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• Chromothripsis in Small Cell Lung Carcinoma Associated with Carcinoid Transformation

  Small cell lung carcinoma (SCLC) is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. We performed detailed clinicopathologic, genomic, and transcriptomic profiling of an atypical subset of SCLC in never/light smokers that lacked RB1 and TP53 co-inactivation and found that most cases were associated with chromothripsis – massive, localized chromosome shattering, recurrently involving chromosomes 11 or 12, among other findings. Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids. Conversely, SCLC never smokers harboring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never smokers.

  Study phs003676

• Molecular response of AML blasts to Aza-treatment.

  Azacytidine (Aza) treatment is effective in some patients with acute myeloid leukemia (AML). Clinical observations suggest that DNMT3A-mutant patients represent a subgroup of AML patients that responds particularly well to Aza-treatment. Data coming from a mouse model support this finding and we have already generated molecular data suggesting a molecular pathway involved in Aza-response in DNMT3A-mutant AML patients. We now aim to validate these findings in primary AML-blasts. To this end, we have FACS-sorted blasts from patients with AML prior to and under Aza-treatment and plan to correlate pre-treatment as well as on-treatment methylomes to clinical Aza-response.

  Study EGAS00001004825

• Genetics_of_gene_expression_in_human_macrophage_response_to_Salmonella

  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 EGAS00001002236

• A distinct monocyte cellular state links systemic immune dysregulation to pulmonary impairment in long COVID

  This is an independent cohort of Long COVID patients recruited from a rehabilitation centre. These patients had Long COVID from 8 months to more than 2 years since their acute COVID-19 disease. PBMC from these patients were collected and single cell transcriptomics dataset was generated.

  Study EGAS50000001216

• Transcriptomic analysis of cell-of-origin CNS neuroblastoma, FOXR2 activated

  The transcription factor FOXR2 is the universal driver of childhood central nervous system neuroblastoma, FOXR2 activated (NB-FOXR2). NB-FOXR2 tumors arise exclusively in the brain hemispheres, and despite morphological similarities to other pediatric brain tumors, they are a molecularly distinct entity based on DNA methylation profiling. The cell-of-origin is unknown. Here, we profiled a cohort of rare NB-FOXR2 tumors by bulk and single-cell transcriptomics. Through systematic comparative analyses, we delineate tumor transcriptional states and candidate cell-of-origin. More broadly, we demonstrate systematic molecular profiling of childhood cancers to orient oncogenic targeting for in vivo modeling, a critical resource for the study of rare tumors and development of therapeutics.

  Study EGAS00001007247

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

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

  Study phs003452

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

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

  Study phs001710

• Exome sequencing of DNA from pituitary neuroendocrine tumor (PitNET) and germline DNA from the same patient

  The goal of the project is to study tumor - normal DNA pairs from the PitNET patients. Total of 15 PitNET patients were recruited for the study to investigate sometic changes in the tumor compared to normal tissue. Illumina technology were used for sequencing and two data analysis pipelines employed for data analysis. Recurrent somatic variations were investigated and genomic disruption analysis from exome sequencing data attempted.

  Study EGAS00001004654

• Pediatric Investigation for Genetic Factors Linked with Renal Progression (PediGFR)

  The Pediatric Investigation for Genetic Factors Associated with Renal Progression (PediGFR) (RO1-DK082394) is an international collaborative study among three large prospective cohort studies of children with chronic kidney disease. The participating parent cohort studies are the Chronic Kidney Disease in Children (CKiD), the Effect of Strict Blood Pressure Control and ACE Inhibition on CRF Progression in Pediatric Patients (ESCAPE), and the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study. In these cohorts, pediatric subjects with CKD have been prospectively followed with standardized measurements for renal progression. The dbGaP data upload will utilize the structure of sub-studies to include the genotype and baseline phenotype for the three cohorts, as well as the RBC trait and anemia data for a sub-study under PI Susan Furth: Role of Genetic Variation in the Anemia of Chronic Kidney Disease (K24DK078737). In brief PediGFR is a prospective study of children with chronic kidney disease (CKD) to determine genetic factors associated with kidney function measured by the estimated glomerular filtration rate (eGFR) by Schwartz equation. The PediGFR_v2 Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000842 PediGFR_v2 Cohort. phs000843 4C phs000650 CKiD phs000844 ESCAPE

  Study phs000842

• Phase II trial of targeted immune-depleting chemotherapy and reduced-intensity allogeneic hematopoietic stem cell transplantation using 8/8 and 7/8 HLA-matched unrelated donors and utilizing two graft-versus-host disease prophylaxis regimens for the treatment of leukemias, lymphomas, and pre-malignant blood disorders

