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• A Phase I/IB Study of Ipilimumab or Nivolumab in Patients With Relapsed Hematologic Malignancies After Allogeneic Hematopoietic Cell Transplantation

  Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is characterized by poor outcomes and novel therapeutic options are urgently needed. Immune checkpoint blockade using CTLA-4 and PD-1 blocking antibodies are a potential concept for reinstating a dormant graft-versus-leukemia (GvL) effect.This study investigated transcriptomic changes in biopsies obtained from patients who received immune checkpoint blockade for relapsed hematologic malignancy post-HSCT and elucidated transcriptional programs associated with successful reinvigoration of GvL. Differential gene expression analysis showed evidence of increased T cell infiltration in biopsies of responders to ipilimumab treatment and demonstrated shared gene programs between GvL and GvHD.

  Study phs002377

• Exploring the Genomic Dark Matter of Neurodevelopmental Disorders

  Neurodevelopmental Disorders (NDDs) are a group of disorders that typically manifest early in development and may give rise to impaired cognition, communication, adaptive behavior, and psychomotor skills. This study aims to take a more comprehensive view into the genomic landscape of structural variants implicated in NDDs with intellectual disability (ID). We have evaluated the genome of families with a genetically unsolved severe NDD via optical genome mapping. This study identified likely pathogenic or pathogenic structural variants in known NDD genes, including BCL11A, OPHN1, PHF8, SON, and NFIA. Data is available in VCF format, following the standard filtering settings in Bionano Access and available as "variants_combine_filters_inMoleRefine1.vcf" files.

  Study phs002937

• My Pediatric and Adult Rare Tumor (MyPART) Natural History Study of Rare Solid Tumors

  The goal of this study is to comprehensively and longitudinally evaluate the natural history of patients with rare solid tumors or tumor predisposition syndromes, estimating and defining their clinical spectrum (e.g. disease course and survival). Clinical data, patient reported outcomes (PROs), and biospecimen associated data are collected. Clinical data includes response to treatment, tumor pathology, and imaging. PROs include measures of pain, depression, anxiety, mobility, and cognitive functioning. Biospecimen data includes next-generation sequencing [RNAseq, whole exome sequencing (WES), whole genome sequencing (WGS), EPIC methylation array data, and TruSight Oncology 500 gene panel sequencing], cytokine analysis of plasma, immune phenotyping of circulating peripheral blood mononuclear cells.

  Study phs003143

• Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) Center for Environmental Health Disparities

  MADRES is a prospective pregnancy cohort based in urban Los Angeles, recruiting predominantly low income Hispanic mothers-to-be as part of a children's health study, funded by Environmental Influences on Child Health Outcomes (ECHO). Participants were measured for a number of chemical exposures and biomarkers. Two epigenetic markers will be available through dbGaP: miRNA expression in pregnancy (measured via Nanostring human assay, v3) and DNA methylation from pregnancy and children's cord blood (measured via EPIC array). Principal findings of this research described differences in miRNA expression profiles between early and late pregnancy, as well as miRNA expression affected by psychosocial stress.

  Study phs003194

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Severe Asthma Research Program (SARP)

  Cohort Description The Severe Asthma Research Program (SARP) has been investigating the clinical, physiologic and molecular phenotypes of asthma since 2000. It is currently following ~400 deeply phenotyped asthma patients. Data Being Submitted Wave 1 questionnaire data includes 397 variables for up to 375 SARP participants in C4R.Wave 2 questionnaire data includes 448 variables for up to 289 SARP participants in C4R.Dried Blood Spot/Serosurvey data includes 7 variables for up to 290 SARP participants in C4R.Derived data includes 43 variables for up to 463 SARP participants in C4R.Phenotype data includes 113 variables for up to 463 SARP participants in C4R.

  Study phs002913

• BIRC5 Upregulation Enhances DNMT3A-Mutant T-ALL Cell Survival and Pathogenesis

  The goal of this study was to determine how patients with T-ALL who have DNA methyltransferase 3 alpha (DNMT3A) mutations develop resistance to therapy. Since DNMT3A is a methyltransferase, we examined the effect of those mutations on epigenetic regulation using whole genome bisulfite sequencing (WGBS). We also assessed any changes in gene expression using RNA-sequencing. We found that T-ALL patients with DNMT3A mutations are resistant to apoptosis and some chemotherapies. WGBS showed that DNMT3A mutated patients clustered together by their epigenetic profile, which was associated with hypomethylation at TERT and HOX genes. RNA sequencing identified differences in JAK/STAT signaling.

