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• Differential gene expression in the colon mucosa of irritable bowel syndrome patients with diarrhea-predominant symptoms

  The aim of this study is to characterize the pathophysiology of the irritable bowel syndrome (IBS) on the functional level and in parallel on the gene expression level. For this purpose RNAseq of mucosal biopsies was performed. The data from the differential expression analysis will be further processed by Ingenuity Pathway Analysis (IPA) software to gather Information on activated or inhibited signaling pathways in the disease.

  Study EGAS50000000046

• Tamoxifen Response at Single Cell Resolution in Estrogen Receptor Positive Primary Human Breast Tumors

  Primary breast tissue, normal and cancerous, was collected immediately after resection. The tissue was dissociated and treated with 10uM tamoxifen or control media for 12 hours in suspension. Single cell libraries were then created using a 10x Genomics gel bead droplet-based kit and sequenced via Illumina sequencing platforms. Differences in cell response to tamoxifen was observed between cell types and distinct responsive and unresponsive cell populations were determined.

  Study phs003186

• Reconstitution of Human Brain Cell Diversity in Organoids via Four Protocols [scRNAseq]

  Single-cell RNA-sequencing of brain organoids at day 120 grown in four distinct growth protocols designed to generate dorsal (D) and ventral (V) forebrain, midbrain (M) and striatum (S) tissue using eight different pluripotent stem cell lines. Per per cell line-protocol combination two organoids (biological replicates) were grown. For cell line 176 the experiment was conducted in two independent biological replicates (repititions E1 and E2).

  Study EGAS50000000662

• Genetic analyses in patients with T or NK cells-associated disorders

  We conduct somatic gene mutation analysis in various diseases involving T cells or NK cells and clarify the gene mutation profile. By comparing clinical information and the results of mutation analysis, we will identify gene groups that influence the onset and refractoriness of the disease. As the analysis continues, the results of mutation analysis may become part of diagnostic criteria in the future, or provide basic data for the development of new therapeutic agents.

  Study JGAS000658

• Genetic analyses in patients with T or NK cells-associated disorders

  We conduct somatic gene mutation analysis in various diseases involving T cells or NK cells and clarify the gene mutation profile. By comparing clinical information and the results of mutation analysis, we will identify gene groups that influence the onset and refractoriness of the disease. As the analysis continues, the results of mutation analysis may become part of diagnostic criteria in the future, or provide basic data for the development of new therapeutic agents.

  Study JGAS000709

• Transcriptome analysis of a novel human iPSC-derived 3D cortical tissue model - WT, APP KI, Abeta-treated, Abeta/Aducanumab-treated

  Single-cell RNA-seq analysis of human iPSC-derived microglia/astrocytes/neurons in a novel, human in vitro 3D cortical tissue model. Samples include distinct conditions (each as biological duplicates): - wild-type cells from cultures after 1 month (WT_1mo, cell lines: A18, KOLF) and 3 months (WT_3mo, cell lines: SA2, KOLF, A18) of culturing - knock-in cells from cultures carrying three familial AD mutations in the APP gene (Swedish, Iberian, Arctic; introduced by CRISPR/Cas9-mediated knock-in) after 3 months of culturing (KI_3mo, cell lines: SA2, A18) - subset of WT 1 month-old samples were exposed to 500nM synthetic Abeta42 for 2 consecutive feeds, and a subset of these subsequently treated with 1µg/ml Aducanumab antibody for 14 days

  Dataset EGAD50000002031

• Relevance of TMPRSS2, CD163/CD206 and CD33 in clinical severity stratification of COVID-19

  Our main objective is to incorporate new markers to classify COVID-19 patients based on mild or severe disease progression. To achieve this, we characterize SNP genotypes in critical genes involved in SARS-CoV infection (ACE2 (rs2285666), MX1 (rs469390), and TMPRSS2 (rs2070788) variants) and study the monocyte population by mass cytometry (CyTOF). Finally, the results obtained will be integrated to search for the best set of predictors of disease aggressiveness.

  Study EGAS00001007003

• Identification of recurrent mutations in Cushing’s disease

  The overall goal of the Identification of recurrent mutations in Cushing’s disease project is to study the impact of whole-exome sequencing (WES) on the clinical care of cancer patients and oncology provider practices. The aims of Project are to implement and establish the feasibility of WES in patients with USP8 wild-type corticotroph adenomas; to develop a framework for understanding of the molecular mechanism of the pathogenesis of corticotroph adenoma.

  Study EGAS00001003029

• Whole-exome sequencing of ovarian clear cell carcinoma in clinical outliers

  Whole-exome sequencing dataset for the Australian Ovarian Cancer Study (AOCS) and The Jikei University School of Medicine (JIKEI) ovarian clear cell carcinoma (OCCC) clinical outliers project, representing 10 donors. Although OCCC are commonly resistant to platinum based chemotherapy, good clinical outcomes are observed in a subset of patients. Exome sequencing was performed in 10 patients who had either unusually long survival (N=5) or had a very short time to progression (N=5).