  Background: Major problems with stem cell transplantation (SCT) for cancer treatment are a lack of suitable donors for patients without an HLA tissue-matched sibling and graft-versus-host disease (GVHD), a serious side effects of immune-suppressing chemotherapy that is given to bring the cancer under control before SCT. In GVHD, the patient's immune system attacks the transplanted donor cells. This study will try to improve the results of SCT from unrelated HLA-matched donors using targeted immune-depleting chemotherapy to bring the cancer under control before transplantation and to lower the chance of graft rejection, followed by reduced-intensity transplant chemotherapy to make the procedure less toxic. Objectives: To evaluate the safety and effectiveness of targeted immune-depleting chemotherapy followed by reduced-intensity transplant chemotherapy in patients with advanced cancers of the blood and immune system. To evaluate the safety and effectiveness of two different drug combinations to prevent GVHD. Both regimens have been successful in preventing GVHD, but they work by different mechanisms and affect the rebuilding of the immune system after the transplant. Eligibility: People 18 to 74 years of age with advanced or high-risk cancers of the blood and immune system who do not have a suitable HLA-matched sibling. Design: All patients receive chemotherapy before transplant to treat the cancer and suppress immune function. All patients receive a conditioning regimen of cyclophosphamide for 4 days and fludarabine for 4 days before SCT to prepare for the transplant. Patients are randomly assigned to one of two combination drug treatments to prevent GHVD as follows: Group 1: Tacrolimus starting 3 days before SCT and continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the SCT and continuing through day 14 following SCT. Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1 day before SCT and continuing for 6 months. Patients receive the donor's stem cells and immune cells 2 days after the conditioning regimen. Patients are followed at the clinic regularly for the first 6 months after SCT, and then less often for at least 5 years. Some visits may include bone marrow aspirates and biopsies, blood draws, and other tests to monitor disease status. A skin biopsy, oral mucosa biopsy, and saliva collection are done to study chronic GVHD.

  Study phs002021

• Resequencing_candidate_genes_for_male_spermatogenic_impairment

  This study aims to identify novel candidate variants from human Y-chromosomal genes DAZ, BPY2 and CDY1 by resequencing the coding regions of these genes from male patients with spermatogenic impairment. The coding regions of the genes have been amplified by standard PCR, amplicon lengths range from 244 to 486 bp. A total of 61 amplicons were amplified for each of the 96 patients, totalling to approx. 25 kb per sample. Amplicons were quantified by gel electrophoresis and pooled in approx. equimolar concentrations per patient. For each of the 96 submitted samples, approx. 1 microgram of amplified DNA pool is provided in a total volume of 120 microlitres. The samples need to be indexed and libraries prepared for a PE250bp Illumina MiSeq run. 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 EGAS00001002157

• Genome-wide chromatin accessibility profiling of primary human glomerular and kidney cortex tubular outgrowth cultures

  We generated primary cultures from mechanically isolated kidney glomeruli (filtration unit of the nephron) which are composed of podocytes and mesangial cells. In parallel, we generated primary kidney cortex tubule cell cultures, which are composed primarily of proximal tubule cells. Early passage cultures of these two cell types were subjected to chromatin accessibility profiling (DNase-Seq) and gene expression profiling (RNA-Seq). We found thousands of dynamically regulated enhancers in both cell types that potentially regulate nearby and distal target genes that are differentially expressed. These data will be useful for understanding the epigenomic regulation of gene transcription in key kidney cell types.

  Study phs001720

• Transcriptome of 2-Hydroxypropyl-Beta-Cyclodextrin Treatment in Niemann-Pick Disease Type C1

  Niemann-Pick type C (NPC) disease is a rare and fatal lysosomal storage disorder. Classically, children with NPC demonstrate neurological dysfunction with cerebellar ataxia, dysarthria, seizures, vertical gaze palsy, motor impairment, dysphagia, psychotic episodes, and progressive dementia. In general, adolescent and adult onset forms have a more insidious onset and slower progression. As part of a multi-omics approach to address the genetic architecture of NPC1 disease, we have recently completed a transcriptome analysis using 43 primary NPC1 patient-derived fibroblasts from an NIH-cohort study (NCT00344331) where extensive clinical data has been obtained regarding the natural history of the disease. Initial transcriptome analysis of this dataset demonstrated a set of 485 genes that are significantly upregulated in patient samples and subsequently downregulated in response to 2-hydroxypropyl-beta-cyclodextrin treatment. 

  Study phs002392

• Identification of Recurrent SMO and BRAF Mutations in Ameloblastomas

  RNA-seq data from two cases of ameloblastoma was analyzed for candidate gene fusions and point mutations. Recurrent point mutations identified in the RNA-seq data, as well as mutations identified with limited panel targeted deep sequencing, were validated as somatic. Expanding to a larger cohort of 28, one of two activating mutations was found in 80% of cases. No recurrent gene fusions events were identified.

  Study phs000739

• Epigenetic Mechanisms of Inflammation and Fatigue in Head and Neck Cancer

  This was a longitudinal observational study to examine the association between fatigue and DNA methylation as well as gene expression among patients with head and neck cancer. Demographic and clinical variables were collected before chemoradiotherapy and/or at follow-up visits as appropriate. Fatigue was assessed and biosamples (for DNA methylation and gene expression) were collected before, immediately after, and at six- and twelve-months post-chemoradiotherapy.