  Study phs003623

• Multi-Ethnic Study of Atherosclerosis (Echocardiogram Image Repository)

  The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced clinical signs and symptoms) and the risk factors that predict progression to clinically overt cardiovascular disease or progression of the subclinical disease. MESA researchers study a diverse, population-based sample of 6,814 asymptomatic men and women aged 45-84. Thirty-eight percent of the recruited participants are white, 28 percent African-American, 22 percent Hispanic, and 12 percent Asian, predominantly of Chinese descent. Echocardiogram Image Repository includes Echocardiogram Images performed during MESA Exam 6 conducted between 2016 and 2018.

  Study phs003702

• 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

• Systematic immune cell dysregulation and molecular subtypes revealed by single cell RNA-seq of subjects with type 1 diabetes

  Type 1 diabetes mellitus (T1DM) is a prototypic endocrine autoimmune disease resulting from an immune-mediated destruction of pancreatic insulin-secreting beta-cells. A comprehensive immune cell phenotype evaluation in T1DM has not been performed thus far at the single. In this cross-sectional analysis, we generated a single-cell transcriptomic dataset of peripheral blood mononuclear cells (PBMCs) from 46 manifest T1DM (Stage 3) cases and 31 matched controls.Our study reveals a surprisingly strong systemic dimension at the level of immune cell network in T1DM, defines disease-relevant molecular subtypes and has the potential to guide non-invasive test development and patient stratification.

  Study EGAS50000000231

• Primary central nervous system lymphoma (PCNSL) biopsies show heterogeneity in gene expression profiles, genetic subtypes, and in vitro drug sensitivity to kinase inhibitors

  Primary central nervous system lymphoma (PCNSL) is an aggressive large B-cell lymphoma, most often of the activated B cell (ABC) subtype, but with limited tumor biology studies due to small biopsy size and lack of strict cohort definition. Here we examined the genetic heterogeneity of 29 HIV- EBV- PCNSL tumors using whole exome sequencing (WES). We compared these tumors to 5 cell lines comprised of two human PCNSL cell lines (TK and HKBML) and three systemic activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) (OCI-Ly3, TMD-8, HBL-1).

  Study EGAS50000000312

• Epigenomic atlas of organoid development

  To investigfate the epigenomic basis of fate decisions in the central nerveous system, we recorded a epigenomic timecourse of human brain organoid development using Cut&Tag with paired scRNA-seq. We further performed perturbation experiment inhibiting EED and profiled the response with scRNA-seq and Cut&Tag. Finally, we profiled a sample of the developing human brain using multiome sequencing and Cut&Tag. In our study, we uncover epigenomic switches during brain region diversification and show that epigenetic activation precedes gene expression during neurogenesis in organoids and in primary tissue. Lastly, we show that transcriptional repression by H3K27me3 is required to stabilize neuroectoderm induction from pluripotency.

  Study EGAS50000000155

• Mitochondrial DNA mosaicism in human somatic cells

  Genomic alterations accumulate in the somatic cells throughout an individual’s lifetime. Recent sequencing studies have documented widespread mutations in the nuclear genome and the frequent clonal competition of normal cells carrying mutations. However, the landscape of mitochondrial DNA (mtDNA) heteroplasmy in normal human tissues is poorly understood. This study investigated the whole genome sequences (WGSs) of 2,096 clones established from non-neoplastic healthy single cells obtained from 31 donors. In addition, we analyzed 31 WGSs of neoplastic cells, including 12 clones established from adenomatous polyps from one individual with MUTYH-associated polyposis and 19 matched colorectal carcinomas from individuals who donated normal colorectal clones.

