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• Transcriptional_Consequences_of_Copy_Number_Changes_MY_HDBR_200531

  Every normal human cell has two copies of each non-sex chromosome. The gain or loss of an extra copy underlies many health conditions, including developmental syndromes and cancer. Ultimately, it is the patterns of genes that are turned on and off that determines which proteins a cell produces and its biological function. Despite the importance of changes in chromosome number (known as aneuploidy or copy number changes), little is known about how these changes impact patterns of gene expression. This project will aim to fill this gap by creating an atlas of patterns of gene expression in cells from developmental tissues with aberrant numbers of chromosomes. These gene expression profiles will then be compared to the patterns of expression in the same cells with two copies of each chromosome, directly measuring the precise, cell specific, consequences of copy number change on gene expression.

  Study EGAS00001005100

• Combination_Immune_Checkpoint_Inhibition_in_Australian_Rare_Cancers_WES

  Combination immune checkpoint inhibition (ICI) with anti-CTLA-4 and anti-PD-1 blockade has demonstrated significant clinical activity across tumour types. Rare cancer patients have limited treatment options due to the scarcity of studies of novel treatment options, so they are often offered chemotherapies untested in their disease. ONJ2016-001/CA209-538 is a prospective, multicentre clinical trial of combination ICI (ipilimumab and nivolumab) in patients with advanced rare cancers, including biliary tract, adrenocortical, rare gynaecological and neuroendocrine cancers (https://clinicaltrials.gov/ct2/show/NCT02923934). The primary endpoint is clinical benefit rate (complete response + partial response + stable disease >3 months) by RECIST 1.1. This study involves generation and analysis of pre-treatment formalin fixed paraffin embedded (FFPE) tumour DNA sequencing data, paired with germline DNA sequencing data, to potentially identify genomic biomarkers that may associate with clinical benefit or other clinical efficacy / toxicity metrics.

  Study EGAS00001005709

• Vento_Placental_Cell_Atlas

  The Human Cell Atlas initiative is an ambitious global research effort which aims to describe every cell in the human body across all developmental stages to generate a reference map to accelerate progress in science and medicine particularly relating to human development and disease. The initiative is led by investigators based at the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and funding support from the Wellcome and NIH. This specific project will assess human development. We aim to interrogate the cellular composition and molecular regulators underpinning development and maturation through single cell RNA-sequencing/spatial transcriptomics and computational algorithms to predict cellular developmental trajectories and cell-cell interactions. We will subsequent validate these findings in situ using allied imaging technologies e.g. immunohistochemistry and RNAscope and in vitro culture of human intestinal organoids (HIOs).

  Study EGAS00001004187

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

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

  Study EGAS00001003285

• Human breast transcriptome analysis

  Obesity is a risk factor for the development of post-menopausal breast cancer and is associated with a worse breast cancer prognosis. Here we carried out transcriptome profiling on nontumorous breast tissue to define the molecular changes that occur related to excess body fat and adipose inflammation. A second goal was to determine if blood biomarkers reflect molecular changes in the breast. Increases in a variety of pathways linked to tumor development and progression were found. Moreover, increased expression of several drug targets including aromatase, the rate-limiting enzyme for estrogen biosynthesis, and PD-1 was observed. Various blood biomarkers that are associated with either elevated risk of breast cancer or worse prognosis were altered and correlated with molecular changes in the breast. Collectively, this study helps to explain both the link between obesity and breast cancer and the utility of blood biomarkers for determining risk and prognosis.

  Study EGAS00001004665

• COPD and neutrophils

  Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small airway inflammation, emphysema and severe breathing difficulties. Low-grade systemic inflammation is an established hallmark of severe disease, however, the molecular changes in peripheral immune cells remain far from understood. We combined multi-color flow cytometry with single-cell RNA sequencing and showed that blood neutrophil numbers are significantly increased in COPD and they are a heterogeneous population. A transcriptomic state that expressed interferon response genes correlated with alveolar damage and acute exacerbations. Furthermore, bronchoalveolar neutrophils expressed gene signatures corresponding to certain blood neutrophil states. Last, our data in a murine model of cigarette smoke exposure demonstrated that bone marrow neutrophil progenitors are expanded in smoke-treated animals and display signs of immune activation. Our study provides evidence that COPD systemic inflammation may derive from an activated haematopoietic precursor compartment.

  Study EGAS00001006281

• COPD and neutrophils sc

  Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small airway inflammation, emphysema and severe breathing difficulties. Low-grade systemic inflammation is an established hallmark of severe disease, however, the molecular changes in peripheral immune cells remain far from understood. We combined multi-color flow cytometry with single-cell RNA sequencing and showed that blood neutrophil numbers are significantly increased in COPD and they are a heterogeneous population. A transcriptomic state that expressed interferon response genes correlated with alveolar damage and acute exacerbations. Furthermore, bronchoalveolar neutrophils expressed gene signatures corresponding to certain blood neutrophil states. Last, our data in a murine model of cigarette smoke exposure demonstrated that bone marrow neutrophil progenitors are expanded in smoke-treated animals and display signs of immune activation. Our study provides evidence that COPD systemic inflammation may derive from an activated haematopoietic precursor compartment.