  Study phs002106

• Molecular profiles in early onset prostate cancer

  Paired germline (blood) and tumour samples were collected from prostate cancer cases <65 years at diagnosis to identify genetic changes in early onset prostate cancer.  Whole exome sequencing was performed on these samples. The aim was to determine if these changes are associated with more aggressive disease and to identify targets for treatment and screening by identifying associations with family history, DNA repair germline mutations, and clinical features.

  Study EGAS50000001467

• Experimental PfSPZ Vaccine in Adults Without Malaria

  The study was performed to evaluate whole-blood transcriptomic profiles via RNA-seq before, during, and after immunization with the PfSPZ Vaccine in malaria-na&#239;ve, healthy adults enrolled in VRC 312 (NCT01441167). VRC 312 was the second study of the PfSPZ Vaccine and the first study to evaluate intravenous (IV) administration of this vaccine. The study was an open-label evaluation of the safety, tolerability, immunogenicity, and protective efficacy of the vaccine at successively higher administered by the IV route. The highest dosages were evaluated for protection against a malaria challenge after 4 to 6 vaccinations. The primary objectives of the study were related to the safety and tolerability of the vaccine at the 4 different dosage levels when administered IV; the secondary objectives were related to PfSPZ vaccine-mediated protection against Plasmodium falciparum (Pf) challenge at the 3 higher dosage levels, and the exploratory objectives were related to the immunogenicity of the PfSPZ Vaccine and defining an immune correlate of protection. To further determine potential molecular correlates of immunogenicity and/or protection, RNA-seq was performed on whole blood collected from subjects in all dose groups at time points before, during, and after immunization.

  Study phs002422

• Integrated genomic characterization of adrenocortical carcinoma

  Adrenocortical carcinomas (ACC) are aggressive cancers originating in the cortex of the adrenal glands. Despite the overall poor prognosis, ACC outcome is heterogeneous. CTNNB1 and TP53 mutations are frequent in these tumors, but the complete spectrum of genetic changes remains undefined. Exome sequencing and SNP array analysis of 45 ACC revealed recurrent alterations in known drivers (CTNNB1, TP53, CDKN2A, RB1, MEN1) and genes not previously reported to be altered in ACC (ZNRF3, DAXX, TERT and MED12), which were validated in an independent cohort of 77 ACC. The cell-surface transmembrane E3 ubiquitin ligase ZNRF36 was the gene the most frequently altered (21%), and appears as a potential novel tumor suppressor gene related to the ß-catenin pathway.Our integrated genomic analyses led to the identification of two distinct molecular subgroups with opposite outcome. The C1A group of poor outcome ACC was characterized by numerous mutations and DNA methylation alterations, whereas the C1B group with good prognosis displayed a specific deregulation of two miRNA clusters. Thus, aggressive and indolent ACC correspond to two distinct molecular entities, driven by different oncogenic alterations.

  Dataset EGAD00001000764

• Whole exome sequencing data for patients with Bosma arhinia microphthalmia syndrome (BAMS).

  The datasets includes 21 samples from 7 families with Bosma arhinia microphthalmia (BAMS). For details of the study please refer to the manuscript "De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development", Nature Genetics 2017. Each sample was exome sequenced and the family ID in sample description refers to the Individual ID in Supplementary figure 2 of the manuscript.

  Study EGAS00001002193

• NHLBI TOPMed: Childhood Asthma Management Program (CAMP)

  The Childhood Asthma Management Program (CAMP) was designed to evaluate whether continuous, long-term treatment (over a period of four to six years) with either an inhaled corticosteroid (budesonide) or an inhaled noncorticosteroid drug (nedocromil) safely produces an improvement in lung growth as compared with treatment for symptoms only (with albuterol and, if necessary, prednisone, administered as needed). The primary outcome in the study was lung growth, as assessed by the change in forced expiratory volume in one second (FEV1, expressed as a percentage of the predicted value) after the administration of a bronchodilator. Secondary outcomes included the degree of airway responsiveness, morbidity, physical growth, and psychological development.

  Study phs001726

• Genetic Evaluation of Autoinflammatory Diseases

  Many pediatric patients with early-onset autoinflammatory disease (AID) phenotypes are mutation-negative for genetically known AIDs. Recent data suggest a role for Type-I interferon (IFN) dysregulation in causing AID phenotypes with clinical features that are distinct from those found in patients with IL-1 mediated AIDs. We screened patients for the presence of an IFN-response gene signature (IRS) to characterize their clinical phenotypes, IFN-related biomarkers, and genetic causes.

  Study phs001946

• Exploration_of__mutational_processes_in_human_cancer_cell_lines__Exome

  Approximately 25 cell lines representative of 11 mutation signatures have been selected and will be grown from a single cell, referred to as parental clone, for a period of 3 months to allow accumulation of mutations. Following that period, we will obtain 2 subclones from each of the parental clone for sequencing analysis. In total we will be sequencing 2 parental clones and 4 subclones per cell line for approximately 25 cell lines.

