestation). The study is investigating the role of the oral, vaginal, and gut microbiome on preterm birth and other pregnancy outcomes as well as biobehavioral factors that shape the microbiome among this socio-demographically diverse group of women. Microbiome sampling involves the oral, vaginal, and gut sites. Biobehavioral factors that are being explored for their association with microbiome composition at the three body sites include measures of sociodemographic status as well as diet and nutrition, infectious and stress exposures.

  Study phs001865

• Glioma International Case Control Study (GICC)

  The main goals of the GICC Study were: 1) to identify novel genetic risk variants for glioma, as well as validate variants implicated by previous genome-wide association studies of glioma; and 2) to explore biologically relevant gene-gene and gene-environment interactions in glioma susceptibility. The GICC Study includes participants from the following centers: Brigham and Women's Hospital (Boston, Massachusetts), Case Western Reserve University (Cleveland, Ohio), Columbia University (New York, New York), the Danish Cancer Society Research Centre (Copenhagen, Denmark), Duke University (Durham, North Carolina), the University of Texas MD Anderson Cancer Center (Houston, Texas), Memorial Sloan Kettering Cancer Center (New York, New York), the Mayo Clinic (Rochester, Minnesota), NorthShore HealthSystem (Chicago, Illinois), Umea University (Umea, Sweden), the University of California, San Francisco (San Francisco, California), the University of Southern California (Los Angeles, California), and the Institute of Cancer Research (London, United Kingdom).

  Study phs001319

• Natural History of and Genetic Modifiers in Spinocerebellar Ataxias

  Spinocerebellar ataxias (SCA) are genetic neurological diseases that cause imbalance, poor coordination, and speech difficulties. There are different kinds of SCA and this study will focus on types 1, 2, 3, and 6 (SCA 1, SCA 2, SCA 3, also known as Machado-Joseph disease and SCA 6). The diseases are rare, slowly progressive, cause increasingly severe neurological difficulties and are variable across and within genotypes. The purpose of this research study is to bring together a group of experts in the field of SCA for the purpose of learning more about the disease. The research questions are: How does the disease progress over time? What are the best ways to measure disease progression? Do some genes, other than the gene that is abnormal in the SCA disease, have any effect on the way the disease behaves?

  Study phs001332

• Gabriella Miller Kids First Pediatric Research Program in Genetics at the Intersection of Childhood Cancer and Birth Defects

  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 pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). 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. Birth defects and childhood cancer share biological pathways that are important for cell growth and division. We propose that sequencing pediatric patients suffering both conditions will allow us to discover the underlying genes and in turn advance our understanding of the causes of these devastating diseases.

  Study phs001846

• Genome-wide Association Study and Meta-Analysis of Ewing Sarcoma

  We combined a set of 122 French Ewing sarcoma (EWS) cases from the Institut Curie, 19 EWS cases from the National Cancer Institute (NCI) Center for Cancer Research (CCR), and 29 EWS cases from the NCI Bone Disease and Injury Study. All EWS cases were confirmed by medical record review and the presence of a specific EWSR1-ETS translocation were noted when data was available. Each participant provided informed consent and each participating study was approved by the Institutional Review Boards of their study center. DNA was extracted using standard methods from blood, saliva (Oragene), or buccal cells. All de novo genotyping of EWS cases was performed at the NCI CGR on the Illumina OmniExpress-24 v1.1 array. Genotyping was performed according to manufacturer's guidelines using the Infinium HD Assay automated protocol.

  Study phs001549

• NIDDK International IBD Genetics Consortium Repository Global Screening Array

  The purpose of this GWAS meta-analysis is to assess IBD risk alleles using data collected by members of the International IBD Genetics Consortium and their collaborators around the world. Data from over 30 cohorts have been identified and are being combined for analysis. Genotyping has been conducted using a variety of chips with most samples genotyped using GSAMD-24v1-0 or GSA-CHO-Custom. Individual level genotype data will be made available whenever possible (some groups are only able to provide summary statistics due to institutional and/or governmental restrictions on data sharing), together with information on sex, self-reported ancestry, IBD affection status and diagnosis. This first batch includes data from North American sites who are members of the NIDDK-funded IBD Genetics Consortium. Additional data will be provided in an update as soon as they have gone through the QC process.

  Study phs002336

• Genomic analysis of primary plasma cell leukemia reveals complex structural alterations and high risk mutational patterns

  Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) that is characterized by poor overall survival despite advances in anti-MM therapy. The disease biology as well as molecular mechanisms that distinguish pPCL from non-pPCL MM remain poorly understood. In an attempt to identify key biological mechanisms that result in the aggressive pPCL phenotype we performed whole exome sequencing in 23 patients with newly diagnosed pPCL. The results reveal an enrichment of complex structural changes and high risk mutational patterns in pPCL that explain, at least in part, the aggressive nature of the disease. In particular pPCL patients with traditional low risk features such as translocation t(11;14) or hyperdiploidy accumulated adverse risk genetic events that could account for the poor outcome in this group.

  Study phs002022

• The Epilepsy Phenome/Genome Project

  The Epilepsy Phenome/Genome Project (EPGP) is a large-scale, international, multi-institutional, collaborative research project, sponsored by the National Institute of Neurological Disorders and Stroke, designed to understand the genes that cause common and rare epilepsies. The overall goal of EPGP is to collect detailed, high quality phenotypic (i.e., characteristics of individuals, from the molecular level to the whole person) information on persons with epilepsy and to compare the phenotypic information with genomic information. 27 clinical centers enrolled more than 4,100 participants of families with epilepsy. EPGP will provide a resource that may lead to many discoveries related to the diagnosis and treatment of epilepsy, including the eventual development of new therapies based on a better understanding of causes of the disorder. Documents and questionnaires that provide context to the variables and measurements available through the current study, are available for download from EPGP: Download EPGP Forms.

  Study phs000742

• Sexual dimorphism in human immune system aging

  We isolated peripheral blood mononuclear cells (PBMCs) from 172 community-dwelling healthy volunteers (91 women, 81 men) ages spanning adult lifespan: 54 young (ages 22-40: 23 men, 31 women), 59 middle-aged (ages 41-64: 31 men, 28 women), and 59 older subjects (65+: 27 men, 32 women). PBMCs were profiled using ATAC-seq (54 men, 66 women), RNA-seq (41 men, 34 women), and flow cytometry (62 men, 67 women). Flow cytometry data is publicly available, genomic data for 121 individuals are provided here. These datasets revealed immune system aging signatures in men and women and showed in which ways aging differentially affects the immune systems of men and women. A subset of these samples have been generated and analyzed previously and can be found at EGA (EGAS00001002605). This dataset on dbGaP include EGA samples as well.

  Study phs001934

• Infant Immune Responses to Early Life Vaccinations

  Infants are vulnerable to life-threatening infections due to an immature immune system. For this reason, vaccinations are provided early in life to increase protection against infectious agents. However, there is a limited understanding on how routine vaccinations alter the different immune cell populations in infants. Here, we profiled peripheral blood mononuclear cells (PBMCs) from six 2-month-old infants at the time of their routine vaccinations. Infants received the standard vaccinations including DTaP (diphtheria, tetanus and acellular pertussis), IPV (inactivated polio vaccine), Hep B (hepatitis B), Hib (Haemophilus influenzae type B), Rotavirus, and PCV13 (pneumococcus conjugate vaccine). Samples were obtained before vaccination, and subsequently around one week, and two-month post-vaccination (n=18 samples). This study sheds light on the dynamic nature of the infant peripheral immune cell transcriptome upon initial routine vaccine exposure. The processed data is available on GEO under GSE204716.

  Study phs002926

• The Role of ZEB2 during Human Neural Crest Cell Formation

  This study examined the role of ZEB2 during human neural crest cell formation. Human neural crest cells were differentiated from WiCell H1 human embryonic stem cells (WA01). Genome-wide transcriptional analysis (RNA-seq) was performed at day-3 and day-5 of human neural crest cell formation following siRNA knockdown of ZEB2 and using an N-terminal ZEB2 mutant H1 human embryonic stem cell line generated using CRISPR genome editing. RNA-seq was also performed on edited and unedited H1 human embryonic stem cells. ATAC-seq analysis was performed at day-3 and day-5 human neural crest differentiated from the N-terminal ZEB2 mutant embryonic stem cell line. Together, these data reveal the regulatory role of ZEB2 in the human neural crest gene regulatory network. We provide raw sequencing files for all RNA-seq and ATAC-seq samples.

  Study phs002701

• Characterization of Macrophage-Tropic HIV Infection of Central Nervous System Cells and the Influence of Inflammation

  In this study, we utilize macrophage-tropic and T cell-tropic HIV-1 Env proteins to establish accurate infection profiles for multiple CNS cells under basal and interferon alpha (IFN-α) or lipopolysaccharide (LPS)-induced inflammatory states. We found that macrophage-tropic viruses confer entry advantages in primary myeloid cells, including monocyte-derived macrophages, microglia, and induced pluripotent stem cell (iPSC)-derived microglia. Following 24-h IFN-α or LPS treatments, total RNA was harvested from 100,000 to 200,000 cells using an RNeasy RNA isolation kit (Qiagen, 74004). RNA was quantified using a NanoDrop spectrophotometer and TapeStation electrophoresis prior to library preparation. cDNA libraries were prepared using the KAPA RNA HyperPrep kit (Roche, 08098115702). Paired-end RNA sequencing was performed on a NovaSeq S4 platform at a read length of 100 bp, resulting in approximately 60 million reads per sample.