  Study EGAS00001006322

• COPD and neutrophils sc rhapsody

  Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small airway inflammation, emphysema and severe breathing difficulties. Low-grade systemic inflammation is an established hallmark of severe disease, however, the molecular changes in peripheral immune cells remain far from understood. We combined multi-color flow cytometry with single-cell RNA sequencing and showed that blood neutrophil numbers are significantly increased in COPD and they are a heterogeneous population. A transcriptomic state that expressed interferon response genes correlated with alveolar damage and acute exacerbations. Furthermore, bronchoalveolar neutrophils expressed gene signatures corresponding to certain blood neutrophil states. Last, our data in a murine model of cigarette smoke exposure demonstrated that bone marrow neutrophil progenitors are expanded in smoke-treated animals and display signs of immune activation. Our study provides evidence that COPD systemic inflammation may derive from an activated haematopoietic precursor compartment.

  Study EGAS00001006323

• Rare coding variants in lupus risk genes

  Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.

  Study EGAS00001003548

• Short and long-read sequencing of Brugada syndrome samples

  Genome-wide association studies (GWAS) are instrumental in identifying loci with an impact on human traits and disease. Typically, however, most GWAS information is considered redundant as it is based on neighboring single-nucleotide variants (SNVs) in strong linkage disequilibrium (LD). In this context, besides the most significant hit (lead SNV) in every trait- or disease-associated locus, the rest of GWAS hits are often marginally reported, examined, or exploited. To interrogate the value of integrating the information provided by the full set of GWAS hits and fine-mapping haplotypes containing these SNVs, here we focused on a locus repeatedly associated with traits of the cardiac electrical conduction system and arrhythmia (SCN5A-SCN10A). We found that the same SNV can exhibit differing associations depending on haplotype. Thus, these analyses provide corroborative evidence that assuming redundancy among neighboring GWAS hits has the risk of missing critical disease-risk associations.

  Study EGAS00001004927

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

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

  Study EGAS00001007112

• Organoid drug profiling identifies methotrexate as a therapy for SCCOHT, a rare pediatric cancer

  Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and lethal tumor in adolescent and young adult patients. Currently, there is no standard-of-care treatment for these patients. Reliable models that represent this disease and can be used for translational research are scarce. To model SCCOHTs, we have established eight patient-derived tumoroid lines from tumor lesions of three patients with SCCOHT. The tumoroids recapitulate genomic and transcriptomic characteristics of the corresponding patient tumors and capture intrapatient tumor heterogeneity. Organoid drug profiling using a library of 153 clinical compounds identified methotrexate as an effective and selective drug against SCCOHTs with a clinically relevant IC50 of 35 nmol/L. RNA sequencing demonstrated that methotrexate induced TP53 pathway activation and apoptosis. These data underscore that organoid technology can support the design of therapeutic strategies for rare cancers.

  Study EGAS00001007911

• RAG mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 Acute Lymphoblastic Leukemia (Rearrangement_sequencing_data)

  The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL), is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize the critical secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, accounting for at least 43% of genomic rearrangements and characterized by the presence of recombination signal sequence motifs near the breakpoints; incorporation of non-templated sequence at the junction and a ten-fold enrichment at promoters and enhancers of genes actively transcribed in early B-lineage development. Single-cell tracking shows that this mechanism is not restricted to one founder cell but is rather active throughout leukemic evolution. Integration of point mutation and rearrangement data identifies recurrent inactivation of ATF7IP and MGA as two new tumor suppressor genes.Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1 lymphoblasts, striking promoters and enhancers of the genes that normally control B-cell differentiation.

  Dataset EGAD00001000635

• RAG mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 Acute Lymphoblastic Leukemia (Whole_exome_sequencing_data)

  The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL), is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize the critical secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, accounting for at least 43% of genomic rearrangements and characterized by the presence of recombination signal sequence motifs near the breakpoints; incorporation of non-templated sequence at the junction and a ten-fold enrichment at promoters and enhancers of genes actively transcribed in early B-lineage development. Single-cell tracking shows that this mechanism is not restricted to one founder cell but is rather active throughout leukemic evolution. Integration of point mutation and rearrangement data identifies recurrent inactivation of ATF7IP and MGA as two new tumor suppressor genes.Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1 lymphoblasts, striking promoters and enhancers of the genes that normally control B-cell differentiation.

  Dataset EGAD00001000636

• RAG mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 Acute Lymphoblastic Leukemia (Whole_Genome_sequencing_data)

  The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL), is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize the critical secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, accounting for at least 43% of genomic rearrangements and characterized by the presence of recombination signal sequence motifs near the breakpoints; incorporation of non-templated sequence at the junction and a ten-fold enrichment at promoters and enhancers of genes actively transcribed in early B-lineage development. Single-cell tracking shows that this mechanism is not restricted to one founder cell but is rather active throughout leukemic evolution. Integration of point mutation and rearrangement data identifies recurrent inactivation of ATF7IP and MGA as two new tumor suppressor genes.Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1 lymphoblasts, striking promoters and enhancers of the genes that normally control B-cell differentiation.