  Study EGAS00001000790

• A non-canonical lymphoblast in refractory childhood T cell leukaemia

  Refractory cancers may arise either through the acquisition of resistance mechanisms by cancer cells or represent distinct diseases. The origin of childhood T-cell acute lymphoblastic leukaemia (T-ALL) that does not respond to initial treatment, i.e. refractory disease, is unknown. Refractory T-ALL carries a poor prognosis and cannot be predicted at diagnosis. Here, we performed single cell mRNA sequencing of T-ALL from children who did or did not respond to initial treatment. We identified a transcriptionally distinctive blast population, exhibiting features of innate-like lymphocytes, as the major source of refractory disease. Evidence of such blasts at diagnosis heralded refractory disease across independent datasets and was associated with survival in a large, contemporary trial cohort. Our findings portray refractory T-ALL as a distinct disease. They may have immediate clinical utility.

  Dataset EGAD00001015381

• Paired exome and low-coverage genome sequencing of osteosarcoma

  We perform longitudinal genome-sequencing analysis of 12 patients with metastatic or refractory osteosarcoma. The study was approved at the University Hospital Basel, following the approval of the ethical committee for mutational analysis of anonymized samples (“Ethikkommission beider Basel” ref. 274/12). All tumor samples were evaluated by an experienced bone pathologist to confirm the diagnosis.

  Study EGAS00001005199

• Evolution of Resistance in ER+ Breast Cancer

  While the combination of endocrine therapy and CDK4/CDK6 inhibitors has been shown to be effective in the metastatic ER+ breast cancer setting, to test whether it is effective in an earlier stage neoadjuvant setting, the FELINE trial (NCT02712723) was established to test the efficacy of letrozole and ribociclib in a ER-positive, HER2-negative patients in a randomized, placebo-controlled, multicenter trial. Patients were randomized to one of three arms: those in Arm A received letrozole and placebo, Arm B letrozole and intermittent ribociclib, and Arm C letrozole and continuous ribociclib. Samples were collected at screening (Day 0), Cycle 1 (Day 14), and end of trial (Day 180). Samples from 24 patients, where cancer cells were present at Day 0 and one additional time point, were subjected to whole-exome sequencing profiling.

  Study phs002287

• Whole Genome Sequencing of Liver Cancers

  Genomic alterations driving tumorigenesis result from the interaction of environmental exposures and endogeneous cellular processes. With a diversity of risk factors including viral infection, carcinogenic exposures and metabolic diseases, liver cancer is an ideal model to study these interactions. Whole genome sequencing of liver tumors identified 10 mutational signatures showing distinct relationships with environmental exposures, replication and transcription. Transcription-coupled damage was specifically associated with the liver-specific signature 16 and alcohol intake. Flood of indels were identified in very highly expressed hepato-specific genes, likely resulting from replication-transcription collisions. Reconstruction of sub-clonal architecture revealed mutational signature evolution during tumor development exemplified by the vanishing of aflatoxin-B1 signature in African migrants. These findings shed new light on the natural history of liver cancers

  Study EGAS00001002408

• Papua New Guinean Lowlanders Dataset

  High-coverage whole genome sequences were collected to study patterns of genomic variation across the southern lowland of Papua New Guinea. This region has experienced an extremely complex demographic history, including repeated bouts of admixture with archaic and modern human groups. This dataset reports whole genome sequences for 41 individuals from this region. Particular attention has been paid in the original study to genomic signals that are informative for population history, including admixture with archaic hominins and the role of modern human admixture during the late Pleistocene and Holocene.

  Study EGAS50000000033

• Whole Exome (WE) sequencing data files for H_NO-JB001

  DNA was derived from the primary tumour, lung metastasis, and peri-aortic lymph node metastasis. DNA from the spleen was used as a normal control.For WE sequencing we user Hybrid capture (Nimblegen version 3.0) of the lymph node and lung metastases, primary tumour and spleen normal; we generated ~100-fold coverage.

  Dataset EGAD00001001252

• Single cell transcriptomics of hESC-derived midbrain dopaminergic neurons generated by a new human development-based protocol

  Recent advances in stem cell technologies provide new opportunities for regenerative medicine and Parkinson’s disease modelling. However, the precise composition and quality of human embryonic stem cell (hESC)-derived preparations at the single cell level, compared to endogenous brain standards, remains to be determined. In addition, multiple developmental pathways important for midbrain dopaminergic (mDA) neuron development remain to be implemented in hESCs. Here we use mouse developmental knowledge and human single cell RNA-sequencing (scRNA-seq) data to generate a new development-based protocol to differentiate hESCs into mDA neurons. We found that Laminin 511, dual WNT activation with CHIR99021 and WNT5A, together with FGF8b, improved different aspects of midbrain patterning. Moreover, mDA neurogenesis and differentiation were enhanced by activation of liver X receptors and inhibition of fibroblast growth factor signaling. Analysis of hESC-derived midbrain cultures by scRNA-seq revealed multiple hESC-derived clusters, which resembled those in the endogenous human ventral midbrain. Moreover, high quality mDA neurons were detected and found to progressively acquire functionality in vitro. Thus, we hereby provide a hESC differentiation protocol that recapitulates several aspects of endogenous mDA neuron development, and a strategy to determine cell composition and quality of hESC-derived preparations that can be useful for disease modeling and cell therapy.