  Study EGAS00001004248

• Differential gene expression in the colon mucosa of irritable bowel syndrome patients with mixed type symptoms

  The aim of this study is to characterize the pathophysiology of the irritable bowel syndrome (IBS) on the functional level and in parallel on the gene expression level. For this purpose RNAseq of mucosal biopsies was performed. The data from the differential expression analysis will be further processed by Ingenuity Pathway Analysis (IPA) software to gather Information on activated or inhibited signaling pathways in the disease.

  Study EGAS00001004835

• Clinical impact of immune checkpoint inhibitor (ICI) response, DNA damage repair (DDR) gene mutations and immune-cell infiltration in subtypes of metastatic melanoma

  Our study identified that immune cell infiltration and DNA damage repair (DDR) gene mutations may have an impact in response to immune checkpoint inhibitors (ICI) treatment in metastatic melanoma but differs among melanoma subtypes. Therefore, a comprehensive understanding of the role of immune infiltration cells, DDR gene mutations and copy number alterations could act as prognostic biomarkers for the ICI treatment among metastatic melanoma subtype patients.

  Study EGAS00001005781

• RNA sequencing of NK cells in human lung

  Human lung tissue-resident NK cells (trNK cells) are likely to play important roles in viral infections, inflammation and cancer. However, knowledge about lung trNK cells is lacking but is fundamental for exploiting these cells in therapeutic approaches. Here we analysed the transcriptome of CD69+CD49a+CD103+CD16-CD56bright, CD69+CD49a+CD103-CD16-CD56bright, CD69+CD49a-CD103-CD16-CD56bright, CD69-CD49a-CD103-CD16-CD56bright, and CD56dimCD16+NKG2A+CD57- NK cells isolated from human lung.

  Study EGAS00001003544

• DAC for the study of response to EGFR Blockade in Colorectal Cancer

  Dac EGAC00001000360

• DAC for study: Frequent mutation of the FOXA1 untranslated region in prostate cancer

  Dac EGAC00001000962

• DAC for study: Evaluation of commercial Guardant360 ctDNA test in metastatic prostate cancer

  Dac EGAC00001001082

• DAC for Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder

  Dac EGAC00001001529

• COVID-19 Severity of First Wave of Infection for Severe Patients in Madrid

  Dac EGAC00001002480

• DAC for ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA

  Dac EGAC00001003141

• COVID-19 Severity of First Wave of Infection for Severe Patients in Madrid

  Dac EGAC00001003435

• Data Access Committee for study Positive Selection in Peruvians from Three Ecological Regions

  Dac EGAC00001002414

• Searching for genetic modulators of the phenotypic heterogeneity in Brugada Syndrome

  Study EGAS00001005848

• Validation study of genome-wide polygenic score for body mass index in South Asians

  Dac EGAC00001003593

• NFE2 and PF4 as Translational Biomarkers for BET Inhibition-Induced Thrombocytopenia in Preclinical and Clinical Studies

  Blood samples from patients treated with BMS-986158 were investigated for association with thrombocytopenia following BET inhibition. Hypotheses of translational biomarkers for early prediction of thrombocytopenia associated with BET inhibition were explored.

  Study EGAS50000001162

• Best Endovascular vs. Best Surgical Therapy in Patients With Critical Limb Ischemia (BEST CLI-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 To compare the effectiveness of surgical treatment to the effectiveness of endovascular treatment in adults with chronic limb-threatening ischemia who are eligible for both treatment options. Background Peripheral artery disease (PAD) affects more than 200 million people worldwide. A portion of those individuals develop chronic limb-threatening ischemia (CLTI). CLTI is associated with severe health outcomes. CLTI is defined by ischemic foot pain at rest, ischemic ulcerations, or gangrene. Treatment for CLTI includes revascularization to improve limb perfusion and limit the risk of amputation. However, the choice of surgery or endovascular therapy for revascularization varies greatly. The extent to which this variability affects clinical outcomes in patients with CLTI is unknown. The BEST-CLI trial was initiated to determine whether endovascular revascularization was superior to surgical revascularization in patients with CLTI. Participants A total of 1434 participants with a single segment of great saphenous vein comprised cohort 1. Of these, 718 participants were randomly assigned to the surgical treatment group and 716 participants were randomly assigned to the endovascular therapy group. A total of 396 participants needing an alternative conduit comprised cohort 2. Of these, 197 participants were randomly assigned to the surgical treatment group and 199 participants were randomly assigned to the endovascular therapy group. Design BEST-CLI was an international, randomized, open-label trial. Participants were assigned to one of two cohorts based on the availability of a single segment of great saphenous vein. Participants in both cohorts were randomly assigned to either surgery or endovascular therapy. Follow-up was performed at 30 days after the procedure, 3 months, 6 months, and every 6 months thereafter up to 84 months after randomization. Telephone visits in lieu of clinic visits were planned at 30 months and every 12 months thereafter and at the end of the trial. Participants were followed for major adverse cardiovascular events (myocardial infarction, stroke, or death from any cause), quality of life, level of pain, and performance on the six-minute walk test. The primary outcome was a composite of major adverse limb events or death from any cause. A major adverse limb event was defined as above ankle amputation of the index limb or a major index-limb reintervention (new bypass, interposition graft revision, thrombectomy, or thrombolysis). Conclusions Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. Farber A, Menard MT, Conte MS, et al. Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia. N Engl J Med. 2022;387(25):2305-2316. PMID 36342173