  Study phs003306

• NHLBI TOPMed - NHGRI CCDG: Malmo Preventive Project (MPP)

  The Malmö Preventive Project (MPP) was a community-based disease prevention program including 33,346 inhabitants from the city of Malmö in Southern Sweden. Complete birth cohorts between 1921-1949 were invited, and the participation rate was 71%. Participants underwent screening between 1974 to 1992 for cardiovascular risk factors, alcohol abuse, and breast cancer. Between 2002-2006, surviving participants were invited to a reexamination which included blood sampling from which DNA has been extracted. Subjects with prevalent or incident AF were identified from national registers as previously described, and cases with DNA were then matched in a 1:1 fashion to controls with DNA from the same cohort by sex, age (±1 year), and date of baseline exam (±1 year). Also, controls required a follow-up exceeding that of the corresponding AF case.

  Study phs001544

• Sequencing Lymphoma

  This repository contains sequencing data to describe the genomic profiles of several B-cell lymphomas including follicular lymphoma and Hodgkin lymphoma. We have used several different high throughput sequencing technologies to interrogate genomic DNA and RNA from tumor cells obtained from lymph node biopsies and normal cells obtained from skin biopsies and peripheral blood mononuclear cells. A number of sequencing platforms for DNA, RNA, and protein were used to generate the data. These platforms include exome sequencing and a custom capture panel (NimbleGen) that targets 7.05 MB corresponding to the exons and splice sites of 1716 genes related to lymphoma biology (WUSM-LP). Other platforms include single-cell RNA-seq and Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq), which was used to describe transcriptional and proteomic changes in immune cell subsets within lymphoma patients pre- and post-therapy.

  Study phs001229

• Combined PDCD1, BRAF and MAP2K7 Inhibition in BRAFV600E Colorectal Cancer: A Phase 2 Trial

  In this study, we evaluated the clinical efficacy of combined PDCD1, BRAF, and MAP2K7 inhibition in metastatic BRAFV600E Colorectal Cancer (CRC) patients (NCT03668431). We performed bulk whole exome sequencing (WXS) and bulk RNA sequencing (RNA-Seq) in 35 pre-treatment tumor biopsies and matching germline for tumor mutational burden (TMB), BM1/BM2 transcriptional subtypes, and consensus molecular subtypes (CMS) analysis, which were previously reported to affect prognosis and response to therapy (PMIDs: 32047001, 27354468, and 26457756). Analysis of bulk data showed that TMB, BM1/BM2 subtypes, and CMS did not correlate with clinical response in this study. Analysis of single cell RNA sequencing (scRNA-Seq) data of tumor epithelial cells from 23 paired day 0 and day 15 tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome.

  Study phs003178

• Transfer Learning Associates CAFs with EMT and Inflammation in Tumor Cells in Human Tumors and Organoid Co-Culture in Pancreatic Ductal Adenocarcinoma

  This study examined the transcriptional changes induced by cancer associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma patient-derived tumor organoids. We hypothesized that cancer associated fibroblasts impacted tumor cell transcription to promote tumorigenic behavior. Using patient-matched cells from 3 patients, we compared the transcriptional profiles of patient-derived organoids in monoculture to patient-derived organoids co-cultured with CAFs. Similarly, we looked at the transcriptional changes in matched patient-derived cancer associated fibroblasts grown in monoculture or co-cultured with patient-derived organoids. With a focus on intercellular crosstalk, we identified crosstalk between cancer associated fibroblasts and patient-derived organoids through VEGFA and NRP1. This was identified by bulk RNA sequencing and examined dynamically in organoid-CAF co-culture. This dbGaP deposit is the bulk RNA sequencing data for these 3 patients.

  Study phs003563

• Shotgun Transcriptome and Isothermal Profiling of SARS-CoV-2 Infection Reveals Unique Host Responses, Viral Diversification, and Drug Interactions

  In less than nine months, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has killed hundreds of thousands of people, including >23,000 in New York City (NYC) alone. The pandemic's sudden emergence highlights the clinical need to detect infection, track strain evolution, and identify biomarkers of disease course. To address these challenges, we provide large-scale shotgun metatranscriptomics (total-RNA-seq) for host, viral, and microbial profiling. In version 1, we sequenced a total of 732 clinical specimens (nasopharyngeal (NP) swabs) gathered from 669 unique patients in New York City during the first two months of the outbreak. In version 2, we sequenced an additional 168 clinical specimens from autopsy tissues (lung, heart, kidney, liver, and lymph node) from 60 patients, yielding a broad molecular portrait of the emerging COVID-19 disease across 900 clinical specimens and 729 patients.

  Study phs002258

• NHLBI TOPMed: Stanford Cardiovascular Institute iPSC Biobank Study (SCVI)

  The proposed Stanford Cardiovascular Institute (SCVI) Biorepository will curate and manage an expanded collection of human induced pluripotent stem cell (iPSC) lines and provide investigators with iPSC materials generated using standardized protocols, with the overall objective of promoting the continued adoption and development of iPSC technology in cardiovascular research. Human iPSCs have revolutionized disease modeling, drug screening, and therapeutic research. However, it is also recognized that the need for specialized technical expertise and the associated cost have largely prevented individual research laboratories from adopting iPSC models in their inquiries, particularly in studies requiring multiple cell lines. To address this bottleneck, the proposed Biorepository will maintain our existing collection of iPSC lines and further expand the collection of iPSCs by recruiting 1,000 healthy, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) donors of both sexes and diverse racial/ethnic backgrounds (African Americans, Asians, Hispanics, and Whites).

  Study phs002338

• "Distinct immunometabolic signatures in circulating immune cells define disease outcome in acute-on-chronic liver failure"

  We performed single-cell transcriptomics of PBMC’s from healthy (n= 3), acute decompensated (AD) (n= 3) and Acute-on-chronic liver failure (ACLF) patients. Lay Summary: Acute-on-chronic liver failure (ACLF) develops in cirrhotic patients and is characterized by an hyper-inflammatory immune state driving multiple organ failure(s). As a paradox, circulating immune cells also show transcription and metabolic evidence of exhaustion, explaining why these patients are often susceptible to secondary infections. We characterized at a transcriptional level all circulating immune cells of ACLF patiens, and specifically unraveled a distinct recovery and non-recovery ACLF signature within the monocyte population. Moreover, these changes were closely linked to metabolic differences within these cells. The described alterations allowed for a robust prediction of recovery and non-recovery of patients at admission to the hospital.

  Study EGAS50000000391

• Beta-Blocker Evaluation in Survival Trial (BEST-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 The Beta-Blocker Evaluation of Survival Trial was designed to determine whether bucindolol hydrochloride- a nonselective beta-adrenergic blocker and mild vasodilator- would reduce the rate of death from any cause among patients with advanced heart failure and to assess its effects in various subgroups defined by ethnic background and demographic criteria- specifically women and members of minority groups. Background Although beta-adrenergic-receptor antagonists reduce morbidity and Mortality in participants with mild-to-moderate chronic heart failure, their effort on survival in participants with more advanced heart failure is unknown. Participants There were 2,708 participants. Conclusions Bucindolol resulted in no significant overall survival benefit. (Krause-Steinrauf et al., 2001, PMID: 11386264).

  Study phs003730

• Is the Gut Important in Multiple Joint Osteoarthritis? A Multimodal Investigation in Humans and Pet Dogs

  The Gut Health in Multiple Joint Osteoarthritis (MJOA) Study leverages data from parallel community-based cohorts in humans and in pet dogs to elucidate the role of altered microbiota in MJOA. One hundred Johnston County Health Study human participants were 35 to 70 years of age at enrollment (2022-2023), self-identified as Hispanic, White, or Black, and lived in Johnston County, North Carolina. Demographic, clinical information, multiple joint radiographs, and stool samples for microbiome profiling by 16S rRNA gene sequencing were obtained from all participants. Similar data were collected from an independent group of pet dogs (N=115) from the local community, at the North Carolina State University (NCSU) College of Veterinary Medicine. The central hypothesis of the study is that intestinal permeability, with or without dysbiosis, is a major driver in the development and worsening of MJOA.

  Study phs003980

• Identification and characterization of tertiary lymphoid structures in brain metastases

  Brain metastases (BrM) are the most common cancers in the brain. We performed transcriptome-wide gene expression profiling combined with spatial immune cell profiling to characterize the tumor immune microenvironment in BrM from different primary tumors. We found that BrM from lung carcinoma and malignant melanoma showed overall higher immune cell infiltration as compared to BrM from breast carcinoma. RNA sequencing-based immune cell deconvolution revealed gene expression signatures indicative of tertiary lymphoid structures (TLS) in subsets of BrM from lung cancer and melanoma. This finding was corroborated by multiplex immunofluorescence staining of immune cells in BrM tissue sections. Detection of TLS signatures was associated with prolonged survival after BrM diagnosis in lung cancer patients. Our findings highlight the cellular diversity of the tumor immune microenvironment in BrM of different cancer types and suggest a role of TLS formation for BrM patient outcome.

  Study EGAS50000000563

• 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.

  Study EGAS50000000582

• High volume culture initiating in vitro evolution in neuroblastoma cell lines

  Despite the advent of advanced molecular prognostic tools, it is still difficult to predict the course of disease for cancer patients at the individual level. This lack of predictability is also reflected in many experimental cancer model systems, begging the question of whether certain biological aspects of cancer (eg. growth, evolution etc.) can ever be anticipated or if there remains an inherent unpredictability to cancer, similar to other complex biological systems. We demonstrate by a combination of agent-based mathematical modelling, analysis of patient-derived xenograft systems from multiple cancer types, and in-vitro culture that certain conditions may invoke chaotic fluctuations in the clonal landscape of cancer growth. Our findings indicate that under those conditions, the cancer genome may behave as a complex dynamic system, making its long-term evolution inherently unpredictable.