  Study EGAS00001006313

• RNA sequencing data of pediatric KMT2A-rearranged acute lymphoblastic leukemia (set 1)

  The dataset includes RNA sequencing FASTQ files from diagnostic tumor samples of two KMT2A-r ALL patients (ALLT-325, ALLT-346). NEBNext Ultra Directional RNA Library Prep Kit (New England Biolabs) was used in library preparation, and Globin-Zero Gold rRNA Removal Kit (Illumina) was utilized for rRNA removal. The diagnostic tumor samples were sequenced using Illumina Novaseq 6000, and the target sequencing depth was 21 Gb per sample.

  Dataset EGAD50000002582

• RNA sequencing data of pediatric hyperdiploid acute lymphoblastic leukemia (set 3)

  The dataset includes RNA sequencing FASTQ files from diagnostic tumor samples of five hyperdiploid ALL patients (ALLT-364, ALLT-367, ALLT-368, ALLT-371, ALLT-377). NEBNext Ultra Directional RNA Library Prep Kit (New England Biolabs) was used in library preparation, and TruSeq Stranded Total RNA Library Prep (Illumina) kit was utilized for rRNA removal. The diagnostic tumor samples were sequenced using Illumina Novaseq 6000, and the target sequencing depth was 21 Gb per sample.

  Dataset EGAD50000002594

• RNA sequencing data of pediatric hyperdiploid acute lymphoblastic leukemia

  The dataset includes RNA sequencing FASTQ files from diagnostic tumor samples of four hyperdiploid ALL patients (ALLT-315, ALLT-320, ALLT-329, ALLT-347). NEBNext Ultra Directional RNA Library Prep Kit (New England Biolabs) was used in library preparation, and Globin-Zero Gold rRNA Removal Kit (Illumina) was utilized for rRNA removal. The diagnostic tumor samples were sequenced using Illumina Novaseq 6000, and the target sequencing depth was 21 Gb per sample.

  Dataset EGAD50000002595

• Splicing signature analysis of RNU2-2 samples

  Dominant pathogenic variants in the snRNA RNU2-2 were recently reported as a cause of neurodevelopmental disorders. In our study we identified additional individuals with dominant variants (n.4G>A and n.35A>G) and we also identified biallelic variants as a novel frequent cause of neurodevelopmental disorder. We obtained blood samples and performed short-term lymhocytes cultures for 19 cases (5 n.4; 5 n.35; 9 biallelic). We generated exome-capture RNA-Seq for these cases that we compared to 49 controls (probands affected from a neurodevelopmental disorder but without RNU2-2 variants). We observed that RNU2-2 variants mainly disturb alternative exon skipping, although affecting different exons.

  Study EGAS50000001410

• Whole-genome methylation profiling of menstrual stem cells identifies novel biomarkers for endometriosis

  Endometriosis, despite its high prevalence, is underdiagnosed and poorly managed due to lack of clinically validated biomarkers and pathophysiological insight. Menstrual bloodderived stem cells (MenSCs) have been implicated in disease pathogenesis, but their diagnostic potential remains unexplored. We conducted a clinical study (n=42; 19 endometriosis, 23 controls) to assess whether DNA methylation profiles of freshly isolated MenSCs can identify disease-specific biomarkers. Whole-genome methylation sequencing revealed differentially methylated regions (DMRs) enriched in genes linked to hallmarks of endometriosis (e.g., inflammation, tissue remodelling, development). These DMRs robustly distinguished cases from controls, independent of technical and clinical variables. Machine learning models trained and validated on these DMRs achieved high diagnostic performance (specificity 83%, sensitivity 79%). Integration with an independent single-cell RNA sequencing dataset showed that the DMRs may modulate gene expression, further supporting their biological relevance. These findings position MenSC DNA methylation profiling as a promising, non-invasive approach for early endometriosis diagnosis and personalised care.

  Dataset EGAD50000002353

• Feasibility study of enzymatic methylation sequencing of cell-free DNA from cerebrospinal fluid of pediatric brain tumors for classification

  Array-based DNA methylation profiling is the gold standard for molecular classification of brain tumors. However, it relies on significant amount of input DNA extracted from surgical tissue, thus limiting its use for tumors where biopsy is challenging or limited in quantity. Cell-free tumor DNA (cfDNA) in cerebrospinal fluid (CSF) presents alternative opportunities for brain tumor diagnosis and disease monitoring following treatment. Novel enzymatic DNA methylation sequencing (EM-seq) methods may allow us to overcome input DNA limitations and accurately quantify methylation from cfDNA for tumor classification.