  Study phs003844

• Pharmacogenomic Analysis Reveals New Therapeutic Options for Pleural Mesothelioma

  Background: Pleural mesothelioma (PM) urgently requires novel effective treatments. Drug repurposing is a relevant strategy to discover new therapeutic options among well-known drugs used in clinical practice. This study aimed to identify new therapies in the context of molecular heterogeneity of PM. Methods: We performed a multi-omics study of the largest cohort of patient-derived primary PM cell lines (n=58) to date, using whole exome sequencing, RNA sequencing and methylome analysis. We also conducted a large-scale drug screening of over 1300 compounds on a subset of cell lines (n=11), as well as an extension screen (n=48) for selected drugs of interest. The best candidates were validated using 3D culture and mouse models. Results: We demonstrated that the molecular landscape of the cell lines cohort recapitulates the main findings in tumours and revealed new specific features of PM. The large-scale drug screening and subsequent validations highlighted notably strong sensitivity to entinostat and fluvastatin. Importantly, both compounds displayed same efficacy in 2D and 3D culture models and single treatment prolonged survival in vivo similarly or even better than standard chemotherapy. Strikingly, combining entinostat treatment with anti-PD1 led to cures in some mice and immunized them against tumour cells. Conclusions: Among several candidates, we identified entinostat, notably in combination with immune checkpoint inhibitor, and to a lesser extent fluvastatin, as promising therapeutic options for patients. We believe our study provides a valuable resource that could contribute to advances in the field and warrants further clinical investigation.

  Study EGAS00001007866

• Implementation of pediatric precision oncology into clinical practice: The individualized Therapies for Children with cancer program “iTHER”

  iTHER is a prospective national precision oncology program aiming to define tumor molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory pediatric tumors in order to identify relevant aberrations to inform treatment. From April 2017 to April 2021, 302 samples of 253 patients were included. Comprehensive molecular profiling utilizing lcWGS, WES, RNAseq, Affymetrix, and/or 850k methylation profiling was performed for 226 samples. Germline pathogenic variants were identified in 16% of patients. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with priority levels very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%). Diagnosis was revised or refined in 8 patients (3.5%). Spatial and temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analysis. Of 137 patients with follow-up beyond 12 months, 21 molecularly matched treatments were applied in 19 patients (13.9%) with modest response. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates feasibility of comprehensive molecular profiling across all ages, tumor types and stages in pediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants within a clinically relevant timeframe. Therefore, WES and RNAseq is implemented into standard clinical care at the Princess Máxima Center for all children. Improved access to targeted treatments within biology-driven combination trials is required to eventually improve survival.

  Study EGAS00001007099

• Single-cell spatiotranscriptomic dissection of ex vivo human heart right atrial appendage and pericardial fluid in ischemic heart disease and heart failure

  We use cardiac and pericardial fluid biopsies collected during open-heart surgery in control, ischemic heart disease, heart failure, and myocardial infarction context. For each sample, single-nuclei RNA sequencing experiment is performed. We also perform spatial transcriptomics on the heart samples. We annotate the cells in major cell types, in addition to subtypes annotation of vascular and immune cells. The disease annotation enables us to reveal substantial differences in gene expression at the cell subpopulation levels. Our results demonstrate the importance of high-resolution cellular type/state mapping in the elucidation of human cardiovascular disease pathogenesis.

  Study EGAS50000000653

• Overrepresentation of genetic variation in the AnkyrinG interactome is related to a range of neurological disorders

  Upon the discovery of numerous genes involved in the pathogenesis of neurodevelopmental disorders, several studies showed that a significant proportion of these genes converge on common pathways and protein networks. Here, we used a reversed approach, by screening the well-characterized AnkyrinG protein-protein interaction network, implicated in a variety of neurodevelopmental disorders, for genetic variation in a large cohort of 1009 cases with neurodevelopmental disorder. We identified a significant enrichment of de novo potentially disease-causing variants in this network, confirming that this protein network plays an important role in the emergence of several neurodevelopmental disorders.

  Study EGAS00001004326

• Comparison of Custom Capture for Targeted Next Generation DNA Sequencing

  Targeted, capture-based DNA sequencing is an economical way to sequence a customized region of the genome. Several targeted sequencing kits are available, but the efficacies of these kits have not been compared. We appraised four targeted DNA technologies for next generation sequencing, considering on-target sequencing, uniformity, and single nucleotide variation and copy number variation discovery. The technologies which utilized sonication to fragment genomic material showed impressive uniformity of capture. The other two had shorter preparation times, but sacrificed uniformity. One of those technologies, which needs transposase to fragment genomic material, has a weakness that requires all samples be pooled and the final one, which uses restriction enzyme digestion, is limited depending on restriction enzymes digest sites. Naturally, all technologies showed some concordance for calling SNVs, the kits that used restriction enzymes or transposase missed several SNVs, due, in large part, to lack of coverage. All technologies showed high integrity for copy number variant calling when compared to SNP arrays. This study aids laboratories in their decision of the proper technology to use for their intended applications.