  Study EGAS00001007962

• RNA Ligation Precedes U6 snRNA/LINE-1 Retrotransposition

  Long Interspersed Element-1 (L1) retrotransposons make up approximately 17% of the human genome. L1 moves throughout the genome via a copy-and-paste mechanism termed retrotransposition. L1 retrotransposition also mobilizes other cellular RNAs such as SINES, U6 snRNA and, mRNA, which for the latter results in the formation of processed pseudogenes. In this study we demonstrate that the RNA ligase RtcB can create chimeric RNAs by joining U6 snRNAs to 5'-truncated L1 or other cellular RNAs. We also show that the retrotransposition of U6/L1 chimeric RNA leads to U6/L1 pseudogene formation. In sum, our data suggests that U6 snRNA and RtcB may have biological roles in addition to their essential functions in mRNA and tRNA splicing, and that the retrotransposition of chimeric RNAs could be a mechanism to create novel genes.

  Study phs001671

• Transcriptome of human trophoblast stem cells derived from normal and HDP placentas

  Hypertensive disorders of pregnancy (HDP) is a disease driven by abnormal placenta formation, which is a leading cause of maternal and fetal death. For investigation of genetic and epigenetic regulation of human trophoblast differentiation, we have previously established human trophoblast stem cells (hTSCs) from first-trimester placentas. Those hTSCs were able to differentiate into extravillous trophoblasts (EVTs) and syncytiotrophoblasts (STs), and their transcriptome was similar to that of cytotrophoblasts in human placenta. However, since HDP happens in the second half of pregnancy, the conventional hTSC derivation method was not enough to investigate the nature of HDP trophoblasts. In this analysis, we improved the derivation method and successfully established the hTSCs from normal and HDP term placentas after delivery. We performed RNA-seq of normal and HDP hTSCs, and HDP hTSCs recapitulated abnormalities in gene expression reported in HDP placentas.

  Study JGAS000660

• The Formation and Propagation of Human Robertsonian Chromosomes

  Robertsonian chromosomes are a type of variant chromosome found commonly in nature. Present in one in 800 humans, these chromosomes can underlie infertility, trisomies, and increased cancer incidence. Recognized cytogenetically for more than a century, their origins have remained mysterious. Recent advances in genomics have allowed us to assemble three human Robertsonian chromosomes completely. We identify a common breakpoint and epigenetic changes in centromeres that provide insight into the formation and propagation of common Robertsonian translocations. Further investigation of the assembled genomes of chimpanzee and bonobo highlights the structural features of the human genome that uniquely enable the specific crossover event that creates these chromosomes. Resolving the structure and epigenetic features of human Robertsonian chromosomes at a molecular level will pave the way to understanding how chromosomal structural variation occurs more generally, and how chromosomes evolve.

  Study phs003920

• The Emirati T2T-level Pangenome: A complete Diploid Graph of 58 Genomes

  This study presents a comprehensive Emirati telomere-to-telomere level (T2T) pangenome, constructed from 116 haplotype-resolved assemblies generated from 58 individuals, including 28 trio-based and 30 single-sample assemblies. The assemblies exhibit high contiguity (median 150 Mb) and high consensus accuracy (median QV 59), with 71.9% of chromosomes reaching T2T-level scaffold status. The resulting pangenome graph captures both globally shared and regionally enriched genetic variation, including sequences in complex regions that are inaccessible to less complete assemblies. Comparisons indicate diversity levels comparable to those of the Human Pangenome Reference Consortium, while highlighting unique Emirati genomic features. This reference forms a key resource for human pangenomics and precision medicine in the UAE. This work provides a foundational resource to improve variant discovery and genome annotation, contributing vital diversity data to global pangenomics efforts and enabling precision medicine in the region.

  Study EGAS50000001232

• A proteogenomic atlas of the human neural retina

  The human neural retina is enriched for alternative splicing, and it is estimated that more than 10% of variants associated with inherited retinal diseases (IRDs) alter splicing. Previous research mainly used short-read RNA-sequencing techniques to investigate retina-specific splicing and splicing factors. However, this technique provides limited information about transcript isoforms. To gain a deeper understanding of the human neural retina and its isoforms, we generated a proteogenomic atlas that combines PacBio long-read RNA-sequencing data with mass-spectrometry and whole-genome sequencing data from three healthy human neural retina samples. About one third of the nearly 60,000 transcript isoforms were novel, and ten novel peptides that confirmed novel isoforms were detected. This study highlights the importance of studying tissue-specific transcriptomes in greater detail to better understand tissue-specific regulation and to identify disease-causing variants.

  Study EGAS50000000070

• Whole genome sequencing data from tumor and normal samples

  Whole genome sequencing FASTQ files from tumor and normal samples from 202 patients. All experiments reported in this article were performed in the Clinical Laboratory Improvement Amendments (CLIA)-certified and College of American Pathologists (CAP)-accredited laboratories at Personalis Inc., as guided by the Association for Molecular Pathology (AMP) and CAP’s joint recommendations52. Preferred input material consisting of FFPE slides (enabling H&E and macrodissection which is part of the standard NeXT Personal process) was not available for the majority (94%) of tumor samples. Most tumor samples (72%) were processed from FFPE curls, with the remaining processed from pre-extracted DNA and fresh frozen material. Where FFPE material on slide was available, tumor sections were macrodissected to increase tumor content, with a minimum allowable cellularity threshold of 20% determined by pathological review. The tumor cellularity threshold of 20% was chosen based on prior work demonstrating that no significant correlation is observed between tumor purity and assay limit of detection (LOD) at this threshold31. Genomic DNA was isolated from tumor and normal samples and WGS libraries prepared as previously described31. Genomic DNA was isolated from matched tumor and normal samples using the Qiagen AllPrep DNA/RNA FFPE Tissue Kit or the QIAamp DNA Mini Kit (QIAGEN, Germantown, MD, USA) using internally optimized workflows. WGS sequencing libraries were prepared with 120-500 ng of acoustically sheared genomic DNA (Covaris LLC, Woburn, MA, USA) using the KAPA HyperPrep Kit (Roche Sequencing Solutions, Pleasanton, CA, USA) and customized methods. Libraries were cleaned-up using AMPure XP beads and then quantified using the KAPA Library Quantification Kit (Roche Sequencing Solutions, Pleasanton, CA, USA), before being sequenced to 30X depth of coverage using a NovaSeq 6000 instrument (Illumina, San Diego, CA, USA).

  Dataset EGAD50000001909

• LifeChange Data Access Committee

  The LifeChange study aimed at tracking the biological consequences of the societal changes undergone by the Yakut people of Far Eastern Siberia, after the colonization of the region by Russians in the 17th century. This study builds upon more than 15 years of archaeological research conducted in Yakutia, Sakha Republic, an autonomous region of the Russian Federation located in northeastern Siberia. The fieldwork was conducted under the MAFSO program (“Mission Archéologique Française en Sibérie Orientale”, or “French Archaeological Mission in Eastern Siberia”), a collaboration between French researchers and local Yakut experts, including scholars from North-Eastern Federal University in Yakutsk. The program was supported by several inter-university collaborative research agreements, notably between Université Paul Sabatier, Krasnoyarsk State Medical University, and North-Eastern Federal University in Yakutsk. It also received endorsement from the Institute of Ecology and Evolution at CNRS through the International Associated Laboratory “Co-evolution Human-Environment in Eastern Siberia”. The LifeChange Data Access Committee, composed of French and Russian archaeogeneticists, geneticists and archaeologists, reviews any access request to LifeChange data, consisting of genomes of ancient and modern Yakut, Eveni and Evenki individuals sampled in Eastern Siberia for the LifeChange study. The DAC grants access to any academic researcher aiming to study the population history of autochthonous peoples from Siberia. When reviewing data access requests, the DAC members ensure that the applicant will not re-use the data to trace present-day descendants of studied ancient individuals. They also ensure that secondary use of the modern genomic data is conducted in full respect of the conditions stipulated in living participants’ informed consent. Specifically, the applicant is not authorised to (i) use the data for diagnostic purposes, (ii) store the data outside of secure servers, (iii) reidentify research participants, and (iv) share the data with a third party.

  Dac EGAC50000000713

• The Multiomics Blueprint of the Individual with the Most Extreme Lifespan

  Although centenarians are becoming more common in the demography of human populations, the so-called supercentenarians (over 110 years old) are still a rarity. In Catalonia, the historic nation where the subject lived, the life-expectancy for women is 86 years old, so she exceeded more than 30 years the mean statistical value. In a similar manner that premature aging syndromes, such as Hutchinson-Gilford Progeria and Werner syndrome, can provide relevant clues about the mechanisms of aging; the study of supercentenarians might also shed light in the pathways involved in lifespan. To unfold the biological properties that exhibited such a remarkable human being, we developed a comprehensive multiomics analysis in different tissues of her genomic, transcriptomic, metabolomic, epigenomic and microbiomic landscapes , comparing the results with those observed in non-supercentenarian populations.

  Study EGAS50000000884

• DNA methylation dynamics during early human development

  DNA methylation is globally reprogrammed during mammalian preimplantation development, which has been well characterized in the mouse but not in other mammals. Here we report on the single base-resolution DNA methylome of human gametes and blastocysts. Near complete demethylation of the paternal genome was apparent, except for tandem repeat-containing CpG-rich regions, whereas the maternal genome was essentially resistant to replication-dependent global demethylation. The human oocyte methylome was characterized by a unique bimodal distribution of gene body methylation, a particular promoter methylation profile and a high proportion of hypomethylated transposable elements. Methylome and transcriptome comparisons between the human and mouse suggested species-specific regulation of many genes including the important DNA methylation regulators. Our findings are essential to understand the unique gene regulatory mechanisms during early human development and will facilitate preimplantation epigenetic diagnosis of human embryos.

  Study JGAS000006

• Controlling cell differentiation with precision through understanding the structure and dynamics of gene regulatory networks

  We established a set of transgenic human ES cell lines that carry inducible expression gene cassette for singe transcriptional factor induction with Tet-ON system. Transcriptome data was obtained 48h after transgene induction by Microarray. We established inducible human ES lines about more than 700 genes, and achieved microarray analysis on 115 genes. Our data set has multiple characteristic properties; 1) the same platform across data set, 2) analyzed with dynamic cell status, 3) pre-determined initiation point on gene perturbation, 4)inducible in different cell status. In parallele, we also performed RNA sequenncig analysis on 435 transgene induced ES lines as well. 32 transgene induced transcriptome data were obtained from both Microarray and RNA sequencing, normalizing technical gaps between them. We hope those systematic data set to reveal transcriptional network structure and molecular mechanisms of cell differentiation.