  Dataset EGAD00001000634

• Transcriptome Changes in ASD (NRXN1α+/-) iPSC-derived neurons

  NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy and the latter is associated with excessive neuronal firing. NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/β/γ. Previous studies on cultured cells show that the short NRXN1β primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of NRXN1α deletions in human neurons Quantitative RNA sequencing was performed by BGI using 50bp single-end strategy with BGI-SEQ500 sequencing device on iPSC-derived cortical neurons from 6 control lines; (2VC1, 3VCX1, 3VC2, 4C3, 4CX1, NCRM-1) of 4 healthy donors, and 4 NRXN1α+/- lines; (ND1C1, ND2C11, ND2CX1, ND4-1C2) from 3 ASD patients.

  Study EGAS00001005536

• Metabolic profiling of patient-derived organoids reveals nucleotide synthesis as a metabolic vulnerability in malignant rhabdoid tumors

  Malignant rhabdoid tumor (MRT) is one of the most aggressive childhood cancers for which no effective treatment options are available. Reprogramming of cellular metabolism is an important hallmark of cancer, with various metabolism-based drugs being approved cancer treatment. In this study, we use patient derived tumor organoids (tumoroids) to map the metabolic landscape of several pediatric cancers. Combining gene expression analyses and metabolite profiling using mass spectrometry, we find nucleotide biosynthesis to be a particular vulnerability of MRT. Treatment of MRT tumoroids with de novo nucleotide synthesis inhibitors lowers nucleotide levels in MRT tumoroids and induces apoptosis. Lastly, we demonstrate invivo efficacy of methotrexate in an MRT PDX mouse model. Our study revealsnucleotide biosynthesis as an MRT-specific metabolic vulnerability, which can ultimately lead to better treatment options for children suffering from this lethal pediatric malignancy.

  Study EGAS00001007877

• CFTR Gene Variant Detection in Moroccan Individuals via Nanopore Long-Read Sequencing

  This is data from LRS of CFTR gene on CF Moroccan patients

  Dac EGAC50000000815

• How upcycled prostate cancer sequences enabled key findings on telomeres length

  The length of telomeres, the chromosomes’ end tails, as depicted in the figure below, physiologically shorten with aging. This means that younger cells have longer telomeres compared to their aged counterparts; one could say that the length of cells’ telomeres is a measure of their replicative power. Cancer cells are known to be able to turn this into their favour, and expand their replicative immortality through telomere lengthening and maintenance. Despite being a well-studied pan-cancer hallmark, the relation of the telomeres length to specific cancer genomic features is poorly understood. Julia Livingstone and her colleagues from P.C. Boutros' team in Los Angeles focused their work on prostate cancer. To investigate the relations between telomere length and the clinico-genomics of prostate tumours, they used whole genome sequencing (WGS) of 392 published tumour–reference pairs previously deposited at the EGA under accession numbers EGAS00001000400 and EGAS00001000900. Their work was published on Nature Communications in November 2021. They determined the telomere length of the sequencing sample, from both tumour and non-tumour adjacent tissues, and subsequently ran statistical analysis to investigate possible correlation between the telomeres length with several cancer features. The team discovered that telomeres length does not correlate with any specific driver gene mutation, but it does with the overall frequency of single nucleotides variants in a sample. This finding suggests that tumours with shorter telomeres accumulate more mutations without strong selective pressures for specific ones. While proliferation rate did not correlate directly with telomere length, methylation of almost half of all genes strongly did. The team’s results are massive and reveal a complicated and fascinating relation of different clinical and genomic features of prostate cancer with telomere length. In the paper discussion, they smartly consider different possibilities. As noted above, all these amazing results have been obtained analysing previously sequenced samples. Remarkably, the researchers who generated the samples did not focus at all on telomeres length. They indeed studied specific genes mutations and the features of early and late-onset prostate cancer. This proves, once again, the power of sequencing data re-use. This data is tremendously rich in information, and can hardly be exhausted with any number of analyses. Generating sequencing data, especially Whole Genome Sequencing, even better if tumor-reference paired, is like shopping every last article at the grocery store. You can then cook several recipes, or prepare a seven-course dinner, and still have ingredients left for someone else to borrow and cook something you have not thought about, a recipe that is just not in your cookbook. Noteworthy, the data retrieved from the EGA for this paper is associated with rich and complete metadata, meaning pheno-clinical information regarding the sample donors. As Julia Livingstone and her team wrote, using rich clinical annotations enabled them to assess the relationship between telomere length and patients outcome. This highlights once again the importance of reporting and annotating metadata correctly; It might feel like extra work for the researchers depositing their data, but it really has a huge value. Our team at the EGA is currently working to improve the metadata annotation process, with the aim to maximize the benefits for the scientific community.