  Study phs000811

• A Multi-Gene Mutation Classification of 468 Colorectal Cancers Reveals a Prognostic Role for APC

  Colorectal cancer (CRC) is a highly heterogeneous disease, for which prognosis has been relegated to clinic-pathologic staging for decades. There is a need to molecularly stratify subpopulations of CRC to better predict outcome and assign therapies. Here we report targeted exome sequencing of 1,321 cancer-related genes on 468 tumor specimens, which identified a subset of 17 genes that best classify CRC, with APC (Gene ID: 324) playing a central role in predicting overall survival. APC may assume 0, 1, or 2 truncating mutations, each with a striking differential impact on survival. Tumors lacking any APC mutation carry a worse prognosis than single APC mutation tumors, but tumors with two APC mutations and KRAS (Gene ID: 3845) and TP53 (Gene ID: 7157) mutations confer the poorest survival among all the subgroups examined. Our study demonstrates a substantial prognostic role for APC and suggests that sequencing of APC may have clinical utility in the routine staging and potential therapeutic assignment for CRC.

  Study phs001111

• BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology)

  The BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) study is an ongoing longitudinal, population-based prospective birth cohort including 4,089 children born between 1994 and 1996 in Stockholm, Sweden. The cohort was initially designed to study risk factors for asthma, allergic diseases and lung function in childhood, and to study factors of importance for prognosis at already established disease.Questionnaires on respiratory symptoms and medication were answered at age of 1, 2, 4, 8 and 16 years. Response rates ranged from 96-82% at each occasion with very minor selection bias over the years. Exposure to air pollutants and other environmental factors has been mapped since birth.At the 8 and 16 year follow-up, spirometry and FeNO measurements were performed and at the latter, impulse oscillometry was measured. Blood samples (including plasma) from around 2,500 children were taken at 4, 8 and 16 years and have been analyzed for different IgE-ab and biomarkers. Genome-wide genetic, global methylation and transcriptomic data exist on a subset of the children.

  Study EGAS00001002746

• An Isogenic Cell Line Panel for Sequence-based Screening of Targeted Anti-cancer Drugs

  We describe the creation and characterization of an isogenic cell line panel representing common cancer pathways, with multiple features optimized for high-throughput screening. More than 1,800 cell lines from three normal human cells were generated using CRISPR-technologies. Surprisingly, we discovered most of these lines did not result in complete gene inactivation, despite integration of sgRNA at the desired genomic site. However, a subset of the lines harbored true, biallelic disruptions of the targeted tumor suppressor gene, yielding a final panel of 100 well-characterize lines covering 19 pathways frequently subject to loss of function in cancers. This panel included genetic markers optimized for sequence-based ratiometric assays for drug-based screening assays. To illustrate the potential utility of this panel, we developed a multiplexed high-throughput screen that identified Wee1 inhibitor MK-1775 as a selective growth inhibitor of cells with inactivation of TP53. These cell lines and screening approach should prove useful for researchers studying a variety of cellular and biochemical phenomena

  Study EGAS00001005974

• Integrated Personal omics Processing (iPoP) Longitudinal multi-omics profiling of prediabetes

  Type 2 diabetes mellitus (T2D) is a significant health problem. Close to 20 million individuals in the United States have T2D, and 79 million aged 20 years or older are clinically pre-diabetic, with a 5-year conversion rate of 10% to 23% from prediabetes to T2D. In a collaborative effort to systematically understand diabetes and its etiology, the team is comprised of leading experts in research on both the human host as well as the microbiome, as properties of both are likely relevant in T2D development. For a better elucidation of mechanisms of onset and progression of T2D disease, the group is performing a detailed analysis of the biological processes that occur in the microbiome and human host by longitudinal profiling of patients at risk for T2D. Both microbiome and host profiles are being analyzed by state-of-the-art omics platforms, and these large-scale and diverse data sets will be integrated to determine the dynamic pathways that change during the onset and progression of T2D, especially during viral infections and other stresses. This longitudinal study is expected to reveal changes in the microbiome and host at an unprecedented level of detail, and identify molecules and pathways that play important roles in diabetes onset and progression.

  Study phs001719

• Full characterization of structural variation

  Structural variants (SVs) are important contributors to human disease. Their characterization remains however difficult due to their size and association with repetitive regions. Long-read sequencing (LRS) and optical genome mapping (OGM) can aid as their molecules span multiple kilobases and capture SVs in full. In this study, we selected six individuals who presented with unresolved SVs. We applied LRS onto all individuals and OGM to a subset of three complex cases. LRS detected and fully resolved the interrogated SV in all samples. This enabled a precise molecular diagnosis in two individuals. Overall, LRS identified 100% of the junctions at single-basepair level, providing valuable insights into their formation mechanisms without need for additional data sources. Application of OGM added straightforward variant phasing, aiding in the unravelment of complex rearrangements. These results highlight the potential of LRS and OGM as follow-up molecular tests for complete SV characterization. We show that they can assess clinically relevant structural variation at unprecedented resolution. Additionally, they detect (complex) cryptic rearrangements missed by conventional methods. This ultimately leads to an increased diagnostic yield, emphasizing their added benefit in a diagnostic setting. To aid their rapid adoption, we provide detailed laboratory and bioinformatics workflows in this manuscript.

