Search Results - EGA European Genome-Phenome Archive

Drug development for pediatric cancers: the importance of patient' s genomic data re-use

Cancer in children is uncommon and the overall prognosis for most pediatric cancers is good. However, while the combined survival rates have improved over the last decades, certain childhood malignancies, such as high-grade gliomas or metastatic sarcomas, still remain incurable in most patients. New strategies for targeting those devastating diseases are imperative, and patient genomic data can become a key asset in the process [1]. The Pediatric Cancer Genome Project’s datasets At EGA, we store over 500 datasets with sequencing data from pediatric cancer patients. A remarkable case is the datasets belonging to the Pediatric Cancer Genome Project (PCGP) from St. Jude Children’s Research Hospital–Washington University (Table 1 - EGAS list). PCGP is an ambitious effort to identify the mutations that drive childhood cancer and find new cures. Those datasets include 600 patients with complete tumor and normal genomes from 15 different tumor types. PCGP datasets have been an important resource for various studies that pooled genomic data from different public and in-house datasets to perform extensive genomic characterizations and publish comprehensive pan-cancer pediatric studies [2],[3]. Other interesting pediatric cancer datasets are from the Pediatric Brain Tumor Consortium, Sickkids or ICGC PedBrain project. How data reuse impacts drug development for pediatric cancers Recently, in October 2024, Nature Communications published a work led by the University of Michigan where authors used data from EGA (PCGP) check the table below as part of their strategy to pursue the identification of new tumor vulnerabilities susceptible to becoming novel therapeutic targets in diffuse midline glioma. Diffuse midline gliomas (DMG) are treatment-resistant and uniformly fatal pediatric brain tumors. The prognosis of this brainstem tumor is dismal with a median overall survival of 9–12 months from diagnosis. In this study, the authors first developed a lab model of the disease and reanalyzed data from the EGA to identify genes potentially linked to tumor severity. This approach revealed involvement of specific metabolic pathways, suggesting new possibilities for therapeutic intervention. In mice, the study shows that the use of statins can improve survival. For a brief overview of the underlying science, diffuse midline gliomas present intratumor heterogeneity with subpopulations of less-differentiated oligodendrocyte precursors and more differentiated astrocytes. Authors established in vitro models to recapitulate both phenotypes and identify metabolic programs in both subpopulations. To determine the clinical relevance, the authors re-used gene expression data from 76 DMG patients identifying a gene signature predicting decreased overall survival. After extensive metabolic characterization of subpopulations, authors defined strategies to target specific metabolic vulnerabilities. Pre-clinical experiments in mice using OXPHOS inhibitors and statins showed a reduction in tumor burden and increased overall survival [4]. In this scenario, the re-use of high-quality patient’s sequencing data appeared as an advantageous strategy to support the clinical relevance of in-vitro and pre-clinical findings. On the other hand, in rare conditions such as childhood cancer, the availability of public datasets and the possibility of pooling data from different sources can be the only way to obtain impactful results that lead to improvements for patients. References Davidoff, A. M. Pediatric Oncology. Seminars in pediatric surgery 19, 225–233 (2010). Gröbner, S. N. et al. The landscape of genomic alterations across childhood cancers. Nature 555, 321–327 (2018). Venu Thatikonda et al. Comprehensive analysis of mutational signatures reveals distinct patterns and molecular processes across 27 pediatric cancers. Nature Cancer 4, 276–289 (2023). Mbah, N. E. et al. Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma. Nature Communications 15, (2024). Datasets and Studies ID Title Access Policy Year EGAD00001000134 Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma McGill-DKFZ Pediatric Brain Tumour Consortium 2016 EGAS0000100192 Somatic Histone H3 Mutations in Diffuse Intrinsic Pontine Gliomas and Non-Brainstem Paediatric Glioblastomas St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project 2017 EGAS00001000575 Whole genome sequencing and whole exome sequencing of DIPG tumors and matched normal tissue The hospital for sick children ("SickKids") 2016 EGAD00001000792 Exome sequencing reads of paediatric glioblastoma McGill-DKFZ Pediatric Brain Tumour Consortium 2016 EGAD00001002006 Whole genome sequencing of paediatric glioblastoma in the ICGC PedBrain project ICGC PedBrain project 2016