  Blog prostate-cancer-sequences-enabled-key-findings-on-telomeres-length

• Tumor-specific expression of let-7i and miR-192 is associated with resistance to cisplatin-based chemoradiotherapy in patients with larynx and hypopharynx cancer

  Background: The majority of patients with locally advanced larynx or hypopharynx squamous cell carcinoma are treated with organ preserving chemoradiotherapy (CRT). Clinical outcome following CRT varies greatly. We hypothesized tumor microRNA (miRNA) expression is predictive for outcome following CRT. Methods: Next-generation sequencing (NGS) miRNA profiling was performed on 37 formalin fixed paraffin embedded (FFPE) tumor samples. Patients with a recurrence free survival (RFS) of less than 2 years (“poor outcome”) and patients without recurrence within 2 years (“good outcome”) were compared by differential expression analysis. Tumor-specific miRNAs were selected based on normal mucosa miRNA expression data from The Cancer Genome Atlas database. A model was constructed to predict outcome using group-regularized penalized logistic ridge regression. Candidate miRNAs were validated in the initial sample set by RT-qPCR as well as in 46 additional tumor samples.Results: 1,938 known mature miRNAs were detected. Thirteen miRNAs were differentially expressed (p<0.05, FDR<0.1) according to outcome group. Initial class prediction in the NGS cohort (n=37) resulted in a model combining five miRNAs and disease stage, able to predict CRT outcome with an area under the curve (AUC) of 0.82. In the RT-qPCR cohort (n=83), 25 patients (30%) experienced early recurrence (median RFS 8 months; median follow-up 42 months). Class prediction resulted in a model combining let-7i-5p and miR-192-5p and disease stage, able to discriminate with an AUC of 0.80 patients with good versus poor clinical outcome.Conclusion: The combined miRNA expression and disease stage prediction model is superior to using either factor alone. ¬¬¬This study indicates NGS miRNA profiling using FFPE specimens is feasible, resulting in clinically relevant biomarkers.

  Study EGAS00001004001

• Cystic Fibrosis Nasal Epithelium Gene Expression by RNAseq

  Cystic fibrosis (CF) is a monogenic disorder leading to multi-organ system dysfunction, with the primary cause of morbidity and mortality being lung disease. Mutations in CFTR result in defective ion channel transport leading to hyperviscous mucus, airway infection, inflammation and lung function decline. While the Phe508del mutation is the most common CFTR mutation in North American people with CF, it is well known that there is a broad range of lung disease severity even amongst Phe508del homozygotes, including twins/siblings. Heritability analyses showing the relative contribution of non-CFTR modifier genes in such differences in phenotype, have led to our genomic and transcriptomic studies of gene modifiers in CF. Complementary to two international CF GWAS studies, this study was performed to a) determine differential expression of genes relative to a quantitative lung disease severity phenotype score (KNoRMA; as used in CF GWAS studies) and b) to assess expression quantitative trait loci. To better understand genetic modification of CF lung disease severity, we analyzed gene expression (transcriptomic) profiles by mRNA sequencing from nasal mucosal biopsy specimens of 134 people with CF. Each study participants was characterized for CF lung disease severity phenotype by averaging three years of lung function data (forced expiratory volume in 1 second; FEV1), normalized to a CF-specific reference population matching for age, sex, and height. Participants completed nasal lavage and nasal curettage mucosal sampling, with directed sampling to the inferior nasal turbinate, a well validated surrogate for cellular characteristics and CFTR function of the lower CF airways. Participants were further invited to complete a second set of these sampling procedures for validation analysis. Specimen and concurrent clinical data collection occurred across four North American study sites and nasal mucosal specimens were subjected to RNASeq analysis. These data were to be made available in the dbGaP. Our association analyses of gene expression relative to quantitative CF lung disease phenotype, taken together with previously identified GWAS signals, identified biological pathways correlated with CF lung disease pathogenesis. Our further association analyses of gene expression relative to single nucleotide polymorphism variation at significant CF GWAS loci further identified potential mechanisms of genetic variants associated with CF lung disease. This resource is intended to aid researchers in characterizing airway mucosal gene expression from the CF airways for the purpose of gene expression profiling in CF and in muco-obstructive airways disease.

  Study phs002254

• Germline and Somatic Genetic Landscape of Pediatric Rhabdomyosarcoma

  Dynamic approaches that integrate population-based research and molecular biology are needed to explain the mechanisms underlying pediatric rhabdomyosarcoma (RMS) and to determine novel prevention strategies. RMS, the most common soft-tissue sarcoma in children and adolescents, has one of the poorest 5-year survival rates among all pediatric cancers (less than 65%). One of the strongest risk factors for RMS is having a cancer predisposition syndrome. The syndromes that are most commonly seen among those with RMS are Li-Fraumeni, neurofibromatosis type 1, Costello, Noonan, and DICER1. Based on smaller clinic-based studies, only about 7% of RMS cases are thought to be associated with the genes responsible for these syndromes. However, there have been no population-based assessments to support this estimate. Even in the most recent large-scale evaluations of germline mutations in predisposition genes among children with cancer, very few RMS cases were included (43 cases). Furthermore, no distinctions were made between the major histologic subtypes of RMS: embryonal (eRMS) and alveolar (aRMS), which display differences in terms of age distribution, incidence, and cytogenetics. For instance, nearly 80% of alveolar cases are driven by a chromosomal translocation between either PAX3 or PAX7 and FOXO1, whereas these fusions are not seen in embryonal cases. In fact, RMS research is shifting from categorization based on histology to fusion status (eRMS is overwhelmingly fusion-negative). Another limitation in previous studies has been the inability to evaluate the frequency of de novo germline mutations (DNMs) in cancer predisposition genes due to the absence of any well-characterized cohorts of RMS case-parent trios. Therefore, a major gap in our understanding of the role of cancer predisposition in pediatric RMS that limit translational impact is there have been no population-based assessments to determine the true impact of these mutations on pediatric RMS, which limits clinical sequencing guidelines and surveillance protocols in these children.Overall Project Strategy: The objective of this project is to advance our understanding of the relationship between cancer predisposition genes and pediatric RMS. Our central hypotheses are: 1) mutations in cancer predisposition genes are more common than expected in children with RMS; and 2) children with fusion-negative tumors have a higher burden of germline mutations than those with fusion-positive tumors. The framework for this study relies on >600 well annotated samples collected from newly diagnosed RMS patients and stored in the Children’s Oncology Group (COG) Biopathology Center.