  Study EGAS50000000520

• Pediatric Non-Down Syndrome Acute Megakaryoblastic Leukemia is Characterized by Distinct Genomic Subsets with Varying Outcomes

  Acute Megakaryoblastic Leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts.  While extremely rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML1-3.  A significant proportion of pediatric AMKL cases occur in children with Down syndrome (DS).  These patients have excellent outcomes and are characterized at the genomic level by a founding GATA1 mutation4-6.  In contrast, AMKL in patients without DS (non-DS-AMKL) is frequently associated with poor outcomes.  Previous efforts have identified chimeric oncogenes in a significant number of cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements and NUP98-KDM5A7-9.  The etiology of 30-40% of cases, however, remains unknown.  To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult).  We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes.  These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes.  Overall, these data shed light on the etiology of AMKL and provide useful information for treatment tailoring. 

  Study EGAS00001002183

• Exome sequencing of a novel cervical cancer cell line

  Human cancer cell lines are largely used in the searching for new antineoplastic agents. However, due to the artifacts of a long-term in culture, cell lines do not always represent the realistic tumor cell behavior. This has motivated the development of models that better mimetics the tumor tissue, among them, the establishment of primary cell cultures. In this work, we establish and characterized a low-passage cervix cancer cell line from a Brazilian patient with squamous cell carcinoma. The phenotype confirms the epithelial and tumor origin, through cytokeratins, EpCAM, and p16 staining. Whole exome sequencing showed relevant somatic mutations in several genes including BRCA2, TGFBR1, and IRX2 genes. CNV analysis by nanostring and WGS revealed amplification in genes related mainly with kinases proteins, involved in proliferation, migration and cell differentiation, such as EGFR, PIK3CA, and MAPK7. Overexpression of EGFR was confirmed by phospho RTK-array and western blot analysis. Furthermore, the cell was sensitivity to cisplatin, with IC50 13 times lower than SiHa cell line. In conclusion, this cervical cancer cell line presents molecular alterations that are an important tool for leading pre-clinical studies of new drugs that target one or more of the altered pathways.

  Study EGAS00001003343

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

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

  Study EGAS00001004327

• Clonal selection and double hit events involving tumor suppressor genes underlie relapse from total therapy

  In order to gain insights into the mechanisms of disease progression in multiple myeloma (MM) patients treated with multi-agent and high-dose chemotherapy we have performed a longitudinal study of 33 patients entered into Total Therapy protocols using gene expression profiling, high resolution copy number analyses and whole exome sequencing. The results of this study show the importance of acquired mutations in MM driver genes, bi-allelic events affecting tumor suppressor genes and increased proliferation rates in driving relapse, which is enhanced by intra-clonal heterogeneity and Darwinian type clonal evolution. Branching was the most frequent evolution pattern, characterized by clonal loss and appearance of new clones. We found a higher number of lost and acquired copy number aberrations and an excess of bi-allelic inactivation of tumor suppressor genes in GEP70 high risk (HiR) cases, consistent with genomic instability being a key feature of HiR MM. In conclusion, our study further stresses the impact of known prognostic markers and driver genes on the fitness level of MM cells to survive multi-agent chemotherapy. The frequent bi-allelic loss of tumor suppressor genes in HiR cases and the potentially resulting failure of treatment with DNA damaging agents highlight the need for new therapies for HiR MM.

  Study EGAS00001001810

• Reconstruction of the personal information from human genome reads in gut metagenome sequencing data

  Human DNA present in fecal samples can result in a small number of human reads in gut shotgun metagenomic sequencing data. However, it is currently unclear how much personal information can be reconstructed from such reads and this has not been quantitatively evaluated. Such a quantitative evaluation is necessary to clarify the ethical concerns related to data sharing and to enable the efficient use of human genetic information in stool samples, such as for research and forensics. Here, we used genomic approaches to reconstruct personal information from fecal metagenomes of 343 Japanese individuals with associated human genotype data.

  Study JGAS000600

• Characterizing the Neurobehavioral Phenotype(s) in MPS III (Pilot Study)

  Mucopolysaccharidosis III (MPSIII) syndrome is characterized by a severe cognitive decline ending in dementia and death. MPSIII is also associated with a range of abnormal and disruptive behaviors that can include, but go well beyond, childhood noncompliance and oppositionality. The purpose of this study is to conduct a cross-sectional investigation to identify the behavioral phenotype and its neural basis in MPSIII. An overall goal of this research is to develop easily administered, sensitive and specific neurobehavioral markers to characterize the behavioral phenotype(s) of MPSIII, track their progression, and to delineate their possible neural substrates. The study looks to develop develop a sensitive and specific behavioral rating of disease progression in MPS III which can be used for clinical outcome studies. The research objectives are: Develop a measure for the use of health professionals to use in tracking MPSIII phenotypes and disease progression. Test our model of MPSIII with objectively recorded behaviors in a well-defined experimental setting. Elucidate the neural bases of MPSIII by correlating behavioral profiles with changes in brain structures through quantitative neuroimaging. Determine the relationship between the loss of cognitive functions and development of behavioral abnormalities in MPSIII. This is an observational pilot study that will enroll 45 individuals with MPS III Type A or B. Those participating in the study will be evaluated during a one-day assessment and chart review.