  Study JGAS000121

• Establishment of xenogfafts and cultured cell lines from clinical samples

  The purpose of the present study was to clarify the presence or absence of alterations in the molecular properties of patient-derived xenografts (PDXs) with up to eight passages in endometrial carcinomas. Alterations in the proportion of immunohistochemically positive/negative cells for PAX8, estrogen receptor, PAX2, and PTEN were observed in established PDXs of endometrioid carcinomas and carcinosarcomas, whereas proportions of cells with AE1/AE3, TP53, ARID1A PMS2, and MSH6 were maintained. Variants of cancer-associated genes in PDX compared to those in the parental tumors were examined in two cases, a frameshift deletion in BRCA1 was observed in the parental tumor tissue, and additional genomic alterations were found in the PDXs of this case. Genomic and phenotypic alterations in endometrial carcinoma PDXs relative to the parental tumors were observed and were partly associated with endometrial cancer-specific characteristics in cellular differentiation and gene mutations.

  Study JGAS000585

• The function of circular RMST in neuroendocrine tumours

  Circular RNA (circRNA) is a class of noncoding RNA with regulatory potentials. Its role in the transdifferentiation of prostate and lung adenocarcinoma into neuroendocrine prostate cancer (NEPC) and small cell lung cancer (SCLC) remains unexplored. Here we identified circRMST as an exceptionally abundant circRNA predominantly expressed in NEPC using total RNA-seq profiling of patient samples. In addition, circRMST is also abundantly expressed in SCLC. Functional studies using shRNA, siRNA, CRISPR-Cas13 and Cas9 consistently demonstrate that circRMST is essential for tumour growth and the expression of ASCL1, a master regulator of neuroendocrine fate. Mechanistically, circRMST physically interacts with lineage transcription factors NKX2-1 and SOX2. Loss of circRMST induces NKX2-1 protein degradation through autophagy-lysosomal pathway and alters the genomic binding of SOX2, collectively leading to the loss of ASCL1 transcription.

  Study EGAS50000000897

• Cell-type, allelic and genetic signatures in the human pancreatic beta cell transcriptome

  Pancreatic beta cells within the islets of Langerhans are centrally involved in the pathogenesis of both type 1 and type 2 diabetes. Describing the differentiated state of the human beta cell has been hampered so far by technical (low resolution microarrays) and biological limitations (whole islet preparations rather than isolated beta cells). We circumvent these by deep RNA sequencing of purified beta cells from 11 individuals, presenting here the first characterization of the human beta cell transcriptome. Additionally, we perform the first comparison of gene expression profiles between beta cells, whole islets (N=7) and beta cell depleted islet preparations (N=5), revealing thus beta cell specific expression signatures. Finally, we combine this with whole-genome sequencing data for 7 of our donors, describing here the first set of genetic variants controlling inter-individual variability in beta cell gene expression.

  Study EGAS00001000442

• Genomic profile of sporadic multiple meningiomas

  Molecular mechanisms underlying the formation of sporadic MMs and clonal formation etiology of these tumors are poorly understood. In this study, we worked on a cohort of patients with spatially separated MMs without prior radiation exposure or a family history who underwent surgical resection of at least two meningiomas. Unbiased, comprehensive next generation sequencing was performed and relevant clinical data was analyzed. We identified that both NF2-loss and non-NF2 driven MMs can form due to monoclonal expansion and those tumors can acquire inter-tumoral heterogeneity through branched evolution. Grade I and II meningiomas can occur in the same patient. Thus, the molecular make-up and clinical behavior of one tumor in MMs, cannot reliably lend insight into that of the others and suggests the clinical management strategy for MMs should be tailored individually.

  Study EGAS00001005700

• RNA-seq, WGS and WES of Hepatocellular carcinomas, enriched in fibrolamellar carcinomas

  DNAJB1-PRKACA fusion is a specific driver event in fibrolamellar carcinoma (FLC), a rare subtype of hepatocellular carcinoma (HCC) occurring in adolescents and young adults. In older patients, molecular determinants of HCC with mixed histological features of HCC and FLC (mixed-FLC/HCC) remain to be discovered.This study aims to molecularly caracterize mixed fibrolamellar hepatocellular carcinoma (mixed FLC/HCC) within the molecular liver tumors diversity, in respect of pure FLC and different HCC subtypes. This study reunites WGS data (n=3, Tumoral/Non-Tumoral pairs), WES data (n=43, Tumoral/Non-Tumoral pairs) and RNAseq data (n=66, Tumoral only). On a trascriptomic level, most of the mixed-FLC/HCC RNAseq clustered in a robust subgroup of tumors all showing mutation or translocation inactivating BAP1 that codes for the BRCA1 associated protein-1.

  Study EGAS00001003837

• ALK_inhibitors_in_the_context_of_ALK_dependent_cancer_cell_lines

  Anaplastic lymphoma kinase (ALK) has recently been found to be a critical cancer gene in cases of lung cancer, neuroblastomas and lymphomas. ALK inhibitors have recently shown significant activity in lung cancer patients with tumours that harbour the EML4-ALK gene rearrangement, but already drug-resistance is emerging. We have taken a lung cancer cell line H3122 (with the EML4-ALK rearrangement) and generated clones resistant to a small molecule inhibitor of ALK by serial exposure to the drug over 8 weeks. We now wish to characterise at the exome level whether the acquisiton of resistance has been accompanied by the development of new mutations that we can take forward for further study as the potential mechansims underlying the resistance. We therefore propose to exome sequence the parental NCI-H3122 cell line as well as drug-resistant clones.

  Study EGAS00001000082

• TRACERx: TRAcking non-small cell lung Cancer Evolution through therapy (Rx). Pilot Study. Multi-region sequencing of early-stage NSCLCs.

  Deciphering the complexity of non-small cell lung cancer (NSCLC) evolutionary histories may elucidate the basis for its dismal outcome. We performed multi-region sequencing of early-stage NSCLCs. Spatial dissection revealed branched tumor evolution, with driver mutations occurring before and after subclonal diversification. Intra-tumor heterogeneity in DNA copy number alterations, translocations and endogenous APOBEC mutational processes demonstrates that NSCLC may follow multiple distinct evolutionary trajectories simultaneously. In smokers, despite maintained carcinogen exposure, temporal dissection reveals a relative decrease in smoking-related mutations during tumor progression, accompanied by an increase in APOBEC-related mutations. In the tumors from ex-smokers, genome-doubling occurred before subclonal diversification, suggesting prolonged latency before clinical detection. Multi-region sequencing demonstrates the relentless and heterogeneous nature of genomic instability processes in early-stage NSCLCs.

  Study EGAS00001000809

• Investigate the evolutionary trajectories during invasiveness acquisition in early lung adenocarcinoma

  The evolutionary trajectories of early lung adenocarcinoma (LUAD) have not been fully elucidated. We hypothesize that genomic analysis between pre-invasive and invasive components will facilitate the description of LUAD evolutionary patterns. We micro-dissect malignant pulmonary nodules (MPNs) into paired pre-invasive and invasive components for panel-genomic sequencing and recognize three evolutionary trajectories. Evolutionary mode 1 (EM1) demonstrates none of the common driver events between paired components, but another two modes, EM2A and EM2B, exhibit critical private alterations restricted to pre-invasive and invasive components, respectively. When ancestral clones harbor EGFR mutations, truncal mutation abundance significantly decrease after the acquisition of invasiveness, which may be associated with the intratumoral accumulation of infiltrated B cells. Harboring EGFR mutations is critical to the selective pressure and further impacts the prognosis. Our findings extend the understanding of evolutionary trajectories during invasiveness acquisition in early LUAD.

  Study EGAS00001004754

• Network-based systems pharmacology identifies heterogeneity in LCK and BCL2 signaling and differential vulnerability of T-cell acute lymphoblastic leukemia to targeted therapy

  T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and novel therapeutics are much needed. Profiling patient leukemia’ drug sensitivities ex vivo, we discovered striking inter-patient variability in T-ALL response to a panel of targeted agents. Applying network-based systems pharmacology analyses, by integrating ex vivo pharmacotyping, bulk and single-cell RNA-seq, genomics, phospho-proteomics, and genome-wide CRISPR screening data, to examine signal circuitry, we identified the pharmacogenomic basis of T-ALL drug response and revealed a therapeutic vulnerability that is directly related to the developmental stage of leukemia cells. In conclusion, our results indicate that heterogeneity in the differentiation of T-ALL drives activation of key signaling pathways in this leukemia, providing unique opportunities for targeted therapy.

  Study EGAS00001004700

• Tracing the origins of relapse in AML to stem cells

  In acute myeloid leukemia (AML), most patients relapse despite achieving remission. While relapse-specific mutations are sometimes detected at low frequency within bulk diagnosis samples, the cell type giving rise to relapse is unknown. Through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identified two major patterns of relapse arising from therapy-resistant cells already present at diagnosis. In some cases relapse originated from rare leukemia stem cells with a primitive immunophenotype, while in other instances relapse developed from larger subclones of immunophenotypically-committed cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in AML. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse underscore the importance of developing new therapeutic approaches that target stemness to prevent relapse.