  Study EGAS50000000254

• IκBε deficiency accelerates disease development in chronic lymphocytic leukemia

  The NFKBIE gene, which encodes the NF-κB inhibitor IκBε, is mutated in 3-7% of patients with chronic lymphocytic leukemia (CLL). The most recurrent alteration is a 4-bp frameshift deletion associated with NF-κB activation in leukemic B cells and poor clinical outcome. To study the functional consequences of NFKBIE gene inactivation, both in vitro and in vivo, we engineered CLL B cells and CLL-prone mice to stably down-regulate NFKBIE expression and investigated its role in controlling NF-κB activity and disease expansion. We found that IκBε loss leads to NF-κB pathway activation and promotes both migration and proliferation of CLL cells in a dose-dependent manner. Importantly, NFKBIE inactivation was sufficient to induce a more rapid expansion of the CLL clone in lymphoid organs and contributed to the development of an aggressive disease with a shortened survival in both xenografts and genetically modified mice. IκBε deficiency was associated with an alteration of the MAPK pathway, also confirmed by RNA-sequencing in NFKBIE-mutated patient samples, and resistance to the BTK inhibitor ibrutinib. In summary, our work underscores the multimodal relevance of the NF-κB pathway in CLL and paves the way to translate these findings into novel therapeutic options.

  Dataset EGAD50000000754

• HSC_population_dynamics___PX001_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001004146

• HSC_population_dynamics___KX009_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001004580

• HSC_population_dynamics___KX010_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001004581

• 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

• Genomic analysis of head and neck squamous cell carcinoma upon acquired resistance to cetuximab

  Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab) remain the only FDA-approved targeted therapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Unfortunately, most patients develop acquired resistance to cetuximab and there is currently no further therapeutic option for these patients (unmet clinical need), thereby highlighting the need to better understand resistance-causing mechanisms. Here, we carried out whole-exome sequencing on 2 cetuximab-sensitive and -resistant patient-derived xenograft models of HNSCC. Our data reveal several genetic alterations (mutations and copy number variations) associated with acquired resistance to anti-EGFR therapy.

  Study EGAS50000000800

• plasma DNA LINE-1 targeted bisulfite sequencing: a new non-invasive multi-cancer detection marker

  The detection of circulating tumor DNA, which allows non-invasive tumor molecular profiling and disease follow-up, promises optimal and individualized management of patients with cancer. However, detecting small fractions of tumor DNA released when the tumor burden is reduced remains a challenge. We developed a PCR-based targeted bisulfite method coupled to deep sequencing to detect methylation patterns of L1PA elements,which we named DIAMOND (for Detection of Long Interspersed Nuclear Element Altered Methylation ON plasma DNA). We used sodium bisulfite chemical conversion to achieve base-pair resolution analysis and designed a multiplexed PCR based on 8 amplicons covering L1PAs .

  Study EGAS50000000446

• Targeting EGFR in NF1 Mutant Melanoma

  Our study focused on melanoma patients with driver mutations in the neurofibromin 1 (NF1) tumor suppressor gene, a subset of melanoma patients that have not benefitted from recent treatment advances. We have leveraged patient-derived short-term cultures (STCs) and multiomics approaches to identify molecular features that could be developed into therapies for NF1 mutant melanoma patients. Our studies revealed that the epidermal growth factor receptor (EGFR) is highly expressed and active in NF1 mutant melanoma cells, and that genetic or pharmacological EGFR inhibition impaired tumor cell proliferation, survival, and cell growth in patient-derived NF1 mutant but not NF1 wild-type melanoma models.

  Study phs003906

• Immune Checkpoint Blockade for Relapsed Hematologic Malignancy Post-HSCT

  Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is characterized by poor outcomes and novel therapeutic options are urgently needed. Immune checkpoint blockade using CTLA-4 and PD-1 blocking antibodies are a potential concept for reinstating a dormant graft-versus-leukemia (Gvl) effect. This study investigated transcriptomic changes in biopsies obtained from patients who received immune checkpoint blockade for relapsed hematologic malignancy post-HSCT and elucidated transcriptional programs associated with successful reinvigoration of GvL. Differential gene expression analysis showed evidence of increased T cell infiltration in biopsies of responders to ipilimumab treatment and demonstrated shared gene programs between GvL and GvHD.

  Study phs003291

• HSC_population_dynamics_KSP_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001002762

• Atezolizumab monotherapy following dCRT indicated a promising cCR rate in patients with unresectable locally advanced esophageal squamous cell carcinoma (EPOC1802)

  The objective is to analyze tumor and normal cell exome sequencing of esophageal cancer patients participating in the Tenergy trial before treatment and RNA sequencing specimens of tumor biopsy specimens at three points before treatment, after radiation chemotherapy, and after atezolizumab administration, in order to search for biomarkers to predict treatment response. Exome sequencing of pretreatment tumor tissue (27 specimens) and normal tissue (27 specimens) from esophageal cancer patients participating in the Tenergy trial, and RNA sequencing of tumor biopsy specimens at three time points before treatment (28 specimens), after radiation chemotherapy (25 specimens) and after atezolizumab administration (25 specimens).