  Study phs001330

• Etiological Investigation of Cancer Susceptibility in Inherited Bone Marrow Failure Syndromes: A Natural History Study

  Background: A prospective cohort of Inherited Bone Marrow Failure Syndrome (IBMFS) will provide new information regarding cancer rates and types in these disorders. Mutations in IBMFS genes are relevant to carcinogenesis in sporadic cancers. Patients with IBMFS who develop cancer differ in their genetic and/or environmental features from patients with IBMFS who do not develop cancer. These cancer-prone families are well suited for cancer screening and prevention trials targeting those at increased genetic risk of cancer. Carriers of IBMFS gene mutations are at increased risk of cancer. The prototype disorder is Fanconi Anemia (FA); other IBMFS will also be studied. Objectives: To determine the types and incidence of specific cancers in patients with an IBMFS. To investigate the relevance of IBMFS gene mutations in the carcinogenesis pathway of the sporadic counterparts of IBMFS-associated cancers. To identify risk factors for IBMFS-related cancers in addition to the primary germline mutations. To determine the risk of cancer in IBMFS carriers. Design: Natural history study, with questionnaires, clinical evaluations, clinical and research laboratory tests, review of medical records, cancer surveillance. Primary endpoints are all cancers, solid tumors, and cancers specific to each type of IBMFS. Secondary endpoints are markers of pre-malignant conditions, such as leukoplakia, serum or tissue evidence of carcinogenic viruses, and bone marrow morphologic myelodyplastic syndrome or cytogenetic clones.

  Study phs001481

• Innate Immune Anti-Viral Deaminase Deregulation Fuels Pre-Leukemia Stem Cell Evolution

  This study evaluates the effect of Rebecsinib treatment on gene expression, isoform splicing, and ADAR1 mediated RNA editing in cells from an in vivo humanized mouse model which have been engrafted with human secondary AML cells. For analysis of cells from Rebesinib-treated animals, CD34+ cells were obtained from bone marrow and spleens of sAML-engrafted mice following once weekly treatment with 0 (Vehicle) or 5 or 10 mg/kg Rebecsinib. For analysis of cells from serial transplant recipients of cells harvested from Rebecsinib-treated mice, CD34+ cells were obtained from bone marrow and spleens of sAML-engrafted mice that were transplanted with cells from animals that received twice weekly treatment with 0 (Vehicle) or 10 mg/kg Rebecsinib. No further treatment was given to serial transplant recipients, thus allowing the analysis of molecular changes that are sustained following serial transplantation. Whole transcriptome sequencing was performed at The Scripps Research Institute Next Generation Sequencing Core on Illumina NextSeq 500 sequencers with 150bp paired-end reads.These data revealed a uniquely expressed ADAR1 splice isoform (with a retrained intronic region), global downregulation of normalized RNA editing events, and isoform switching from MCL1-L to MCL1-S in Rebecsinib-treated sAML-engrafted mice. These results demonstrate the anti-survival and anti-self-renewal effects of Rebecsinib treatment on the leukemia stem cell (LSC) population in sAML-engrafted mice as well as the reduction in the inflammation-induced, hyper-editing p150 isoform of ADAR1. Thus, Rebecsinib treatment has promise for reducing the LSC population in myeloproliferative disorders and associated cancers.

  Study phs002228

• Digitalis Investigation Group (DIG-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 To determine the effect of increasing age on mortality, hospitalizations, and digoxin side effects in patients with heart failure (HF), and to determine whether the effect of digoxin on clinical outcomes varies as a function of age. Background The incidence and prevalence of HF increase with advancing age, but there are limited data on the clinical course and response to specific interventions in elderly patients with HF. Participants A total of 302 centers in the United States and Canada enrolled 7,788 patients between February 1991 and September 1993. Design The Digitalis Investigation Group (DIG) study was a prospective, randomized clinical trial involving 7,788 patients with HF randomized to digoxin or placebo and followed for an average of 37 months. Interactions between age and the following clinical outcomes were examined: total mortality, all-cause hospitalizations, HF hospitalizations, the composite of HF death or HF hospitalizations, hospitalization for suspected digoxin toxicity and withdrawal from therapy because of side effects. Conclusions Increasing age is associated with progressively worse clinical outcomes in patients with HF. However, the beneficial effects of digoxin in reducing all-cause admissions, HF admissions, and HF death or hospitalization are independent of age. Thus, digoxin remains a useful agent to the adjunctive treatment of HF due to impaired left ventricular systolic function in patients of all ages.