  Study EGAS00001002225

• Exome sequencing data from two myelosarcomas

  Isolated myeloid sarcoma (MS, i.e. acute myeloid leukemia without detectable bone marrow infiltration) is rare and most patients subsequently develop overt AML. We prospectively performed whole exome sequencing of uterine MS, concomitant morphologically normal bone marrow (BM) and subsequently developing AML from two women. Both patients harbored preleukemic clones in the morphologically normal BM, including DNMT3A mutations. In addition, recurrent mutations were identified in the NFE2 gene, a gene not previously associated with AML or isolated MS. Retrospective studies of further MS samples, twelve with and four without preceding or concomitant bone marrow AML, revealed NFE2 mutations in two additional cases, both with isolated MS and prior myeloid malignancies. We conclude that DNMT3A mutated preleukemia may predispose for the frequent bone marrow relapses following isolated MS and that recurrent NFE2 mutations may have a role in the development of isolated MS.

  Study EGAS00001002562

• BLUEPRINT DNase accessibility of Epigenetic programming during monocyte to macrophage differentiation and trained innate immunity

  Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. Transcriptomes and epigenomes in four primary cell types: monocytes, in vitro differentiated naïve, tolerized and trained macrophages were characterized. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and pathways functionally implicated in trained immunity were identified. Strikingly, β-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in DNase I hypersensitive sites at cell-type specific epigenetic loci unveiled differentiation and treatment specific repertoires. Altogether, this study provides a resource to understand the epigenetic changes that underlie innate immunity in humans.

  Study EGAS00001000954

• BLUEPRINT RNA-seq of Epigenetic programming during monocyte to macrophage differentiation and trained innate immunity

  Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. Transcriptomes and epigenomes in four primary cell types: monocytes, in vitro differentiated naïve, tolerized and trained macrophages were characterized. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and pathways functionally implicated in trained immunity were identified. Strikingly, β-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in DNase I hypersensitive sites at cell-type specific epigenetic loci unveiled differentiation and treatment specific repertoires. Altogether, this study provides a resource to understand the epigenetic changes that underlie innate immunity in humans.

  Study EGAS00001000953

• CRLF2_sequencing_project_

  I hope to gain insight into novel genetic aberrations present in these patients that will highlightimportant pathways that are involved in this subtype of leukaemia. It would be interesting to see ifthe mutations and pathways that are activated are consistent between the patients, or differencesare observed dependent upon whether the patient has the translocation or the PAR1 deletion. Ofnote is the high association with either numerical gains of chromosome X or numerical/structuralabnormalities of chromosome 21 (Down syndrome, iAMP21) in patients with CRLF2 deregulation. Ihope to find abnormalities linking chromosomes X and 21 to CRLF2 deregulation in BCP‐ALL. Byincluding the three patients that are normal for CRLF2, but have consistent genetic abnormalitiesfound in the experimental cohort, I expect to find genetic differences between these two groupsthat will help us to identify novel molecular targets specific to CRLF2 deregulation.

  Study EGAS00001000080

• Transcriptome sequencing of Gingivo-buccal Cancer : ICGC-India Project_YR03

  Transcriptome Sequencing of Gingivo-buccal Cancer: ICGC-India ProjectAs a part of the ICGC, India has undertaken genomic studies on gingivobuccal cancer of the oral cavity, which is the most prevalent form of cancer among men in India. There are various known environmental (life-style) correlates of this cancer, the most important of which are tobacco chewing and HPV infection. Transcriptome sequencing of paired RNA samples – isolated from the tumor and adjacent normal tissues of 12 patients – have been performed. Detailed clinical characterization of the patients, collection of data on demographic and environmental exposures, and isolation of DNA samples from adjacent normal and tumor tissues collected from each patient are being done at the Advanced Centre for Research, Treatment and Education on Cancer, Mumbai. Sequencing is being performed at the National Institute of Biomedical Genomics, Kalyani.

  Study EGAS00001002851

• Whole genome characterisation of lung cancer organoids and tissue

  Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here we describe a method to establish long-term expanding human airway organoids from broncho-alveolar biopsies or lavage material. The pseudostratified airway organoid epithelium consists of basal cells, functional multi-ciliated cells, mucus-producing goblet cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoid culture conditions also allow gene editing as well as the derivation of various types of lung cancer organoids. Respiratory syncytial virus (RSV) infection recapitulated central disease features and dramatically increases organoid cell motility, found to be driven by the non-structural viral NS2 protein. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.

  Study EGAS00001002899

• Genomic Heterogeneity and the Small Renal Mass

  Tumor heterogeneity is believed to represent a barrier to pre-operative genomic characterization in kidney cancer. Previous studies of heterogeneity in clear cell renal cell carcinoma (ccRCC) evaluated only large and metastatic tumors. In small renal tumors in which multiple biopsies are not feasible, the extent of heterogeneity remains unknown. In this study, we evaluated how the extent of genomic heterogeneity in small and large ccRCC. A total of 23 small (<4cm ) and 24 large (>7cm ) ccRCC had 3 regions sampled for evaluation of copy number, clear-cell A/clear-cell B (ccA/ccB) classification, and cell cycle progression (CCP) score. Small tumors have less genomic complexity and significantly fewer subclonal events. Pre-treatment genomic characterization based on a single biopsy in small ccRCC can provide insight into biologic potential to make clinical decisions.

  Study EGAS00001002919

• MuTHER_adipose_tissue_small_RNA_expression

  We investigate the naturally occurring variation of small RNA expression in conjunction with genetic and gene expression variation. We shall assess the variation in subabdominal fat tissue small RNA levels in 168 unrelated MuTHER individuals. Using gene expression data from the same samples, we can survey how much the small RNA expression contributes to the variance in gene expression profiles. We can also take advantage of the high density genotyping data on these samples to identify genetic associations of small RNA expression levels, and the downstream effect of the genetic variants in small RNA sequence. Previous small RNA sequencing efforts have also extended the repertoire of small RNAs, and we hope to potentially find additional small RNAs active in adipose tissue biology. Altogether, the project should provide an exciting view into small RNA biology in humans, and lead to development of new methodology for analysis of molecular phenotype data.

  Study EGAS00001000212

• Comparison_of_transcriptional_response_of_induced_pluripotent_stem__iPS__cell_derived_and_monocyte_derived_macrophages_to_bacterial_lipopolysaccharide_stimulation

  In the first part of this project, we will differentiate IPS cells from 5 human donors into macrophages, and extract RNA from unstimulated and LPS stimulated macrophages to perform RNA sequencing. We will also extract RNA before and after stimulation in blood- derived macrophages from 5 additional, unrelated healthy samples. In the second part of the project, RNA-seq data will be analysed to compare LPS response of these two macrophage populations. In summary, we will perform 75bp PE RNA-seq on 20 samples (10 pre and post stimulus), on the HiSeq 2500 platform. Samples will be multiplexed at 5 samples / lane, so we will require 4 flow cells in total.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001000563

• Acquisition_of_additional_mutations_drives_accelerated_progression_of_NPM1_positive_CMML_to_AML_

  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/We performed exome sequencing on serial samples from a patient with CMML who progressed to AML. The exome sequencing suggests that NPM1, TET2 and DNMT3a mutations were present in the dominant clone in the CMML sample and that NRAS is a new subclonal mutation in the AML sample. Diagnostic data shows the presence of a FLT3-ITD mutation in the AML sample, which is likely to have driven progression. Here we are performing re-sequencing of the putative driver and some passenger mutations which appear to be in the same clone to validate these mutations and to verify the relative quantification of these abnormalities .

  Study EGAS00001000619

• Spatial and temporal diversity in genomic instability processes define early stage lung cancer evolution.

  Deciphering the complexity of non-small cell lung cancer (NSCLC) evolutionary histories may elucidate the basis for its dismal outcome. We performed multi-region sequencing on 25 regions from seven early-stage NSCLCs. Spatial dissection revealed branched tumor evolution, with driver mutations occurring before and after subclonal diversification. Intra-tumor heterogeneity in DNA copy number alterations, translocations and endogenous APOBEC mutational processes, demonstrates that NSCLC may follow multiple distinct evolutionary trajectories simultaneously. In smokers, despite maintained carcinogen exposure, temporal dissection reveals a proportional decrease in smoking-related mutations during tumor progression, accompanied by an increase in APOBEC-related mutations. We observed genome-doubling events early in tumor development of ex-smokers, suggesting prolonged latency periods before clinical detection. Multi-region sequencing demonstrates the relentless and heterogeneous nature of genomic instability processes in early-stage NSCLCs.

  Study EGAS00001000840

• CRLF2_sequencing_project_Exomes

  I hope to gain insight into novel genetic aberrations present in these patients that will highlight important pathways that are involved in this subtype of leukaemia. It would be interesting to see if the mutations and pathways that are activated are consistent between the patients, or differences are observed dependent upon whether the patient has the translocation or the PAR1 deletion. Of note is the high association with either numerical gains of chromosome X or numerical/structural abnormalities of chromosome 21 (Down syndrome, iAMP21) in patients with CRLF2 deregulation. I hope to find abnormalities linking chromosomes X and 21 to CRLF2 deregulation in BCP‐ALL. By including the three patients that are normal for CRLF2, but have consistent genetic abnormalities found in the experimental cohort, I expect to find genetic differences between these two groups that will help us to identify novel molecular targets specific to CRLF2 deregulation.

  Study EGAS00001000081

• Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci

  Multiple regulatory elements distant to their targets on the linear genome can influence the expression of a single gene through chromatin looping. Chromosome conformation capture implemented in Hi-C allows for genome-wide agnostic characterization of chromatin contacts. However, detection of functional enhancer-promoter interactions is precluded by its effective resolution that is determined by both restriction fragmentation and sensitivity of the experiment. Here we have developed a capture Hi-C (cHi-C) approach to allow an agnostic characterisation of these physical interactions on a genome-wide scale. Single nucleotide polymorphisms associated with complex diseases often reside within regulatory elements and exert effects through long-range regulation of gene expression. Applying this cHi-C approach to 14 colorectal cancer risk loci has allowed us to identify key long-range chromatin interactions in cis and trans involving these loci.