Blog drug-development-for-pediatric-cancers

Genome-Wide Association Study of Breast Cancer in the African Diaspora - the ROOT study

The paucity of data on the genetic epidemiology of breast cancer for racial/ethnic groups other than those of European ancestry hinders the development of innovative interventions to reduce health disparities. Women in the African Diaspora experience a disproportionate burden of pre-menopausal breast cancer in comparison to all other races for reasons that remain unknown and understudied. This higher proportion of early-onset breast cancer might suggest a stronger genetic component in these populations. Genome-wide association studies (GWAS) have revealed several genetic loci that confer risk of breast cancer. Because all GWAS started the discovery stage in women of European ancestry and replicated mainly in women of European ancestry, we propose a novel approach for a GWAS in indigenous African women to identify alleles associated with breast cancer risk which will then be replicated in other populations. This innovative design builds on our current understanding of the etiologic heterogeneity in breast cancer and the distribution of breast cancer molecular subtypes which differ between women of African ancestry and women of European ancestry. The major objective of the proposed studies is to get to the "root" causes of breast cancer by identifying breast cancer risk alleles in a pooled sample of women of African ancestry and to replicate our findings in other populations. To achieve this objective, we conducted a case control study of breast cancer in women of African ancestry, including Africans living in Nigeria, African Americans and African Barbadians. We will genotype ~3800 individuals using the Illumina HumanOmni2.5-Quad platform. We will conduct both standard and novel genetic analyses of the data to map genes associated with breast cancer susceptibility, verify genotyping and carry out fine-mapping studies in genes or regions showing association with breast cancer risk, and replicate in other African American and non-African American populations. By pooling unique resources from studies throughout the African Diaspora, this study has the potential to identify risk alleles in several genes that contribute to increased breast cancer risk and may have implications for early detection, prognosis and treatment of breast cancer in ALL women. This should ultimately lead to improved outcomes for those who suffer a disproportionate burden of early-onset breast cancer.

Study phs000383

GEI Studies - Psoriasis

The GEI Studies Project was started as an NIH consortium involving 5 disease groups with funding provided through the Genes, Environment, and Health Initiative (GEI). The objective of the project was to optimize strategies for identifying rare variants as a follow up to genome-wide association studies (GWAS) using next-generation sequencing technology. One of the five targeted diseases, Psoriasis, is a multifactorial skin disease characterized by epidermal hyperproliferation and chronic inflammation that affects approximately 2% of Americans. Because only about one-third of all patients with psoriasis have a relative who is also affected with the disorder, psoriasis is not widely recognized as a genetic disease. However, previous research on families and identical twins has shown psoriasis has a strong genetic component, although environmental factors (such as infections, stress, and injuries) are also important. Although no definite psoriasis gene has yet been identified, research during the last ten years has revealed over forty potential gene locations that may contribute to the disease. Large amounts of data generated using next-generation sequencing technology would provide a more detailed characterization of sequence variation which would in turn increase the likelihood of detecting causative loci. With the presumption that rare variants are frequently the cause of a large portion of phenotypic variation, it was necessary to use large sample sets. In the main body of this study, we sequenced 4,966 samples (812 dermatologist-diagnosed cases of purely cutaneous psoriasis (PsC), 1,497 cases of rheumatologist-diagnosed psoriatic arthritis, 665 cases of cutaneous psoriasis with uncertain psoriatic arthritis status (PsV) and 1,992 controls) across 5.7 Mb of sequence containing 100 psoriasis candidate loci and 769 genes. For each candidate locus, we considered sequences within 250 kb of the strongest association signal. Within this window, three strategies were employed. For ten of the strongest psoriasis signals, we used a whole-region approach which included non-coding intergenic and intronic sequence. For four established loci of lesser significance, we targeted all full transcription units within the +/- 250 kb interval. For the remaining signals, we targeted the exons of all transcription units within the +/- 250 kb interval. Due to complexities of high-efficiency targeting of HLA genes we selected 5 specific candidate genes for sequencing near the HLA-C gene.