  Study phs003872

• DNA methylation and the adverse metabolic outcomes of adiposity

  Overweight and obesity affect ~1.5 billion people worldwide, and are major risk factors for type-2 diabetes (T2D), cardiovascular disease and related metabolic and inflammatory disturbances.1,2 Although the mechanisms linking adiposity to its clinical sequelae are poorly understood, recent studies suggest that adiposity may influence DNA methylation,3-6 a key regulator of gene expression and molecular phenotype.7 Here we use epigenome-wide association to show that body mass index (BMI, a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci at P<1x10-7, range P=9.2x10-8 to 6.0x10-46; N=10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find the methylation loci are enriched for functional genomic features in multiple tissues (P<0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P<9.0x10-6, range P=5.5x10-6 to 6.1x10-35, N=1,785 samples). The methylation loci identified highlight genes involved in lipid and lipoprotein metabolism, substrate transport, and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future type-2 diabetes (relative risk per 1SD increase in Methylation Risk Score: 2.3 [2.07-2.56]; P=1.1x10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type-2 diabetes and other adverse clinical consequences of obesity.

  Study EGAS00001001922

• Dilgom_Exome

  The Finrisk sample sets are part of the National FINRISK Study. It is a large population survey on risk factors of chronic, noncommunicable diseases. The survey is carried out since 1972 every five years using independent, random and representative population samples from different parts of Finland. The main results from the previous FINRISK 2007 survey are published.The National FINRISK Study Survey was carried out in 5 areas in Finland and 2000 inhabitants aged 25-75 years were invited to participate in each year. Among findings were that Finns continue to gain weight.Data from FINRISK surveys are used for many different research projects and for national health monitoring needs. The recent research activities deal, in addition to cardiovascular diseases and the classical risk factors, also with e.g. asthma and allergy, alcohol, socioeconomic factors and genetic epidemiology.The FINRISK study is part of the MORGAM Project (MONICA Risk, Genetics, Archiving and Monigraph), sponsored by the EU and MDECODE (Molecular Diversity and Epidemiology of Common Disease) program coordinated by the University of Michigan.The exome sequencing study will be part of the Dilgom study, which is a part of the larger Finrisk population based health study performed in Finland. It consists of 5000 individuals with a prospective aspect of metabolic traits. The cohort has been extensively phenotyped for their cardiovascular and metabolic status. So far, we have performed a 660K Illumina GWAS and a full genome wide expression study from peripheral blood cells of 500 individuals. The cohort has also been in total genotyped by the cardiometabochip

  Study EGAS00001000086

• UK10K_RARE_THYROID

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.Two cohorts of subjects are being analysed: Individuals with Congenital Hypothyroidism (CH) due either to dysgenesis or dyshormonogenesis; Patients with Resistance to Thyroid hormone (RTH), a disorder characterized by elevated thyroid hormones and variable tissue refractoriness to hormone action. The CH cohort has been enriched for genetic aetiologies by recruiting cases that are familial, on a consanguineous background or syndromic. The RTH cohort consists of cases in which candidate gene analyses have been negative.For further information with regard to this cohort please contact Krishna Chatterjee (kkc1@medschl.cam.ac.uk).

  Study EGAS00001000131

• Parallel CRISPR Editing of Familial ALS Mutations

  Induced pluripotent stem cells (iPSCs) provide a modeling system for human disease within the critical context of the human genome. CRISPR editing of iPSCs allows the construction of isogenic pairs where the cells have nearly identical genomes except for the desired edited change. Here, we used CRISPR editing on a healthy control line to generate three new isogenic iPSC lines that each contains a different familial amyotrophic lateral sclerosis (fALS) mutation (TARDBP[G298S/+], SOD1[G85R/+], and PFN1[G118V/+]). As controls for each mutation, we retained iPSC lines that went through the editing process but did not have the desired heterozygous mutation. We have also performed editing in a patient cell line with a hexanucleotide repeat in C9ORF72. This edit mutates a non-canonical start codon upstream of the hexanucleotide repeat. These edited lines have been used in three different studies:(1) In “Human sensorimotor organoids derived from healthy and amyotrophic lateral sclerosis stem cells form neuromuscular junctions” (PMID: 34362895), we performed exome sequencing to confirm the absence of off-target CRISPR events. We also performed single-cell sequencing on sensorimotor organoids from a second healthy control iPSC line, which is deposited alongside the exome sequencing data.(2) In “iPSC motor neurons, but not other derived cell types, capture gene expression changes in postmortem sporadic ALS motor neurons (PMID: 37651231), we differentiated these isogenic lines into motor neurons, sensory neurons, cortical neurons, and astrocytes and then performed bulk RNA-sequencing. We then assessed similarities between fALS mutations, differences between cell types, and the capacity of iPSC modeling to capture differentially expressed genes in postmortem sporadic ALS motor neurons.(3) In "Blocking RAN translation without altering RNA foci rescues C9ORF72-related ALS/FTD phenotypes" (Jiang et al. 2025), we mutate a non-canonical start codon upstream of a hexanucleotide repeat in C9ORF72. This mitigates several phenotypes related to neurodegeneration.