  Study EGAS00001001085

• G&T-seq: parallel sequencing of the genomes and transcriptomes of single cells

  The ability to simultaneously sequence the genome and transcriptome of the same single cell offersa powerful means to dissect functional genetic heterogeneity at the cellular level. Here we describeG&T-seq, a method for separating and sequencing genomic DNA and full-length mRNA from singlecells. By applying G&T-seq to over 220 single cells we reveal cellular properties that cannot beinferred from DNA or RNA sequencing alone, including associations between DNA copy numbervariation and gene expression dosage. We further demonstrate the detection of coding interchromosomalfusions and single nucleotide variants in both the genomes and transcriptomes ofindividual cells. G&T-seq enables the study of genotype-phenotype associations in single cells, andthe investigation of DNA cell lineage trees of healthy and diseased tissues with transcriptome inferredcell types and states.

  Study EGAS00001001204

• Papuan_Genotyping

  By array based genotyping of indigenous individuals from different areas of Papua New Guinea, this project aims to provide the most comprehensive overview thus far of population structure and history in this part of the world. Papuans represent a key component in the current understanding of human history outside of Africa. Additionally, PNG harbours enormous cultural and linguistic diversity. Genotyping of diverse individuals, combined with previously generated whole-genome sequencing data, will allow the study of general patterns of population structure, the degree of genetic differentiation between groups, the extent of external gene flow into PNG and the genetic relationships to Australian Aboriginals.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001001587

• Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors.

  Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells, we identify the CCDC6-RETI788N mutation and drug-induced mitogen-activated protein kinase pathway reactivation as possible mechanisms by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors.

  Study EGAS00001002335

• multi-OMICs study of a pair of infant monozygotic twins with concordant B-cell ALL

  B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common cancer in childhood. Studying identical twins with B-cell ALL provides a unique and tractable model for deciphering the developmental timing of pre- and post-natal mutations contributing to clonal evolution. To date, this has mainly focused on major cytogenetic subgroups of childhood B-cell ALL, including MLL fusions, ETV6-RUNX1, hyperdiploidy, and BCR-ABL1. However, formal demonstration of the prenatal origin and “backtracking” the natural history of the leukemia remains understudied in “B-other”/Normal Karyotype (NK) B-cell ALL. To characterize the genetic and the epigenetic landscape of this particular leukemia subtype, we performed whole genome DNA-, B-cell receptor (BCR)-, and DNA bisulfite-sequencing on a pair of 8-month-old monozygotic twins diagnosed with concordant “B-other”/NK B-cell ALL.

  Study EGAS00001003651

• Integrative sequencing reveals alterations in untreated and castration resistant prostate cancer

  We report the integrative sequencing of genomic, transcriptomic and DNA methylation changes in 28 untreated (PC) and 13 castration resistant prostate cancers (CRPC). AR, TGF-β and WNT signaling pathways were altered in CRPCs. We identified two new fusion genes, TMPRSS2-SKIL and DOT1L-HES6. Fusion analysis in an independent cohort validated SKIL as a recurrent 3’ fusion partner and oncogene in prostate cancer. The HES6 fusion was found in an AR-negative CRPC, and HES6 overexpression in vitro led to androgen independent growth. A distinct DNA methylation signature was found for CRPC. Transcriptome assembly uncovered 128 previously unannotated prostate cancer associated transcripts, including the ERG regulated transcript TPCAT-10-36067 whose knockdown had a dramatic effect on the growth, invasiveness, and rate of apoptosis of prostate cancer cells.

  Study EGAS00001000526

• Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation

  Tumor-initiating cells are a subpopulation of cells that have self-renewal capacity to regenerate a tumor. Here, we identify stem cell-like chromatin features in human glioblastoma initiating cells (GICs) and link them to a loss of the repressive histone H3 lysine 9 trimethylation (H3K9me3) mark. Increasing H3K9me3 levels by histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by a loss of the activating H3 lysine 9 acetylation (H3K9ac) modification and accumulation of DNA damage and downregulation of DDR genes. Upon knockdown of histone demethylases KDM4C and KDM7A both differentiation and DNA damage was induced. Thus, the H3K9me3-H3K9ac equilibrium is crucial for GIC viability and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.

  Study EGAS00001003750

• BLUEPRINT ChIP-seq of Epigenetic programming during monocyte to macrophage differentiation and trained innate immunity

  Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. Transcriptomes and epigenomes in four primary cell types: monocytes, in vitro differentiated naïve, tolerized and trained macrophages were characterized. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and pathways functionally implicated in trained immunity were identified. Strikingly, β-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in DNase I hypersensitive sites at cell-type specific epigenetic loci unveiled differentiation and treatment specific repertoires. Altogether, this study provides a resource to understand the epigenetic changes that underlie innate immunity in humans.

  Study EGAS00001000951

• Analysis of IDHwt-glioblastoma samples from paired primary and recurrent tumor samples

  IDHwt-glioblastomas rapidly recur after initial treatment. To study genetic evolution in glioblastoma, we analyzed whole genomes of 21 pairs of primary and recurrent tumor samples using next generation sequencing. In addition we sequenced RNA from 16 tumor pairs and a panel of 50 glioma-associated genes in tumor pairs from 43 patients (including 14 of the 21 patients included in the WGS discovery set). Glioblastoma subtypes were determined using 450k/EPIC methylation arrays. This study was supported within the e:med program of the German Ministry of Education and Research (BMBF) by the collaborative research project ‘SYS-GLIO - Systems-based prediction of the biological and clinical behavior of gliomas’ (https://www.sys-med.de/de/demonstratoren/sys-glio/) This study is part of the Heidelberg Center for Personalized Oncology - HIPO-043

  Study EGAS00001003184

• Transcriptome sequencing of Gingivo-buccal Cancer : ICGC-India Project_Batch05

  Transcriptome Sequencing of Gingivo-buccal Cancer: ICGC-India ProjectAs a part of the ICGC, India has undertaken genomic studies on gingivobuccal cancer of the oral cavity, which is the most prevalent form of cancer among men in India. There are various known environmental (life-style) correlates of this cancer, the most important of which are tobacco chewing and HPV infection. Transcriptome sequencing of paired RNA samples – isolated from the tumor and adjacent normal tissues of 28 patients – have been performed. Detailed clinical characterization of the patients, collection of data on demographic and environmental exposures, and isolation of DNA samples from adjacent normal and tumor tissues collected from each patient are being done at the Advanced Centre for Research, Treatment and Education on Cancer, Mumbai. Sequencing is being performed at the National Institute of Biomedical Genomics, Kalyani.

  Study EGAS00001003285

• Novel mutations in TOP2A in gliomas

  High grade gliomas (HGGs) are aggressive, primary brain tumors with poor clinical outcomes. To better understand glioma pathobiology and find potential therapeutic susceptibilities, we designed a custom- panel 664 cancer- and epigenetics-related genes and employed targeted next generation sequencing to study the genomic landscape of somatic and germline variants in 182 glioma samples of different malignancy grades. Besides known alterations in TP53, IDH1, ATRX, EGFR genes, we found several novel variants that can be potential drivers in gliomas. In four patients from the Polish glioma cohort, we identified a novel recurrent mutation in the TOP2A gene coding for Topoisomerase 2A in glioblastomas (GBM, WHO grade IV gliomas). The mutation results in a substitution of glutamic acid (E) 948 to glutamine (Q) of TOP2 A and we predicted this E948Q substitution may affect DNA binding and a TOP2A enzymatic activity.

  Study EGAS00001004556

• The endometrial transcription landscape of MRKH syndrome

  The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (OMIM 277000) is characterized by agenesis of the uterus and upper part of the vagina in females with normal ovarian function. While genetic causes have been identified for a small subset of patients and epigenetic mechanisms presumably contribute to the pathogenic unfolding, too, the etiology of the syndrome has remained largely enigmatic. A comprehensive understanding of gene activity in the context of the disease is crucial to identify etiological components and their potential interplay. So far, this understanding is lacking, primarily due to the scarcity of samples and suitable tissue. In order to close this gap, we profiled endometrial tissue of uterus rudiments in a large cohort of MRKH patients using RNA-seq and thereby provide a genome-wide view on the altered transcription landscape of the MRKH syndrome.

  Study EGAS00001004601

• Forty-Five patient-derived xenografts capture the clinical and biological heterogeneity of Wilms tumor

  The lack of model systems has limited the preclinical testing of novel therapies for Wilms tumor (WT) patients who have poor outcomes. Herein, we established 45 heterotopic WT patient-derived xenografts (WTPDX) in CB17 scid-/- mice that capture the biological heterogeneity of Wilms tumor (WT). These WTPDX include 6 from patients with diffuse anaplasia, 9 from patients who later experienced disease relapse, and 13 from patients with bilateral disease. Early passage WTPDX showed enrichment of blastemal gene expression. Favorable histology WTPDX were chemosensitive, whereas unfavorable histology WTPDX were resistant to conventional chemotherapy with vincristine, actinomycin-D, and doxorubicin given singly or in combination. This WTPDX library is a unique scientific resource that retains the spectrum of biological heterogeneity present in WT and provides an essential tool to test novel targeted therapies in the era of precision medicine.

  Study EGAS00001003361

• Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

  Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRC). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF-1 and non-canonical RAS/RAF-aberrations with primary resistance and validated transcriptomic CRC-subtypes as non-genetic predictors of benefit. 64% of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype pre-treatment to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PDL1 and LAG3 immune-checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.

  Study EGAS00001003367

• single nuclei RNASeq of 5 regions of the human prenatal brain

  Data generated through single nuclei RNA sequencing on 5 regions of the brain (frontal cortex, ganglionic eminence, hippocampus, thalamus and cerebellum) from 3 fetuses (two of 14 and one of 15 post-conception weeks, all female). Tissue was acquired from the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR) with ethical approval. snRNA-seq libraries were prepared from ∼10,000 nuclei from each sample using Chromium Single Cell 3ʹ (v3) reagents (10X Genomics). Quality control of libraries was performed using the Agilent 5200 Fragment Analyzer before sequencing on an Illumina NovaSeq 6000 to a depth of at least 865 million (median = 1.01 billion) read pairs per library. Raw sequencing data were converted into FASTQ files. For a full description of data generation, please see Cameron et al, Biological Psychiatry 2022, https://doi.org/10.1016/j.biopsych.2022.06.033.