Study phs000766

Cooperative Study of Sickle Cell Disease (CSSCD)

The Cooperative Study of Sickle Cell Disease was initiated in 1977 to determine the natural history of sickle cell disease (SCD) from birth to death in order to identify those factors contributing to the morbidity and mortality of the disease. Specific objectives included: 1) to study the effect of sickle cell disease on growth and development from birth through adolescence 2) to study the conditions or events that may be related to the onset of painful crises 3) to obtain data on the nature, duration, and outcome of major complications of SCD 4) determine the nature, prevalence, and age- related incidence of organ damage due to SCD, and 5) study the role of SCD and its interaction with selected health events.Phases 2 and 3 of the study involved followup of the infant cohort. A total of 709 infants (age less than 6 months) were enrolled during Phase 1 of the Cooperative Study of Sickle Cell Disease (CSSCD), and Phases 2 and 3 of the CSSCD was designed to follow these children for an additional 10 years. The study objectives included: 1) define prospectively the natural history of sickle cell disease; 2) determine the relationships between cognitive and academic functioning and brain status as determined by MRI; 3) determine the cognitive or behavioral markers of silent infarct; 4) determine the relationship of family functioning on the Family Environment Scale (FES) to brain status, cognitive functioning, and social and demographic factors; 5) continue studies that will enhance the state of knowledge on the influence of sickle cell disease on the psychosocial adjustment of children and adolescents. Phase 2A of the study sought to examine the progression of organ damage in the heart, lung, kidney, and liver in adult cohort patients (born before 1/1/56) enrolled in phase 1 of the study between 3/79 and 5/81. A total of 620 patients from 11 centers were eligible for phase 2A.Instructions for requesting individual-level data are available on BioData Catalyst at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BioData Catalyst. For questions about availability, you may contact the BioData Catalyst team at https://biodatacatalyst.nhlbi.nih.gov/contact.

Study phs002362

(Epi)genetic Risk Architectures of Opioid-Dependent Brain

With nearly 20,000 overdose deaths in 2014 alone, opioid addiction (OA) has emerged as one of the most pressing public health crises in recent US history. One-fifth of individuals who try heroin develop an addiction to opioids. Genetics is a major contributor to OA with an estimated 60% heritability, only somewhat less than schizophrenia (80%) which has recently seen substantial gains in identified underlying genetics. Yet, studies to date have failed to uncover most of the genes that predispose individuals to OA, leaving the overwhelming fraction of OA heritability unexplained. The proposed study takes a novel, integrated "omics-based" strategy to investigate the molecular basis of OA and uncover both genetic and epigenetic factors associated with opioid addiction. The premise for our approach is founded on studies from our labs, and others, implicating regulatory variation in common traits and diseases, including those associated with complex brain phenotypes like addiction. We have collected the largest known cohort of postmortem brains from addicts who overdosed on opioids, along with matched control brains from non-users. From both cases and control specimens, we will isolate cells from 2 regions of the brain closely implicated in the addiction phenotype: the Prefrontal Cortex (PFC) and the Nucleus Accumbens (NAc). In Aim 1, we propose ChIP-seq studies to identify regulatory elements that distinguish cases from controls and define the opioid addiction phenotype. The regulatory differences will be connected to their gene targets through high resolution in situ Hi-C. In Aim 2, we propose QTL-based approaches to identify genetic variants that underlie the regulatory differences (hmQTLs). We also propose eQTL analyses to identify genetic variants that underlie differences in transcript levels between cases and controls. Aim 3 leverages the largest heroin addiction GWAS meta-analysis to date to test the hypothesis that SNPs in regions associated with chromatin and expression differences between cases and controls define novel loci for predisposition to OA. Each Aim has the potential for discovery independent of the others (differential HM, RNAexp, QTLs, and variant-phenotype associations) but their synergy is the most powerful component of the proposed study: identifying regulatory pathways that generate, not only phenotype associations, but hypothesized mechanisms for those associations which can be the focus of new opioid addiction prevention and treatment development.