  Study EGAS50000000871

• 2014_AML_WES_51 samples

  2014 AML WES study contains 51 paired WES samples which were collected from SNUH. The study was designed to examine the molecular abnormalities from leukemic patients at initial diagnosis in comparison with corresponding germ line control (saliva samples). The results of WXS were analyzed by Mutect for ranking cancer variants and creating mutational matrix.

  Study EGAS00001002819

• Glioblastoma_CRISPR_Screen

  This is an in vitro genome-wide CRISPR/cas9 screen in human glioblastoma stem cells, screening for genes essential for survival of these cells. These cells express cas9 and have been transfected with a guide RNA library causing gene knockouts. We will analyse the sequencing data for depletion of guide RNAs.

  Study EGAS00001001519

• Identification_of_drug_resistance_genes_in_melanoma_by_mRNA_gene_expression

  We aim to sequence the mRNA transcriptome of 22 human melanoma cell lines in biological triplicate in order to define the gene expression profile of each cell line. The data will be correlated to the mutation status and the sensitivity to a panel of drugs in order to identify genes whose deregulation is associated to drug resistanceThis 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 EGAS00001000815

• Identification_of_drug_resistance_genes_in_melanoma_by_small_RNAs_expression_analysis

  We aim to sequence the small RNAs of 22 human melanoma cell lines in biological triplicate in order to define the microRNAs expression profile of each cell line. The data will be correlated to the mutation status and the sensitivity to a panel of drugs in order to identify genes whose deregulation is associated to drug resistanceThis 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 EGAS00001000816

• BAP1 study

  Background: Mutations in BAP1 have been identified in many aggressive cancers. Current therapeutic strategies for BAP1-deficient tumors are not effective. Goal: Discover novel strategies for BAP1-deficient tumors. Details: In our study, we identified a potential therapeutic strategy for BAP1-deficient cancers. We used multi-omics approaches to understand the underlying mechanisms behind why the discovered potential therapeutic strategy is effective.

  Study EGAS50000000235

• Hyperdiploid Acute Lymphoblastic Leukemia RNA-Seq

  Few genetic drivers of children with hyperdiploid precursor B-cell acute lymphoblastic leukemia (ALL) have been identified to date. In an effort to detect novel genomic rearrangements that could be promoting leukemogenesis in this subset of patients, we sequenced ribosomal RNA-depleted transcriptomes isolated from 5 hyperdiploid acute lymphoblastic leukemia samples. In addition to looking for novel genomic rearrangements, we also sought to identify transcripts that could be created as a result of a novel posttranscriptional process. Surprisingly, we identified transcripts created as the result of exon circularization. The results of our studies are present in the paper "Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types" published in PLoS ONE (PMID: 22319583).

  Study phs000522

• Poly(A) RNA sequencing of hepatocellular carcinoma tumors and their matched noncancerous liver tissues

  Background &amp; Aims: The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy Methods: A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patientswith multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to con-trast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174).Results: The multi-omics profiling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual specificity protein kinase TTK, which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort.Conclusions: Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identification of novel biomarkers and therapeutic targets in HCC.

  Study EGAS00001002337

• whole genome sequence data of multifocal hepatocellular carcinoma

  Background &amp; Aims: The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy Methods: A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patientswith multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to con-trast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174).Results: The multi-omics pro?ling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual speci?city protein kinase TTK, which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort.Conclusions: Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identi?cation of novel biomarkers and therapeutic targets in HCC.

  Study EGAS00001002338

• Chromothripsis in human breast cancer (HIPO K26K/H017/A017)

  Chromothripsis is a form of genome instability, by which a presumably single catastrophic event generates extensive genomic rearrangements of one or a few chromosome(s). Widely assumed to be an early event in tumor development, this phenomenon plays a prominent role in tumor onset. We analyzed chromothripsis in 252 human breast cancers from two patient cohorts (149 metastatic breast cancers, 63 untreated primary tumors, 29 local relapses, 11 longitudinal pairs) using whole-genome and whole-exome sequencing. We showed that chromothripsis affects a substantial proportion of human breast cancers, with a prevalence over 60% in a cohort of metastatic cases and 25% in a cohort comprising predominantly luminal breast cancers (cohorts from HIPO K26K and H017 and A017). In the vast majority of cases, multiple chromosomes per tumor are affected, with most chromothriptic events on chromosomes 11 and 17 including, among other significantly altered drivers, CCND1, ERBB2, CDK12 and BRCA1. Importantly, chromothripsis generates recurrent fusions that drive tumor development. Chromothripsis-related rearrangements are linked with univocal mutational signatures, with clusters of point mutations due to kataegis in close proximity to the genomic breakpoints, and with the activation of specific signaling pathways. Analysis of the temporal order of events in tumors with and without chromothripsis as well as longitudinal analysis of chromothriptic patterns in tumor pairs revealed important insights on the role of chromothriptic chromosomes in tumor evolution.