  Study JGAS000708

• Genetic mutation profiling of lymphomas arising in the uterine cervix and vagina

  Follicle center lymphoma (FCL) of the lower female genital tract (LFGT) is a rare lymphoma, with fewer than 20 cases reported to date. Since the genetic features of FCL of the LFGT have not been well characterized, we aimed to identify genetic alterations in this tumor through whole-exome sequencing or targeted gene panel analysis. Genomic DNA was extracted from a frozen tissue sample obtained from a surgically resected uterine cervical tumor. Whole-exome sequencing was performed using the Illumina NovaSeq X Plus platform. Library preparation was conducted with the SureSelect Human All Exon V6 kit, and sequencing was carried out with 150 bp paired-end reads.

  Study JGAS000823

• Circulating cell-free DNA methylation profiles as noninvasive multiple sclerosis biomarkers: A proof-of-concept study

  In chronic neurodegenerative diseases such as multiple sclerosis (MS), there is a critical unmet need for cost-effective non-invasive blood biomarkers to concurrently classify disease subtypes, monitor disability severity, and predict long-term progression. In this proof-of-concept study, we performed low-coverage whole-genome bisulfite sequencing (WGBS) on 75 plasma cell-free DNA (cfDNA) samples collected from a well-characterized real-world prospective clinic cohort with longitudinal disability outcome measurements. We assessed the clinical utility of cfDNA methylation profile for differentiating MS patients from non-MS controls, classifying MS subtypes, estimating disability severity, and predicting disease trajectories.

  Study EGAS50000001277

• DNTR sequencing data of paediatric acute lymphoblastic leukemia

  This study used the DNTR-seq method in leukaemia samples to profile the whole-genome and mRNA jointly in single cells. Direct tagmentation is used in a collection of single-cell whole genome sequencing (scWGS) methods, including DNTR-seq, which provide high quality data at ultra-low to low coverage. The overall goal was to characterize the genetic and transcriptional heterogeneity of cancer samples. To infer clonal structure and evolutionary history, copy number analysis based workflows were implemented. Bone marrow mononuclear cells from pediatric acute lymphoblastic leukemia samples were FACS sorted into 384 plates to generate the DNA and RNA profiles.

  Study EGAS50000001247

• CLUSTER RNAseq Study of Juvenile Idiopathic Arthritis patients in methotrexate cohort

  CLUSTER aims to discover novel disease mechanisms and biomarkers in children suffering from Juvenile idiopathic arthritis (JIA). Currently, little is known about the pathological disease mechanisms of JIA and there are no validated tools capable of predicting response or non-response to treatment. The study aims to identify biomarkers for treatment response using RNAseq technology. The samples used in this study comes from blood samples that were collected prior to patients receiving methotrexate treatment (naive). These samples were then processed for PBMC isolation followed by sorting cells into 4 different immune cell types. All of these samples were then sequenced by NovaSeq6000.

  Study EGAS50000000995

• Development of Novel Histiocytic Sarcoma Organoid Model for Drug Discovery

  Histiocytic sarcoma is an extremely rare and aggressive hematopoietic malignancy. Its pathogenesis remains poorly understood and effective treatments are lacking. We treated a patient with histiocytic sarcoma of soft tissue in Osaka International Cancer Institute and established an organoid culture from a resected tumor specimen using a modified air���liquid interface method. After serial passaging, the organoid was successfully xenografted into NOD-scid IL2Rgnull (NSG) mice. The established organoid retained key histological features and genetic characteristics of the original tumor. This organoid model offers a novel and reliable platform for studying the biology of histiocytic sarcoma and may contribute to the development of future therapeutic strategies.

  Study JGAS000807

• CLUSTER Read-counts matrix of RNAseq Datasets of JIA in methotrexate cohort

  CLUSTER aims to discover novel disease mechanisms and biomarkers in children suffering from Juvenile idiopathic arthritis (JIA). Currently, little is known about the pathological disease mechanisms of JIA and there are no validated tools capable of predicting response or non-response to treatment. The study aims to identify biomarkers for treatment response using RNAseq technology. The samples used in this study comes from blood samples that were collected prior to patients receiving methotrexate treatment (naive). These samples were then processed for PBMC isolation followed by sorting cells into 4 different immune cell types. All of these samples were then sequenced by NovaSeq6000.