  Study phs002304

• MP2PRT: Evaluation of an Inflammation Polygenic Risk Score (iPRS) to Predict Cancer Related Cognitive Impairment and Fatigue in Patients Receiving Chemotherapy for Non-Metastatic Breast Cancer in URCC0701 and URCC10055

  This study is a secondary analysis of cancer related cognitive impairment (CRCI) and cancer related fatigue (CRF) among participants in URCC0701 and URCC10055 from the University of Rochester NCI Community Oncology Research Program (NCORP) Research Base. CRCI and CRF are common, troublesome, and dose-limiting toxicities reported by patients undergoing breast cancer chemotherapy that have an etiologic basis linked to low-grade systemic inflammation. Chronic, low-grade systemic inflammation is, in part, genetically determined with common single nucleotide polymorphisms (SNPs) capturing variation across individuals. This study aimed to 1) determine whether an inflammation polygenic risk score (iPRS) is associated with CRCI or CRF, 2) determine whether the relationship between the iPRS and CRCI or CRF is modified by exercise at the time of cancer treatment, 3) identify SNPs associated with serum cytokines measured at the time of cancer treatment, and 4) identify novel CRCI- and CRF-associated risk SNPs via genome-wide association analyses. We found that there was a significant inverse correlation between the iPRS and change in fatigue score from pre-chemotherapy to post-chemotherapy while there was no statistically significant association between the iPRS and cognitive impairment score. The inverse relationship between the iPRS and fatigue may be explained in part by the finding that the iPRS was also significantly associated with greater pre-chemotherapy fatigue, suggesting that women with a genetic predisposition to low-grade systemic inflammation (i.e., high iPRS) have more fatigue at the time of breast cancer diagnosis and, therefore, are less likely to worsen over the course of treatment. In contrast, women with a low iPRS had significantly less fatigue pre-chemotherapy and a significant worsening of fatigue from pre- to post-chemotherapy. The relationship between the iPRS and fatigue remained after adjustment for patient and cancer treatment covariates and was most pronounced in women who reported regularly exercising for at least 6 months prior to starting their cancer treatment. Exploratory genome-wide analysis identified a novel risk locus on chromosome chr6q27, tagged by rs9365961, associated with CRCI. This locus is upstream of TBXT, which encodes an embryonic nuclear transcription factor previously associated with susceptibility to neural tube defects. The genome-wide SNP data, patient-reported CRCI and CRF outcome measures, and covariate data used in this analysis are available through dbGaP.