Study phs002724

NHLBI GO-ESP Family Studies: Idiopathic Bronchiectasis of unknown etiology that is not related to cystic fibrosis or classic primary ciliary dyskinesia or immune deficiency or any other known causes

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The major goal of this project is to apply next generation resequencing technology to identify disease-causing variants that cause bronchiectasis of unknown etiology (e.g. non cystic fibrosis (CF), classic primary ciliary dyskinesia (PCD), immune deficiency, or any other known cause of bronchiectasis), i.e., "idiopathic bronchiectasis." As part of our ongoing efforts to define the genetic cause of rare lung diseases, we have also studied families in whom diagnosis of PCD or other known etiologies could not be confirmed. We have systematically collected and stored the DNA and phenotypic data on each of the families in our cohort. The phenotypic data includes age, gender, ethnicity information, clinical data pertaining to the airways disease, including neonatal respiratory distress, otitis media, sinusitis and bronchiectasis, ciliary ultrastructure analysis, and microbial colonization (status of nontuberculosis mycobacterium). During the course of our study, we have acquired 98 unrelated patients in whom bronchiectasis seemed to be of unknown causes. We will be using 11 unrelated patients, 5 unrelated affected sib-pairs, and 3 affected sibs from a family from this cohort, based on 1) development of bronchiectasis in the absence of smoking, 2) a good family pedigree with available DNA, and 3) a family history of bronchiectasis and/or occurrence of airways disease in a sibling. Classic CF, PCD and immune deficiency were ruled out, based on the tests described above. Alpha-1 antiprotease deficiency work up was negative and none of the patients were tobacco users or smokers.

Study phs000518

Center for Common Disease Genomics [CCDG] - Cardiovascular: Cardiology Biobanking for Biomarker Discovery

This study is a part of NHGRI's Center for Common Disease Genomics, which is a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation, congestive heart failure and type 2 diabetes. Atrial fibrillation will affect between 6-12 million individuals in the US by 2050. AF also is associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1. Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules.Source: https://ccdg.rutgers.edu/sites/default/files/CCDG_CVD_EOAF_FINAL_w_link.pdfThe BioHEART study is a multi-center, prospective, observational cohort study to identify new biomarkers in stable coronary artery disease (CAD) and acute myocardial infarction (MI) (ACTRN12618001322224). Participants are recruited at time of clinically indicated computed tomography (CT) coronary angiogram (CTCA). 1,950 of 5,000 planned participants have been recruited and serum/plasma/erythrocytes/monocytes stored, with follow-up ongoing. CTCA imaging studies provides volumetric quantification of total calcified and non-calcified plaque, which is assessed using established and novel scoring systems. Comprehensive molecular phenotyping is performed on blood samples using state-of-the-art genomic, transcriptomic, proteomics, metabolomic, lipidomic, and immunophenotyping. Outcome data will be used to build improved risk models for CAD.Reference: http://www.anzctr.org.au/ - ACTRN12618001322224

Study phs002726

International Consortium to Identify Genes and Interactions Controlling Oral Clefts

Oral clefts represent the most common group of craniofacial birth defects in humans, and include cleft lip with or without cleft palate (CL/P) and cleft palate (CP). Oral clefts have a complex and heterogeneous etiology, with strong evidence for both genetic and environmental causal factors. Candidate gene studies and genome wide linkage studies have yielded compelling but inconsistent evidence that multiple genes control risk, and several studies have shown evidence for interaction between genes and environmental exposures, especially maternal smoking and nutrient intake. This consortium pulls together a very large collection of cases and their parents from multiple populations, and offers a unique opportunity to expand the search for genes controlling risk to the genome wide level. The specific aims are: To conduct a genome wide analysis on 2000+ case-parent trios ascertained through a case with isolated, non-syndromic CL/P or CP to test for linkage and disequilibrium. Initial analysis will consist of individual tests for gene effects while simultaneously testing for GxE interaction with common maternal exposures including vitamin supplementation, cigarette smoking and alcohol consumption (which have all been implicated as environmental risk factors for oral clefts). To use haplotypes in tests for GxE interaction incorporating population specific estimates. Since haplotype frequencies vary among populations, trios will be assigned haplotypes in a stratified estimation and then a pooled test statistic will be constructed. To test for interaction between SNPs in different genes showing evidence of influencing risk in a test for GxG interaction. To test for interaction between genes and maternal biomarkers using trios from Utah where measures of plasma folate, vitamin B-6, homocysteine and zinc in mothers are available. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org), which was developed through the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to oral clefts through large-scale genome-wide association studies of well-characterized cases and their parents from multiple populations. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). The study was supported by the National Institute of Dental and Craniofacial Research (NIDCR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