  Study EGAS00001006537

• Genomic profiling of localized (lFL) and systemic follicular lymphoma (sFL) reveals novel insights into FL pathogenesis

  At diagnosis, the majority of FL presents with symptomatic disease in advanced/systemic stages of FL (sFL). In contrast only around 10 to 15% of cFL are diagnosed in localized stages (lFL). The biological knowledge is mainly based on data derived from global sFL analysis and only small cohorts of lFL were characterized intensively so far. It is well-known that the hallmark BCL2 translocation is less frequently observed in lFL. Furthermore, lFL differs from sFL concerning their gene expression and their N-glycosylation profiles. In consequence, comprehensive global analysis with CNA profiling and whole exome sequencing was performed in a large cohort of lFL. Additionally, the mutational profile as well as the CNA landscape of lFL and sFL, as well as for BCL2 translocation-positive and -negative was compared.

  Study EGAS00001006927

• RNAseq of whole blood in 359 idiopathic pulmonary arterial hypertension patients reveals biological heterogeneity

  Patients with idiopathic, heritable, or drug-induced pulmonary arterial hypertension (referred to throughout as PAH) were recruited from expert centers across the UK as part of the PAH Cohort study (www.ipahcohort.com). In each case, diagnosis was confirmed by right heart catheterization following established international guidelines, which remained unchanged for the duration of this study. Healthy volunteers were recruited at the same centers and samples processed using the same standard operating procedure at all sites. All individuals gave written, informed consent with local ethical committee approval. Whole blood (3 ml) was collected in Tempus Blood RNA Tubes, and RNAseq was performed using established Illumina methodologies (see online supplement for further details).

  Dataset EGAD00001007981

• WGS files for Genomic Landscape ALL paper

  WGS files for Genomic Landscape ALL paper titled "The genomic landscape of pediatric acute lymphoblastic leukemia"

  Dataset EGAD00001008600

• Genome wide association study of Coeliac Disease

  We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression

  Study EGAS00000000057

• Single cell characterization of T-cell lymphoma: RNA (2025-07-31)

  Lymphomas are types of blood cancer derived from lymphocytes, and can be classified into two main categories, Hodgkin's lymphomas (HL) and non-Hodgkin lymphomas (NHL). T-cell lymphoma is a type of NHL that develops from T lymphocytes and accounts for 10-15% of total NHL cases. As a rare disease, T-cell lymphoma is functionally, pathologically, and clinically complex and heterogeneous. The 2016 revision of the WHO classification has listed 29 subtypes of mature T/NK-cell neoplasms, among which over 25 are T lymphocyte in origin. These subtypes of T-cell lymphomas have different biological behaviours and clinical prognosis. Clinically, T-cell lymphoma ranges from indolent (slow-growing) to aggressive (fast-growing and spreading) disease. According to the guideline booklet provided by the Lymphoma Research Foundation (https://lymphoma.org/aboutlymphoma/nhl/), indolent T-cell lymphoma subtypes include adult T-cell leukaemia/lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), and mycosis fungoides (MF), while the aggressive subtypes include anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell lymphoma (PTCL), and T lymphoblastic lymphoma (TLBL). PTCL and ALCL represent the most common subtypes of aggressive T-cell lymphoma whereas TLBL is a rare and aggressive subtype mostly diagnosed in children. In this study, we will use single cell RNA sequencing and single cell multiomic methods three aggressive T-cell lymphoma subtypes (ALCL, PTCL and TLBL) and try to gain a deeper insight into the genotypic and phenotypic features of these T-cell lymphomas. . This dataset contains all the data available for this study on 2025-07-31.

  Dataset EGAD00001015669

• miRNA expression data from primary tumors, metastasis and matched normals.

  MicroRNAs (miRs) have been recognized as promising biomarkers. It is unknown to what extent tumor-derived miRs are differentially expressed between primary colorectal cancers (pCRCs) and metastatic lesions, and to what extent the expression profiles of tumor tissue differ from the surrounding normal tissue. Next-generation sequencing (NGS) of 220 fresh-frozen samples, including paired primary and metastatic tumor tissue and non-tumorous tissue from 38 patients, revealed expression of 2245 known unique mature miRs and 515 novel candidate miRs. Unsupervised clustering of miR expression profiles of pCRC tissue with paired metastases did not separate the two entities, whereas unsupervised clustering of miR expression profiles of pCRC with normal colorectal mucosa demonstrated complete separation of the tumor samples from their paired normal mucosa. Two hundred and twenty-two miRs differentiated both pCRC and metastases from normal tissue samples (false discovery rate (FDR) &lt;0.05). The highest expressed tumor-specific miRs were miR-21 and miR-92a, both previously described to be involved in CRC with potential as circulating biomarker for early detection. Only eight miRs, 0.5% of the analysed miR transcriptome, were differentially expressed between pCRC and the corresponding metastases (FDR &lt;0.1), consisting of five known miRs (miR-320b, miR-320d, miR-3117, miR-1246 and miR-663b) and three novel candidate miRs (chr 1-2552-5p, chr 8-20656-5p and chr 10-25333-3p). These results indicate that previously unrecognized candidate miRs expressed in advanced CRC were identified using NGS. In addition, miR expression profiles of pCRC and metastatic lesions are highly comparable and may be of similar predictive value for prognosis or response to treatment in patients with advanced CRC.

  Dataset EGAD00001001644

• Cooperative activity of BRAF F595L and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling

  Mutations that activate the RAF-MEK-ERK signaling pathway, in particular BRAFV600E, occur in many cancers, and mutant BRAF-selective inhibitors have clinical activity in these diseases. Activating BRAF alleles are usually considered to be mutually exclusive with mutant RAS, whereas inactivating mutations in the D594F595G596 motif of the BRAF activation segment can coexist with oncogenic RAS and cooperate via paradoxical MEK/ERK activation. We determined the functional consequences of a largely uncharacterized BRAF mutation, F595L, which was detected along with an HRASQ61R allele by clinical exome sequencing in a patient with histiocytic sarcoma and also occurs in epithelial cancers, melanoma, and neuroblastoma, and investigated its interaction with mutant RAS. We demonstrate that, unlike previously described DFG motif mutants, BRAFF595L is a gain-of-function variant with intermediate activity towards MEK that does not act paradoxically, but nevertheless cooperates with mutant RAS to promote oncogenic signaling. Of immediate clinical relevance, BRAFF595L shows divergent responses to different mutant BRAF-selective inhibitors, whereas signaling driven by BRAFF595L with and without mutant RAS is efficiently blocked by pan-RAF and MEK inhibitors. Mutation data from primary patient samples and cell lines show that BRAFF595L, as well as other BRAF mutations with intermediate activity, frequently coincide with mutant RAS in a broad spectrum of cancers. These data define a novel class of activating BRAF mutations that cooperate with oncogenic RAS in a non-paradoxical fashion to achieve an optimal level of MEK-ERK signaling, extend the spectrum of patients with systemic histiocytic disorders and other malignancies who are candidates for therapeutic blockade of the RAF-MEK-ERK pathway, and underscore the value of comprehensive genetic profiling for understanding the signaling requirements of individual cancers.

  Dataset EGAD00001001384

• Characterisation of the genomic landscape of CRLF2-d ALL

  To determine the clinical and genetic landscape of CRLF2 deregulated acute lymphoblastic leukaemia (CRLF2-d ALL). We identified 172 patients with a CRLF2 rearrangement treated on either the UKALL2003 trial for children and adolescents (1-24 years) or the UKALLXII trial for adolescents and adults (15-59 years). Genomic technologies from conventional karyotyping, and FISH through to whole genome and exome sequencing were used to characterise the genomes of patients with CRLF2-d ALL. This is the largest study to date to investigate the genomic landscape of CRLF2-d ALL and define CRLF2-d as a unique subgroup of B-other ALL. We have confirmed the high incidence of CRLF2-d in Down syndrome-ALL and demonstrated the co-existence of CRLF2-d with other primary chromosomal rearrangements, suggesting that in these patients CRLF2-d can be a secondary genetic abnormality. Other defining features included enrichment of IKZF1, BTG1 and ADD3 deletions in IGH-CRLF2 patients and specific chromosomal gains seen at much higher frequencies than B-other ALL . We report recurrent established and new co-operating abnormalities and the novel involvement of USP9X and DDX3X in CRLF2-d ALL. It is clear from these data that CRLF2-d ALL is heterogenoeus, requiring a combination of genetic abnormalities in functionally relevent genes, to work alongside the deregulated expression of CRLF2 in order to initiate and drive leukaemogenesis in this subtype. Although the functional relevance of many of the abnormalities presented here are currently unknown, many are likely to activate alternate pathways or sensitize patients to current therapies.

  Dataset EGAD00001002007

• Characterisation of the genomic landscape of CRLF2-d ALL

  To determine the clinical and genetic landscape of CRLF2 deregulated acute lymphoblastic leukaemia (CRLF2-d ALL). We identified 172 patients with a CRLF2 rearrangement treated on either the UKALL2003 trial for children and adolescents (1-24 years) or the UKALLXII trial for adolescents and adults (15-59 years). Genomic technologies from conventional karyotyping, and FISH through to whole genome and exome sequencing were used to characterise the genomes of patients with CRLF2-d ALL. This is the largest study to date to investigate the genomic landscape of CRLF2-d ALL and define CRLF2-d as a unique subgroup of B-other ALL. We have confirmed the high incidence of CRLF2-d in Down syndrome-ALL and demonstrated the co-existence of CRLF2-d with other primary chromosomal rearrangements, suggesting that in these patients CRLF2-d can be a secondary genetic abnormality. Other defining features included enrichment of IKZF1, BTG1 and ADD3 deletions in IGH-CRLF2 patients and specific chromosomal gains seen at much higher frequencies than B-other ALL . We report recurrent established and new co-operating abnormalities and the novel involvement of USP9X and DDX3X in CRLF2-d ALL. It is clear from these data that CRLF2-d ALL is heterogenoeus, requiring a combination of genetic abnormalities in functionally relevent genes, to work alongside the deregulated expression of CRLF2 in order to initiate and drive leukaemogenesis in this subtype. Although the functional relevance of many of the abnormalities presented here are currently unknown, many are likely to activate alternate pathways or sensitize patients to current therapies.