  Study phs002440

• Highlights from 2025: Our top 10 requested studies

  In 2025, as in previous years, EGA has facilitated the reuse of numerous datasets spanning a broad range of research and healthcare topics. To reflect on this activity, we would like to highlight the top 10 studies behind the most requested datasets of last year. Notably, the vast majority of these highly requested datasets are cancer-focused, particularly involving the study of immune checkpoint inhibitor therapies. Immune checkpoint inhibitors (ICIs) have become one of the most transformative advances in modern cancer therapy. These monoclonal antibodies enhance antitumor immune responses by targeting inhibitory immune checkpoint molecules. While ICIs have led to remarkably favorable and durable responses in some patients, treatment outcomes vary widely. This variability has fueled intense research efforts aimed at understanding resistance mechanisms, exploring combination therapies, and discovering predictive biomarkers to better stratify patients and guide treatment decisions. Study Title Disease 1 EGAS00001005503 Integrated genomic analyses reveal molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma Liver Cancer 2 EGAS00001005013 Intratumoral plasma cells predict outcomes to PD-L1 blockade in non-small cell lung cancer Lung Cancer 3 EGAS00001004809 BIOKEY: A single-cell catalogue of the dynamic changes underlying Checkpoint Immunotherapy response in Early Breast Cancer Breast Cancer 4 EGAS50000000138 BIOKEY: Immune heterogeneity in small cell lung cancer and vulnerability to immune checkpoint blockade Lung Cancer 5 EGAS50000000497 Bladder cancer subtyping study across 4 atezo clinical trials Bladder Cancer 6 EGAS50000000689 MOSAIC - Multi-Omics Spatial Atlas In Cancer Cancer Atlas 7 EGAS00000000083 METABRIC (Breast cancer - genome and transcriptome) Breast Cancer 8 EGAS00001005702 Human genomic and phenotypic synthetic data for the study of rare diseases Synthetic data 9 EGAS00001002556 TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells Bladder Cancer 10 EGAS00001004353 Molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade Renal Cancer The most requested dataset of the year was EGAD00001008128. It belongs to a study that analyzed 358 liver cancer patients enrolled in clinical trials and treated with the combination of atezolizumab (anti–PD-L1) and bevacizumab (anti-VEGF), atezolizumab alone, or sorafenib. The study highlights how bevacizumab enhances anti-PD-L1 effect and identifies candidate biomarkers to predict treatment response. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer-related death worldwide [1]. Because symptoms often appear late, many patients are diagnosed at advanced stages, when curative options are no longer viable. For many years, sorafenib—a multikinase inhibitor approved in 2007—was the only systemic treatment available. Although numerous clinical trials followed, it was not until a decade later that additional therapies showed meaningful clinical benefit. Among these advances, immunotherapy emerged as a promising first-line option [2]. In particular, the combination of atezolizumab and bevacizumab demonstrated improved survival in patients with advanced HCC, reshaping the treatment landscape. However, treatment efficacy remains limited by the complex and diverse hepatic microenvironments that influence immune responses, as well as by high intratumoral heterogeneity. Identifying robust predictors of treatment response is critical to enable effective patient stratification and maximize the benefits of these therapies [2]. The continued demand for these datasets highlights the interest and critical role of data reuse in deepening our understanding of cancer, accelerating the development of more effective therapies, and improving patient outcomes. By providing secure access to high-quality genomic and clinical data, EGA acts as a catalyst for biomedical progress. References Sung, Hyuna, et al. "Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries."CA: a cancer journal for clinicians 71.3 (2021): 209-249. Ladd, Alexandra D, et al.“Mechanisms of drug resistance in HCC.” Hepatology 79(4) (2024): 926-940

  Blog top-10-studies-2025

• Performance Characteristics of Selective Targeted Enrichment in Genetic Diagnostic Testing

  The Nex-StoCT and ACMG recommend that validation of an NGS-based diagnostic test include performance test characteristics for assay accuracy, analytical sensitivity and specificity, reproducibility and repeatability. To measure these parameters for the GEDi capture and sequencing test, 4 samples (three randomly selected patient samples and the NA12878 HapMap sample) were prepared and sequenced in triplicate on each of three separate days. We also performed WES and SNP array genotyping analyses of these 4 samples using Agilent V4+UTR whole exome enrichment kit and Illumina Omni 2.5 SNP arrays, respectively.

  Study phs000798

• The Vaginal Microbiome in Reproductive Age Women

  The focus of this cross-sectional study was to characterize the vaginal microbiota of asymptomatic, sexually-active, and reproductive-age women representing four self-reported ethnic groups (White, Black, Asian, and Hispanic). Each woman self-collected two mid-vaginal swabs. The first swab was used to prepare a vaginal smear for Nugent gram stain analysis. The second swab was used for DNA extraction, 16S rRNA gene amplicon sequencing, and detection of Candida albicans. In addition, participants measured vaginal pH and completed a detailed questionnaire on sexual health and behaviors.

  Study phs001909