  Study EGAS50000001501

• The EGA joins EUCAIM, the European project powering AI and imaging in cancer research

  EUCAIM (EUropean Federation for CAncer IMages) is the cornerstone of the European Cancer Imaging Initiative, one of the flagships of the Europe’s Beating Cancer Plan (EBCP). The European Genome-Phenome Archive (EGA), as member of the EUCAIM consortium, attended the kick-off meeting organized this week in Brussels for the launch of the Initiative. The EGA will contribute to the project with the experience gained in the deployment of our federated network, the Federated EGA (FEGA), and the experience gained as partners of EuCanImage (AI4HI initiative) contributing to the definition of common data models, ontologies and data standards. The ultimate goal of the project is to unlock the power of imaging and Artificial Intelligence for the benefit of cancer patients, clinicians and researchers. The consortium will deploy a pan-European digital federated infrastructure hosting cancer-related images, and associated pathology, molecular and laboratory data from Real-World. This endeavour will provide a comprehensive dashboard for imaging data discovery, federated search, metadata harvesting, annotation and distributed data processing. EUCAIM joins 76 partners, gathering the experience and previous effort made by the different repositories of the AI4HI initiative, European Research Infrastructures and national/regional repositories. Find out more information about the EUCAIM launch here

  Blog the-ega-joins-eucaim

• North American Brain Expression Consortium (NABEC) Exome Sequencing

  A fundamental challenge in the post-genome era is to understand and annotate the consequences of genetic variation, particularly within the context of human tissues. We describe a set of integrated experiments designed to investigate the effects of common genetic variability on mRNA expression distinct human brain regions. We show that brain tissues may be readily distinguished based on expression profile. We find an abundance of genetic cis regulation mRNA expression. We observe that the largest magnitude effects occur across distinct brain regions. We believe these data, which we have made publicly available, will be useful in understanding the biological effects of genetic variation.

  Study EGAS00001002110

• Identification of cis-regulatory mutations generating de novo edges in personalized cancer gene regulatory networks

  The identification of functional non-coding mutations is a key challenge in the field of genomics. Here we introduce μ-cisTarget to filter, annotate and prioritize cis-regulatory mutations based on their putative effect on the underlying ‘personal’ gene regulatory network. We validated μ-cisTarget by re-analyzing the TAL1 and LMO1 enhancer mutations in T-ALL, and the TERT promoter mutation in melanoma. Next, we re-sequenced the full genome of ten cancer cell lines and used matched transcriptome data and motif discovery to identify master regulators with de novo binding sites that result in the up-regulation of nearby oncogenic drivers.

  Study EGAS00001002571

• Feasibility Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN) in resectable stage III melanoma patients

  OpACIN is a feasibility study including 20 patients with palpable stage III melanoma that were 1:1 randomized to receive ipilimumab 3mg/kg and nivolumab 1mg/kg, either 4 courses after surgery (adjuvant arm), or 2 courses prior to surgery and 2 courses post-surgery (neoadjuvant arm). WES and RNA-seq was performed on baseline biopsy material and correlated with outcome of the patients (relapse free survival). TCRseq from baseline tumor samples was used to analyse the top 100 tumor resident clones and analyse their change in PBMC comparing baseline versus week 6 of immunotherapy.

  Study EGAS00001003099

• A Study to Evaluate Denosumab in Young Patients With Primary Breast Cancer (D-Beyond)

  This is a prospective, single arm phase IIa trial in which patients with early breast cancer will receive pre-operatively two doses of denosumab 120mg subcutaneously one week apart (maximum 12 days) followed by surgery. Tumor, normal breast tissue and blood samples will be collected at baseline and at surgery. Post-operative treatment will be at the discretion of the investigator.Primary objective: to determine if a short course of RANKL inhibition with denosumab can induce a decrease in tumor proliferation rates as determined by Ki67 immunohistochemistry (IHC) in newly diagnosed, early stage breast cancer in pre-menopausal women.

  Study EGAS00001003252

• MutWP5__CRUK_Mutographs_of_Cancer__Lung__PD43291_Novaseq__WG_

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from lung tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will deeply sample from individuals with smoking-related lung diseases (COPD, pulmonary fibrosis, lung cancer) and those without smoking history. This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumor development.