  Dataset EGAD00001002008

• Single cell multi-omic study of H3-K27M mutant diffuse midline glioma across age and location

  Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in childhood diffuse midline gliomas (DMGs) of the pons, but are also increasingly recognized in adult DMGs. Their potential heterogeneity at different ages and midline locations are vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We conducted multi-omic profiling of 50 H3-K27M mutant patient tumors. We performed deep full-length Smart-seq2 fresh single-cell (n=18) or frozen single-nucleus (n=25) RNA-sequencing (sc/snRNA-seq) of 43 tumors). We additionally analyzed the open chromatin profiles of 8 tumors utilizing the single-cell/nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq)

  Study EGAS00001006994

• Whole-genome sequencing across 449 samples spanning 47 ethnolinguistic groups provides insights into genetic diversity in Nigeria

  African populations have been drastically underrepresented in genomics research and failure to capture the genetic diversity across the numerous ethnolinguistic groups (ELGs) found in the continent has hindered the equity of precision medicine initiatives globally. Here, we describe the whole-genome sequencing of 449 Nigerian individuals across 47 unique self-reported ELGs. Population structure analysis reveals genetic differentiation amongst our ELGs, consistent with previous findings. From the 36 million SNPs and indels discovered in our dataset, we provide a high-level catalog of both novel and medically-relevant variation present across the ELGs. These results emphasize the value of this resource for genomics research, with added granularity by representing multiple ELGs from Nigeria. Our results also underscore the potential of using these cohorts with larger sample sizes to improve our understanding of human ancestry and health in Africa.

  Study EGAS00001007036

• Cancer of Low survival and UnMet Need – Pathologist Initiated

  Despite significant advances in diagnostic cancer histopathology, a subset of tumors remain unable to be classified using WHO criteria. The resulting diagnostic uncertainty can result in inappropriate clinical management and negative patient outcomes. We investigated whether combining histopathology with whole genome and transcriptome sequencing (WGTS) could improve the classification of tumors that posed diagnostic dilemmas despite extensive histopathology and standard molecular work-up at a quaternary oncology center. We successfully sequenced 45 tumors from an initial set of 54 unclassified tumors (83% success rate). A confident diagnosis was made for 38/45 tumors (84%). Additionally, potential treatment targets were identified in 21/45 tumors (47%). Theoretical comparison with alternative assays demonstrated that WGTS was uniquely capable of detecting critical diagnostic findings in 15/38 tumors (39%). This work supports augmenting histopathology and standard molecular pathology with WGTS in the classification of difficult-to-diagnose tumors.

  Study EGAS00001008112

• Understanding_the_development_of_resident_memory_T_cells__Trm__in_the_human_small_intestine_using_integrative_multiomic_approaches__Adult_RNA

  Animal studies have demonstrated that resident memory T (Trm) cells provide enhanced protective responses to a broad array of tissue-tropic pathogens, thus making Trm cells promising targets for novel vaccination strategies. However, the biological pathways that enable the long-term survival of Trm cells are poorly understood in humans. Here, we will employ a unique human intestinal transplantation setting that allows us to study the retention of persistent T cells in the grafts and the temporal development of resident T-cell populations from recruited recipient T cells. We will integrate high resolution transcriptomics, epigenetics, proteomics and immune repertoire single-cell data from purified intestinal T cells. These single-cell multiomics approaches will uncover the diversity and differentiation of the T cell populations in the human intestine, allowing us to temporally resolve the generation and maintenance of gut resident T cells.

  Study EGAS00001008257

• Single-cell and spatial transcriptomic profiling of hormone-naïve localised prostate cancer

  Localised prostate cancers (PCa) are heterogeneous and multifocal, with diverse outcomes. Current prognostic methods are epithelium-centric, overlooking the complex cellular landscape within the tumour microenvironment (TME), which remains incompletely characterised. We performed a comprehensive analysis of cancerous and adjacent-benign cores from 24 patients with hormone therapy-naïve localised PCa using single-cell RNA-sequencing. By integrating copy number variation and transcriptional signatures, we classified epithelial cells across a malignant spectrum, revealing widespread molecular perturbation. We found an expansion of Club cell phenotypes, suggestive of Luminal dedifferentiation. We also performed a detailed annotation of stromal phenotypes, focusing on fibroblasts, and identified a novel peri-neural fibroblast population. Spatial transcriptomics elucidated the precise anatomical distribution of CAFs within the PCa TME. This study provides a valuable foundation for advancing our understanding of PCa pathobiology and developing a comprehensive cellular model of the disease.

  Study EGAS00001008332

• RNA stability controlled by m6A methylation contributes to X-to-autosome dosage compensation in mammals

  In mammals, X-chromosomal genes are expressed from a single copy since males (XY) possess a single X chromosome, while females (XX) undergo X inactivation. To compensate for this reduction in dosage compared to two active copies of autosomes, it has been proposed that genes from the active X chromosome exhibit dosage compensation. However, the existence and mechanism of X-to-autosome dosage compensation are still under debate. Here, we show that X-chromosomal transcripts are reduced in m6A modifications and more stable compared to their autosomal counterparts. Acute depletion of m6A selectively stabilises autosomal transcripts, resulting in perturbed dosage compensation in mouse embryonic stem cells. We propose that higher stability of X-chromosomal transcripts is directed by lower levels of m6A, indicating that mammalian dosage compensation is partly regulated by epitranscriptomic RNA modifications.

  Study EGAS00001007112

• Establishment and characterization of an Epstein-Barr virus-positive cell line from a non-keratinizing differentiated primary nasopharyngeal carcinoma

  Nasopharyngeal carcinoma (NPC), a cancer that is etiologically associated with the Epstein-Barr virus (EBV), is endemic in Southern China and Southeast Asia. The scarcity of representative NPC cell lines owing to the frequent loss of EBV episomes following prolonged propagation and compromised authenticity of previous models underscores the critical need for new EBV-positive NPC models. Herein, we describe the establishment of a new EBV-positive NPC cell line, designated NPC268 from a primary non-keratinizing, differentiated NPC tissue. NPC268 can undergo productive lytic reactivation of EBV and is highly tumorigenic in immunodeficient mice. Whole-genome sequencing (WGS) revealed close similarities with the tissue of origin, including large chromosomal rearrangements, while whole-genome bisulfite sequencing (WGBS) and RNA sequencing demonstrated a hypomethylated genome and enrichment in immune-related pathways, respectively.

  Study EGAS00001007172

• ATAC-Seq of healthy and IBD blood samples

  PBMCs from blood samples of 9 age- and gender-matched healthy subjects and 25 IBD patients were isolated through a Ficoll density gradient and used to isolate live CD4 T cells through a magnetic cell isolation kit (Miltenyi Biotec). Twelve thousand live CD4 T cells were then used to prepare ATAC-Seq libraries. Briefly, crude nuclei of live CD4+ T cells were treated with Tagment DNA buffer and Tagment DNA Enzyme (Nextera DNA Library Prep Kit, Illumina), and then the DNA was purified by MinElute PCR Purification Kit (Qiagen). Transposed DNA fragments were amplified using specific adapters followed by purification with MinElute PCR Purification Kit (Qiagen). Fragments from 240-360pb were selected in the PippinHT system (Sage Science). The quality of the library and its DNA concentration were assessed by Bioanalyzer instruments (Agilent Technologies) and ultimately submitted for sequencing using Illumina HiSeq 2500 sequencer, V4 chemistry.

  Study EGAS00001007343

• Detecting and quantifying clonal selection in somatic mosaicism

  In this study, we introduce a scalable method to identify clonal selection in an individual tissue, agnostic of the underlying mutations. To study clonal selection in the haematopoietic system, we performed whole genome sequencing on bone marrow CD34+ haematopoietic stem and progenitor cells from 22 non-leukemic individuals, 30-89 years of age. We performed 90x whole genome sequencing for all samples and re-sequenced 19 samples with sufficient DNA to a total target coverage of 270x. Whole genome sequencing of hair follicle DNA from the same individuals was used as germline control. In addition, we sequenced unseparated bone marrow mononuclear cells, CD3-CD34- bone marrow mononuclear cells, and peripheral blood granulocytes from 14 samples. Samples were collected from individuals undergoing hip replacement surgery as part of the Mechanisms of Age-Related Clonal Haematopoiesis (MARCH) Study (REC Ref: 17/YH/0382).

  Study EGAS00001007558

• Genetic origins of the Kiritimati population from central-eastern Micronesia

  The migration of Austronesian-speaking populations through Oceania has intrigued researchers for decades. The Kiribati islands, situated along the boundaries of Micronesia and Polynesia, provide a crucial link in this migration. We analyzed the genome-wide data of the Kiritimati population of Kiribati to uncover their genetic origins and connections with other Oceanian groups. Our study reveals that the Kiritimati population primarily exhibits Remote Oceanian-related ancestry associated with ancient Lapita and present-day Polynesian populations. In addition, our identity-by-descent analysis identifies populations from Philippines as their closest relatives in Island Southeast Asia. The genetic links between Kiritimati, ancient Lapita, and modern Polynesians underscore the shared ancestry and continuous gene flow across these regions. This genetic continuity and ongoing links are supported by linguistic and cultural evidence, illustrating a complex history of migration and admixture in Oceania.

  Study EGAS00001008060