  Study phs003688

• GA4GH

  Standards The EGA is a long-standing supporter of the Global Alliance for Genomics & Health (GA4GH) to enhance responsible sharing of human genetic data through the development of interoperable global standards for human data access. The EGA is one of the founding GA4GH Driver Projects and has contributed to the development and implementation of several GA4GH standards and APIs. Below is a list of the GA4GH standards and APIs that are currently available or planned for implementation at EGA. TechnicalStandards Purpose SpecificationVersion SupportedVersion Implementation Large Scale Genomics htsget A protocol for secure, efficient, and reliable access to sequencing read and variation data. V1.3.0 V1.0.0 Specification Documentation Endpoint Read File Formats (SAM/BAM/CRAM) Specifications for storing next-generation sequencing read data. V3.0.0 V3.0.0 Implementation Example of Usage Variation File Formats (VCF/BCF) The specifications for Variant Call Format Files (VCF) and its binary counterpart BCF. V4.0.0 V2.0.0 V4.0.0 V2.0.0 Implementation Example of Usage Crypt4GH v1.0 Enables direct byte-level compatible random access to encrypted genetic data stored in community standards (e.g. CRAM, VCF) V1.0 V1.0 Specification Documentation Endpoint refget API Enables access to reference sequences using an identifier derived from the sequence itself. V1.2.6 NA Specification RNAget API v1 Provides a means of retrieving data from several types of RNA experiments including (i) feature-level expression data from RNA-seq type measurements and (ii) coordinate-based signal/intensity data similar to a bigwig representation via a client/server model. V1.0.0 NA Documentation Discovery Beacon v2 Supports discovery of genomic variants, phenotypes, and individuals V1.0.1 V0.3 Web UI API Source Code Service Info API v1 The Service Info API is an endpoint for describing GA4GH service metadata, designed for extension and inclusion in other APIs. Service info is used to describe a single service, while Service Registry is used to describe multiple services. V1.0.0 NA Documentation Service Registry API v1 provides information about other GA4GH services, primarily for the purpose of organizing services into networks or groups and service discovery across organizational boundaries. V1.0.0 NA Documentation Data Use Researcher Identities Data Use Ontology (DUO) Allow users to semantically tag genomic datasets with usage restrictions, allowing them to become automatically discoverable based on a health, clinical, or biomedical researcher’s authorisation level or intended use. 2021-02-23 2021-02-23 Specification Documentation Endpoint Authentication & Authorization Infrastructure (AAI) The GA4GH AAI specification leverages OpenID Connect (OIDC) Servers for use in authenticating the identity of researchers desiring to access clinical and genomic resources from data holders adhering to GA4GH standards, and to enable data holders to obtain security-related attributes of those researchers. V1.2.0 V1.2.0 API URI: ega.ebi.ac.uk:8443 Documentation Repository Researcher IDs (passport, visa) Specify the collection of researchers that may access a dataset at any given time, and the credentials they must supply. V1.0.1 V1.0.1 Specification Documentation Endpoint Cloud Tool Registry Service API TRS is a standard API for exchanging tools and workflows to analyze, read, and manipulate genomic data. V2.0.1 NA Documentation Repostiory Data Repository Service API ​DRS API is a standard for building data repositories and adapting access tools to work with those repositories, works with other approved APIs from the GA4GH Cloud Work Stream to allow researchers to discover algorithms across different cloud environments and send them to datasets they wish to analyse. V1.0.3 NA Documentation Repostiory Workflow Execution Service API This API lets users run a single workflow (defined using CWL or WDL) on multiple different platforms, clouds, and environments, and be confident that it will work the same way. The API provides methods to request that a workflow be run, pass parameters to that workflow, get information about running workflows, and cancel a running workflow. V1.0.1 NA Documentation Repostiory Genomic Knowledge Standards Variation Representation v1 Provides a flexible framework of computational models, schemas, and algorithms to precisely and consistently exchange genetic variation data across communities. V1.3.0 EGA team is contributing to including it in in Beacon v2 Specification and Elixir Reference Implementation Documentation Repostiory Clin/ Pheno Data Capture Phenopackets Provides information models with different levels of complexity to enable high level clinical phenotype information as well as deep clinical phenotype information to be exchanged. V2.0.0 Included in Ongoing Submissions EGA team is contributing to including it in in Beacon v2 Specification and Elixir Reference Implementation Documentation Repostiory Driver Project The EGA, jointly coordinated by the EBI and the CRG, was announced, in 2017, to be one of the 15 Driver Projects for GA4GH. Driver Projects are international genomic data initiatives, focussed on real projects and challenges that will guide the development efforts in order to accelerate and enable completely responsible and standarised data sharing by 2022. All chosen Driver Projects make a cross-sectional effort by playing an important role across the different workstreams. Thomas Keane, Jordi Rambla, Mallory Freeberg, and Aina Jené have been named Driver Project Champions for the EGA. All Driver Project Champions will be leading this ambitious initiative for the following years.

  Documentation about/projects-and-funders/ga4gh

• Tumor Profiler DAC

  The Tumor Profiler DAC is responsible for the access to data generated in the Tumor Profiler Study.

  Dac EGAC50000000199

• Dataset that contains analyses of submission 6

  This is the description of analyses dataset of submission 6

  Dataset EGAD50000001107

• Melanoma post mortem analysis

  This is the affymetrix gene expression data of the metastatic tumours related to this study.

  Dataset EGAD00010001717

• RBtargetedSeq

  Retinoblastoma is a rare childhood cancer of the retina. We studied retinoblastoma by Targeted Sequencing.