  Study EGAS00001003502

• Chracterising_cellur_pathways_underlying_CD3_CD28_activation_of_human_CD4__cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Sorted Tcons were activated using a titration of anti-CD3 and anti-CD28 in combination as well as individually. As a control we cultured cells in the same conditions but without the stimuli. In total, we defined seven conditions from four individuals for sequencing. 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 EGAS00001004147

• Volasertib preclinical activity in high-risk hepatoblastoma

  Relapsed and metastatic hepatoblastoma represents an unmet clinical need with limited chemotherapy treatment options. In a chemical screen, we identified volasertib as an agent with in vitro activity, inhibiting hepatoblastoma cell growth while sparing normal hepatocytes. Volasertib targets PLK1 and prevents the progression of mitosis, resulting in eventual cell death. PLK1 is overexpressed in hepatoblastoma biopsies relative to normal liver tissue. As a potential therapeutic strategy, we tested the combination of volasertib and the relapse-related hepatoblastoma chemotherapeutic irinotecan. We found both in vitro and in vivo efficacy of this combination, which may merit further preclinical investigation and exploration for a clinical trial concept.

  Study EGAS00001004827

• Multi-omics analysis of cocaine use disorder in postmortem brain tissue of the ventral striatum [Proteomics data to study EGAS50000000623]

  We performed a multi-omics analysis of cocaine use disorder in postmortem human brain tissue of the ventral striatum in N=41 individuals (N=20 CUD cases, N=21 non-affected individuals). From the postmortem brain tissue samples, we generated miRNA-seq, RNA-seq, proteomics, and snRNA-seq data. The miRNA-seq, RNA-seq and snRNA-seq datasets can be found in the EGA under study ID EGAS50000000623. Proteomics data is deposited under study ID EGAS00001007945 (this study). The proteomic dataset was obtained using TMT-labeling. Measurement was performed on an Orbitrap Fusion Lumos device.

  Study EGAS00001007945

• Chordoma_Sequencing_Project_RNAseq

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

  Study EGAS00001000410

• 2014_Lung_sq_WES

  Purpose Lung squamous cell carcinoma (SqCC) is the second most prevalent type of lung cancer. Currently, no targeted-therapeutics are approved for treatment of this cancer, largely due to lack of systematic understanding of the molecular parthenogenesis of the disease. To identify therapeutic targets and comparatively analyze them in lung SqCC, we probed somatic alterations of Korean lung SqCC. Patients and Methods We performed massively parallel whole-exome sequencing of 104 Korean lung SqCC patients’ samples with matched normal samples. In addition, copy number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated.

  Study EGAS00001002844

• Sequential single-cell transcriptional and protein marker profiling reveals TIGIT as a marker of CD19 CAR-T cell dysfunction in patients with non-Hodgkin’s lymphoma

  Employed single cell RNA sequencing and protein surface marker profiling of serialCAR-T cell samples from patients with non-Hodgkin’s lymphoma (NHL) to reveal CAR-T cell evolution, identify biomarkers of response, and test for evidence of exhaustion inCAR-T cells of poor responders. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a non-proliferative, highly-differentiated, andexhausted state that is enriched in CAR-T cells of patients with poor response.Furthermore, we identified the checkpoint receptor TIGIT as a novel prognosticbiomarker and potential driver of CAR-T cell exhaustion.

  Study EGAS00001005356

• Isala Citizen Science Project: Cross-sectional branch

  The Isala Citizen Science Project, is named after the first female doctor in Belgium, Isala Van Diest (1842-1916). In a co-creative way, volunteers provided samples and data, proposed research objectives and survey questions, and helped to disseminate and interpret the objectives and results through different media platforms, jointly breaking taboos on women’s and vaginal health. In Flow 1, we collected a single sample from a cross-section of the population, characterized the microbiome, and associated it with data collected in questionnaires. Here, we provide extensive sample meta-data for over 3000 women who completed questionnaires on their lifestyle, diet, health, contraceptive use and environment.

  Study EGAS00001006934

• Linked-read based analysis of Medulloblastomas

  Medulloblastoma (MB) is the most common type of malignant pediatric brain tumor with group 4 medulloblastomas (G4 MBs) accounting for 40% of cases of medulloblastomas. The molecular mechanisms that underlie this subgroup are still poorly understood. Point mutations are detected in a large number of genes at low incidence per gene while the detection of complex structural variants (SVs) in recurrently affected gene typically requires the application of long-read technologies. Here, we applied linked-read sequencing, which combines the long-range genome information of long-read sequencing with the high base pair accuracy of short read sequencing and very low sample input requirements.