Study phs000094

NHLBI GO-ESP: Early-Onset Myocardial Infarction Exome Chip (Broad EOMI)

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. As part of this initiative, the Broad has performed genotyping on several thousand subjects from 4 different cohorts on Illumina's ExomeChip platform as described below: The Duke Study: The Duke study enrolled cases from the Duke University Medical Center with myocardial infarction or coronary artery stenosis > 50%. Controls were individuals who were > 50 years old without coronary stenosis > 30% and without history of myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, or heart transplant. The InterMountain Heart Study: The Intermountain Heart Study is an observational registry of individuals with coronary artery disease and healthy controls who received care at participating Intermountain Healthcare facilities. The Ottawa Heart Study: The Ottawa heart study enrolled cases with angiographically confirmed coronary artery disease (> 1 coronary artery with > 50% stenosis) who did not have type 2 diabetes and were ≤ 50 years old for males and ≤ 50 years old for females. Controls were also enrolled who were asymptomatic males > age 65 and females > age 70. PennCATH: PennCATH is a case-control study that recruited individuals undergoing coronary angiography at the University of Pennsylvania Hospital. Cases had angiographically confirmed coronary artery disease (>1 coronary artery with 50% stenosis) and were ≤ 55 years old if male and ≤ 60 years old if female. Controls were men > 40 years old and women > 45 years old with normal coronary angiography.

Study phs000936

PRE-DETERMINE: Biologic Markers and MRI SCD Cohort Study

The PRE-DETERMINE Study is a prospective, multi-center study of 5,764 patients with a history of coronary artery disease (CAD) and documentation of either a prior myocardial infarction (MI) or mild to moderate left ventricular dysfunction (LVD) with left ventricular ejection fraction (LVEF) 35-50%. Patients were enrolled at 136 sites where information on baseline demographics, clinical characteristics, pertinent past medical history, lifestyle habits, cardiac test results, and medications were collected via electronic data capture. Electrocardiograms (ECG) along with a blood sample was also collected at baseline, sent to central laboratories, and stored for future analyses. Contrast-enhanced magnetic resonance imaging (CE-MRI) scans were collected on a subset of patients and analyzed. Enrollment closed in November 2013 and patients are now being followed centrally by the Clinical Coordinating Center via mail/phone to document interim non-fatal arrhythmic events and cause-specific mortality. Questionnaires that inquire about intervening implantable cardiac defibrillator (ICD) implantations, ICD therapies, cardiac arrest, and other pertinent cardiovascular endpoints are mailed to participants every six months, and follow-up telephone calls are made to non-responders. Study endpoints are being confirmed through review of medical records, interviews with next-of-kin, and autopsy reports, if available.The primary objective of PRE-DETERMINE is to determine whether biologic markers and ECGs can be utilized to advance sudden cardiac death (SCD) risk prediction in patients with coronary heart disease (CHD) and LVEF >30-35%. The overarching goal of the study is to identify a series of markers that alone or in combination specifically predict risk of arrhythmic death as compared to other causes of mortality among this at risk population of CHD patients with preserved LVEF> 30-35%. If biologic or ECG markers are identified that can specifically predict risk of ventricular arrhythmias, then these markers may serve as relatively inexpensive methods to identify those at risk. The public health impact of identifying markers could be quite substantial, leading to more efficient utilization of ICDs and advances in our understanding of mechanisms underlying SCD.Among the 95% of participants that provided a blood sample at baseline, genome wide genotyping using the Illumina Global Screening Array (GSA) has been performed. A total of 4,335 participants with European ancestry gave consent that allows genetic research and deposition of data into dbGaP.

Study phs002940

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