  Study EGAS00001004662

• Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C)

  Reprinted from http://www.haltctrial.org/ Purpose The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial is a randomized controlled trial designed to evaluate the safety and efficacy of long-term use of pegylated interferon for the treatment of chronic hepatitis C in patients who failed to respond to previous interferon therapy. The HALT-C Trial was developed to determine whether prolonged interferon therapy altered histological and clinical outcomes in a group of patients who had failed to eradicate hepatitis C virus with previous interferon treatment. Study Hypotheses In patients with chronic hepatitis C and bridging fibrosis who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can prevent progression to cirrhosis. In patients with cirrhosis secondary to chronic hepatitis C who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can reduce the risks of hepatic decompensation or of hepatocellular carcinoma. Study Design 1145 patients with chronic HCV and advanced hepatic fibrosis (Ishak stage 3-6) who failed to respond to previous treatment with interferon were enrolled at 10 clinical centers and entered into a Lead-in phase. They were treated with a combination of pegylated interferon (Pegasys&#174;, Hoffmann-La Roche) 180 &#181;g/week and ribavirin (1000-1200 mg/day) for 24 weeks. Patients who had no detectable HCV-RNA at week 20 continued on combination therapy until week 48. 662 patients who did not clear virus were randomly assigned at week 24 to either continue treatment with pegylated interferon alone (90 &#181;g/week) for an additional 42 months, or to have treatment discontinued. All patients were followed at 3-month intervals following randomization. Liver biopsy was performed at baseline and after 1.5 and 3.5 years of treatment. Because of slower than expected enrollment and the approval by the FDA of peginterferon alfa-2b after the start of the trial, we modified the study protocol in three ways. First, criteria for admission to the trial were liberalized to allow patients to enter the trial with lower platelet and white blood cell counts than had been initially considered safe or tolerable. Second, 151 Lead-in patients and those continuing on therapy after 24 weeks who demonstrated return of viremia during or after their 48-week treatment period (called "Breakthrough" or "Relapse" patients, respectively) were allowed to return to enter the randomized trial. Third, 237 patients treated with peginterferon alfa-2b (or with peginterferon alfa-2a in licensing trials) outside the HALT-C Trial who in other respects met all study criteria, having received the equivalent of Trial Lead-in period therapy, were allowed to enter the long-term trial as "Express" patients. A total 1050 patients were randomized. Those patients who completed Month 48 were offered an "extended follow-up (observation only)" until October 2009. These visits will primarily be to identify outcome events, and to provide information to patients concerning the current status of the trial. Some questionnaires, blood tests, and an ultrasonogram will be performed. Quarterly (every 3 months) Interval history of complications, adverse events Current medications Brief physical examination Laboratory tests: liver panel, CBC, INR, AFP Child-Pugh Score Stored serum Annual Complete physical examination Ultrasound of liver 1.5 years (M24 visit, middle of study) Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients) 3.5 years (M48, end of study) Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients) Endoscopy: evaluate esophageal varices and portal hypertension After Month 48 Observation only (no treatment) to determine clinical outcomes Clinic visit every 6 months with current medications, brief PE, liver panel, CBC, AFP, stored Serum Ultrasound of liver every 6 months Outcome Variables Primary outcome variables to be assessed in the two groups of patients include: Development of cirrhosis on liver biopsy (progression of Ishak fibrosis score by 2 points or more) Development of hepatic decompensation, as shown by: Sustained increase in the Child-Turcotte-Pugh score to 7 points or higher Variceal hemorrhage Ascites Spontaneous bacterial peritonitis Hepatic encephalopathy Development of hepatocellular carcinoma Death Secondary outcomes include quality of life, serious adverse events, events requiring dose reductions, and development of presumed hepatocellular carcinoma.

  Study phs000430

• WES of tumor samples from patients with renal medullary carcinoma (RMC)

  The dataset, in .bam file format, consists of whole exome sequencing (WES) data of tumors from patients (n=24) with Renal Medullary Carcinoma (RMC), generated using Illumina NovaSeq 6000 sequencing technology. DNA was extracted from FFPE solid tumor samples using the AllPrep DNA FFPE Kit (Qiagen, CA). Libraries from FFPE tissue were prepared with the SureSelect XT HS2 DNA Kit (Agilent, CA) for exome capture. The All Exon V7 exome probe set (Agilent, CA) was used for hybridization and capture of DNA.

  Dataset EGAD50000001822

• Gene expression matrix for Smart-seq2 data of peripheral blood B cells

  The dataset contains scRNA-seq gene expression matrix (csv file) and metadata (csv file) after quality control filtering for data generated with the Smart-seq2 protocol. Transcript expression was quantified with Salmon v0.11.3 using cDNA sequences from GRCh38.94 and k-mer length 25, and was aggregated to gene level and transcript-length-corrected using tximport v1.8.0. The dataset comprises IgA+ transglutaminase 2-specific and other IgA+ B cells from the peripheral blood of 355 cells from two untreated celiac disease patients.