  Study EGAS00001007064

• PAGE: Prenatal Assessment of Genomes and Exomes

  The Prenatal Assessment of Genomes and Exomes (PAGE) study is a multicentre prospective trial, performing exome sequence analysis on samples from 1000 families with structural anomalies in prenatal ultrasound screening but normal aneuploidy results. The data will enable discovery of novel genetic disorders and increase the diagnostic yield. Where appropriate, results will be reported back to the families at the end of the pregnancy, after thorough clinical review. Ultimately, the translation of the acquired know-how into cost-effective prenatal diagnostic sequencing will improve genetics-derived prognoses and allow more informed parental counselling as well as management of pregnancy and childbirth.

  Study EGAS00001001713

• HSC_population_dynamics___LEUK4_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001004247

• Deciphering Intratumoral Molecular Heterogeneity in Clear Cell Renal Cell Carcinoma with a Radiogenomics Platform

  Intratumoral heterogeneity (ITH) challenges the molecular characterization of clear cell renal cell Carcinoma (ccRCC) with percutaneous biopsies and is a confounding factor in selection of molecular-targeted versus immune-based therapy. Magnetic Resonance (MR) Imaging can noninvasively assess the spatial landscape of the entire tumor. To validate MRI for ITH assessment, we implemented a radiogenomic platform through a systematic imaging based co-localization approach for multi region tissue acquisition from single tumors. We investigated if the spatial changes in imaging can predict the molecular changes using transcriptome and histopathological correlatives. Our study confirmed imaging heterogeneity as a predictor of molecular heterogeneity in ccRCC.

  Study EGAS00001003846

• Meisal temporal lobe epilepsy sequencing study

  Our understanding of mesial temporal lobe epilepsy (MTLE) is one of the most common forms of drug-resistant epilepsy in humans. Using RNA- and small RNA-sequencing in parallel, we explored differentially expressed genes in the hippocampus and cortex of MTLE patients who had undergone surgical resection and non-epileptic controls. We found significant enrichment for astrocytic and microglial genes amongst up-regulated genes and down-regulation of neuron-specific genes in the hippocampus of MTLE patients. The transcriptome profile of the small RNAs reflected disease state more robustly than mRNAs, even across brain regions which show very little pathology.

  Study EGAS00001003922

• Evolution of GBM through therapy

  Primary glioblastoma (GBM) tumours recur following treatment. This is likely due to intratumour heterogeneity (ITH), which reduces the effectiveness of cancer therapies by enabling therapy-driven tumour evolution: Darwinian selection of genotypically and/or phenotypically distinct cells (subclones) that resist treatment to seed regrowth of an even less treatable recurrence. To investigate this we sequenced a pilot cohort of nine paired primary and locally recurrent GBM tumours, alongside matched blood samples, in order to begin characterising therapy resistant cells and thereby infer the mechanisms by which they evaded treatment. These data were included in the first data release from the Glioma Longitudinal AnalySiS (GLASS) consortium.

  Study EGAS00001003546

• Exome-sequencing of two UFM individuals and their Fragile X family members.

  Fragile X syndrome (FXS) is a monogenic neurodevelopmental disease often caused by a CGG triplet expansion in the 5’UTR of the FMR1 gene, which results in DNA methylation of the FMR1 promoter and its transcriptional silencing. Exceptional healthy individuals named "unmethylated full mutation (UFM)" have been identified in the families of FX patients. They carry an expanded CGG repeat, but show normal FMR1 epigenetic configuration and expression. In this study we performed exome-sequencing of two UFM individuals and their family members to identify possible genetic mutations responsible for the escape of silencing in the unmethylated full mutation (UFM) phenotype.

  Study EGAS00001001737

• LifeLines-DEEP population multi-omix cohort from the noth of the Netherlands.

  The LifeLines-DEEP cohort is a sub-cohort of the LifeLines cohort (167,729 participants) that employs a broad range of investigative procedures to assess the biomedical, socio-demographic, behavioral, physical and psychological factors that contribute to health and disease in the general Dutch population, (Scholtens 2015). A subset of approximately 1,500 participants also took part in LifeLines-DEEP. For these participants, additional biological materials were collected, including analysis of the gut microbiome composition. The phenotyping and processing of LifeLines-DEEP has been described in Tigchelaar (2015).

  Study EGAS00001001704