  Dataset EGAD00001008004

• Dental Caries: Whole Genome Association and Gene x Environment Studies

  Dental caries (also known as tooth decay) remains the most common chronic disease of childhood, five times more common than asthma and seven times more common than environmental allergies, with more than 40% of children exhibiting caries when they enter kindergarten. In 2005, it was estimated that dental health care costs were approximately $84 billion, of which 60% or about $50 billion were related to treatment of dental caries. Although overall caries prevalence has declined over the last 40 years, dental caries in the primary dentition and mean caries rates in children ages 2-11 has increased markedly over the past 12 years. Childhood caries is a serious public health issue because of associated health problems and because disparities in oral health have led to substantially higher average disease prevalence among children in poverty and in under-served racial and ethnic groups. These issues are of such concern that in 2005, the American Academy of Pediatrics made children's oral health one of their top areas of focus, as it is for the majority of the NIDCR "Disparities Centers". The etiology of dental caries has been studied for many years. Multiple factors contribute to a person's risk for caries, including: 1) environmental factors such as diet, oral hygiene, fluoride exposure and the level of colonization of cariogenic bacteria and 2) host factors such as salivary flow, salivary buffering capacity, position of teeth relative to each other, surface characteristics of tooth enamel and depth of occlusal fissures on posterior teeth. In spite of all that is known about this disease, there are still individuals who appear to be more susceptible to caries and those who are extremely resistant, regardless of the environmental risk factors to which they are exposed, implying that genetic factors also play an important role in caries etiology. This conclusion is supported by studies in both humans and animals, with the most compelling evidence coming from studies of twins reared apart in which investigators found significant resemblance within monozygotic (MZ) but not dizygotic (DZ) twin pairs for percentage of teeth and surfaces restored or carious and estimated the genetic contribution to caries as 40%. Other recent studies of twins reared together estimated the heritability for caries, adjusted for age and gender, as ranging from 45-64%. Despite the strong evidence of a genetic component to risk for dental caries, there have been only a few studies of candidate genes in caries, and no published genome-wide scans. A comprehensive genome wide search is the only approach that will allow us to identify those genetic regions likely to harbor genes increasing the risk for dental caries, and eventually to identify the etiologic genes and to explore the interaction of those genes with microbiological, dietary, fluoride, and behavioral factors that are known to be associated with caries risk and progression. Therefore, the goal of this study is to perform genome-wide association (GWA) studies of dental caries with a large panel of SNP's (610,000) in families and individuals ascertained through multiple US sites (University of Pittsburgh and University of Iowa). The v2 release of this study includes 96 additional individuals who were genotyped with the CCDG: Dental Caries and CL/P in Guatemala project (dbGaP accession number phs000440) to augment the data initially presented here. These subjects were genotyped on the Illumina 610 platform to make their data comparable. 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 dental caries through large-scale genome-wide association studies of well-characterized families and individuals at multiple sites in the U.S. 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, U01-DE018903). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington. Samples of some participants in this study were selected for further genomic analysis. These results will be available in the dbGaP CIDR study: Center for Oral Health Research in Appalachia (COHRA) Genomic Studies of Oral Health and Disease (phs001591).

  Study phs000095

• Center for Common Disease Genomics [CCDG] - Inflammatory Bowel Disease (IBD) - Global Microbiome Conservancy Host Exomes

  The human body is a complex ecosystem, hosting tens of billions of bacteria, primarily in the gut. This community, known as the 'gut microbiome', is vital to human health, affecting functions ranging from metabolism, immunity, and development, to behavior. Conversely, reduced microbiome diversity and other imbalances of the gut community (dysbiosis) are associated with many diseases of the industrialized world, such as metabolic syndrome, asthma, and inflammatory bowel diseases among others. Microbiome-based interventions thus hold the potential to revolutionize our understanding of, and therapeutic approaches to, many aspects of human health and disease. Despite many advances, current understanding of the human microbiome is largely limited to majority ethnic groups in industrialized nations, and does not reflect the full diversity of human commensal microbiota. In addition to the scientific ramifications of minority underrepresentation, there are significant translational and ethical implications as well: First, failing to capture the full diversity of healthy human microbiota may limit our ability to understand and generate effective therapeutics for many microbiome-associated diseases. Second, underrepresented groups are less likely to benefit from microbiome-based medical advances tailored to well-studied populations, propagating healthcare inequities. The window of opportunity to characterize human microbiome diversity is closing rapidly. Human gut microbial diversity is diminishing around the globe, due to the spread of Westernized diets and lifestyles, which are associated with reduced microbiome biodiversity. The Global Microbiome Conservancy (GMbC) is a non-profit collaboration between scientists and communities around the world that aims to 1) preserve the full biodiversity of the human gut microbiome, 2) characterize its evolution across populations and host lifestyles and 3) investigate its interactions with the human host. We are collecting gut microbiome and human DNA samples from diverse populations around the world, from isolated groups to urbanized populations, to culture and study this essential biodiversity and to preserve it in a living "seed bank" as a long-term safeguard against future extinctions. The National Human Genome Research Institute (NHGRI) has funded a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Called the Centers for Common Disease Genomics (CCDG), this initiative will explore a range of diseases with the ultimate goal of: Undertaking variant discovery for enough different examples of disease architectures and study designs to better understand the general principles of the genomic architecture underlying common, complex inherited diseases. Understanding how best to design rare variant studies for common disease. Developing resources, informatics tools, and innovative approaches and technologies for multiple disease research communities and the wider biomedical research community. The initial focus of the CCDGs will be in cardiovascular disease (early-onset coronary artery disease, atrial fibrillation, hemorrhagic stroke), neuropsychiatric disease (epilepsy, autism), and autoimmune/inflammatory disease (type 1 diabetes, inflammatory bowel disease). The Broad Institute is one of four selected CCDG project centers. Both exome and genotyping information of GMbC participants will help understanding how recruited human populations are structured and genetically related. This human genetic structure will be analyzed in light of gut microbiome compositional and genomic differences to illuminate associations between specific microbiome traits and human groups and the evolutionary processes involved in the co-evolution of human hosts and their gut microbiome. It will also provide variant information for critical genes shaping the composition of microbiomes, such as genes involved in innate and adaptive immunity (e.g. antimicrobial peptides) or in the regulation of the immune response (e.g. Nod2). Association studies between specific variants in these genes and microbiome features will be performed, which will then be validated with in vitro and in vivo experiments. Human data from GMbC cohorts will also increase the genetic diversity of human populations, providing additional variant information for many susceptible loci that were found to be associated with Crohn's disease and ulcerative colitis. The whole genome sequencing data generated is comprised of samples from diverse and indigenous populations. Raw sequencing data, metadata, vcf and phenotype data at the individual level for a subset of the cohort's samples are available at https://anvilproject.org/data. For questions about availability, contact help@lists.anvilproject.org. Microbiome data for the samples sequenced in this study can be found in phs002235 Global Microbiome Conservancy Sequence Data.