  Dataset EGAD50000000338

• Access to "BMP9 controls pulmonary vascular growth and remodeling"

  Pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia (HHT) are two distinct vascular diseases linked to impaired signaling through bone morphogenetic protein (BMP) receptor complexes in endothelial cells. Although BMP-9 plays a central role in activating this pathway by binding to ALK1 and BMPR-II, its precise function in the pulmonary microvasculature has remained unclear. In this study, we uncover a previously unrecognized role for BMP-9 in regulating pulmonary vascular architecture and homeostasis. Our findings demonstrate that BMP-9 signaling intersects with VEGF pathways and contributes to the delicate balance between vascular growth and remodeling in the lungs. We also show that disruption of this pathway can shift vascular responses toward an HHT-like state, potentially altering disease susceptibility. These insights offer a unique perspective on how BMP-9 and ALK1 shape pulmonary vascular biology and suggest that targeting this axis could inform future strategies for treating complex vascular diseases such as PAH.

  Dac EGAC50000000640

• An autoinflammatory RIG-I variant causing Singleton-Merten Syndrome associates with small non-coding Y-RNAs

  The RNA sensor RIG-I performs a critical role in surveying the cytoplasm for the presence of viral nucleic acids and initiating the downstream anti-viral type I interferon pathway. Through recognition of specific features, such as the presence of a 5’ di/triphosphate motif or highly structured base-paired regions, RIG-I effectively differentiates between RNA of viral- and self-origin. In Singleton-Merten syndrome (SMS), gain-of-function variants in RIG-I lead to a breakdown in this surveillance system and results in aberrant sensing of self-RNAs and deleterious upregulation of type I interferons. The identity of the self-RNAs binding to gain-of-function RIG-I mutants has remained elusive and would provide a greater understanding of the aetiology of SMS. Here we used an infrared individual-nucleotide resolution UV-crosslinking and immunoprecipitation (irCLIP) approach to determine the RNA profile bound to a previously characterised ATPase-deficient SMS variant, RIG-IC268F. irCLIP identified a broad array of self-RNAs, primarily those transcribed by RNA polymerase III, that were bound to RIG-I. Subsequent native RNA immunoprecipitation confirmed a prominent and specific interaction between RIG-IC268F and Y-RNAs, a family of four structurally similar non-coding RNAs. Manipulation of Y-RNAs alone by targeting either Y-RNA transcripts or Y-RNA stabilising proteins was insufficient to negate RIG-I induce interferon, hinting at a broader profile of RNA polymerase III-derived RNAs being influential in driving the sterile activation of gain-of-function RIG-I variants.

  Study EGAS50000001660

• Mapping the epigenomic landscape of human monocytes following innate immune activation reveals context-specific mechanisms driving endotoxin tolerance

  Background Monocytes are key mediators of innate immunity to infection, undergoing profound and dynamic changes in epigenetic state and immune function which are broadly protective but may be dysregulated in disease. Here, we aimed to advance understanding of epigenetic regulation following innate immune activation, acutely and in endotoxin tolerant states. Methods We exposed human primary monocytes from healthy donors (n=6) to interferon-γ or differing combinations of endotoxin (lipopolysaccharide), including acute response (2hr) and two models of endotoxin tolerance: repeated stimulations (6+6hr) and prolonged exposure to endotoxin (24hr). Another subset of monocytes was left untreated (naïve). We identified context-specific regulatory elements based on epigenetic signatures for chromatin accessibility (ATAC-seq) and regulatory non-coding RNAs from total RNA sequencing. Results We present an atlas of differential gene expression for endotoxin and interferon response, identifying widespread context specific changes. Across assayed states, only 24-29% of genes showing differential exon usage are also differential at the gene level. Overall, 19.9% (6884 of 34616) of repeatedly observed ATAC peaks were differential in at least one condition, the majority upregulated on stimulation and located in distal regions (64.1% vs 45.9% of non-differential peaks) within which sequences were less conserved than non-differential peaks. We identified enhancer-derived RNA signatures specific to different monocyte states that correlated with chromatin accessibility changes. The endotoxin tolerance models showed distinct chromatin accessibility and transcriptomic signatures, with integrated analysis identifying genes and pathways involved in the inflammatory response, detoxification, metabolism and wound healing. We leveraged eQTL mapping for the same monocyte activation states to link potential enhancers with specific genes, identifying 1,946 unique differential ATAC peaks with 1,340 expression associated genes. We further use this to inform understanding of reported GWAS, for example involving FCHO1 and coronary artery disease. Conclusion This study reports context-specific regulatory elements based on transcriptomic profiling and epigenetic signatures for enhancer-derived RNAs and chromatin accessibility in immune tolerant monocyte states, and demonstrates the informativeness of linking such elements and eQTL to inform future mechanistic studies aimed at defining therapeutic targets of immunosuppression and diseases.

  Study EGAS00001007362