  Study phs002205

• Transcriptomic profiles studies CAREs group - IDIBGI

  The purpose of this DAC document is to outline the principles and procedures governing access to the transcriptomic data generated from endothelial progenitor cells, or any biological origin from patients. Data Access Policy: 1) Access to this dataset is restricted and subject to approval by the DAC to ensure ethical and legal compliance. 2) The DAC reserves the right to evaluate all applications for access based on: 2.1) The scientific validity and merit of the proposed research. 2.2) The ethical considerations and adherence to data protection regulations, including GDPR. 2.3) The qualifications and affiliations of the applicants. 3) Applicants must submit a detailed research proposal, including objectives, methods, and anticipated outcomes. 4) Data usage is limited to the specified research project approved by the DAC. Any secondary use of the data requires additional approval. Confidentiality: All applicants must agree to maintain the confidentiality of the dataset. Personal identifiers have been pseudonymized to protect patient privacy. Application Process: 1) Researchers must complete the application form provided by the DAC. 2) Submit proof of ethical approval and relevant certifications for their research project. 3) Provide a signed agreement affirming adherence to the DAC's terms and conditions.

  Dac EGAC50000000607

• Hypermutation of the inactive X chromosome is a frequent event in cancer

  Mutation is a fundamental process in tumorigenesis. However the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. As part of the ICGC PedBrain and Malignant Lymphoma (MMML-Seq) consortium we performed a cross-cancer comparison of whole genomes comprising a diverse set of childhood and adult tumors including both solid and hematopoietic malignancies. In addition we performed whole genome sequencing of clonally expanded hematopoietic stem/progenitor cells (HSPCs) from healthy individuals to compare somatic mutation rates.

  Study EGAS00001000565

• Progression to AML is predictable and distinct from age related clonal hematopoiesis

  To examine the occurrence of somatic mutations prior to the development of acute myeloid leukemia, we undertook deep ECS (estimated limit of detection 1 mutation in 2500 cells) of 261 AML associated genes in 96 pre-AML cases and 420 age and gender-matched healthy controls of an average of 3853 unique DNA molecules covering each of the 1.19M bases spanning the target gene panel. The findings suggest that the development of clonal hematopoiesis and accumulation of somatic mutations is distinct and accelerated in pre-AML cases compared to healthy individuals

  Study EGAS00001002570

• Whole exome sequencing (WES) of EBV- primary central nervous system lymphoma (PCNSL)

  This dataset contains whole exome sequencing (WES) of 29 HIV- EBV- primary central nervous system lymphoma (PCNSL) tumors and 5 activated B-cell-like PCNSL (ABC-PCNSL) and activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cell lines (TK, HKBML, OCI-Ly3, HBL-1, TMD-8). Cases with secondary involvement of the CNS were excluded. DNA was extracted with AllPrep DNA/RNA FFPE kit and libraries were prepared using the Agilent SureSelect Human All Exon v6 + UTR kit. Paired end reads were aligned to GRCh37 using bwa mem v.0.7.17, and reads were sorted and duplicated were marked in the final BAM files. Access to this data is controlled. There are a number of steps that a researcher must take to obtain access to this data, including execution of a Data Access Agreement between the institutions. The process is overseen by the Technology Development Office; please contact our general email address TDOadmin@phsa.ca. Please only click the "request data" button on the EGA website after a Data Access Agreement is fully executed.

  Dataset EGAD50000000451

• Sequencing component for the whole genome methylation analysis in PBMCs and cell subsets (pilot study)

  DNA methylation has been shown to play a major role in determining cellular phenotype by regulating gene expression. Moreover, dysregulation of differentially methylated genes has been implicated in disease pathogenesis of various conditions including cancer development as well as autoimmune diseases such as systemic Lupus erythematosus and rheumatoid arthritis. Evidence is rapidly accumulating for a role of DNA methylation in regulating immune responses in health and disease. However, the exact mechanisms remain unknown. The overall aim of the project is to investigate the role of epigenetic mechanisms in regulating immunity and their impact on autoimmune disease pathogenesis.The aim of this pilot study is to perform whole genome methylation analysis in peripheral blood mononuclear cells (PBMCs) and cell subsets (CD4, CD8, CD14, CD19, CD16 and whole PBMCs) obtained from 6 healthy volunteers. Whole genome methylation analysis will be performed using two methodological approaches, the Infinium Methylation Bead Array K450 (Illumina) and MeDIP-seq. mRNA expression arrays will also be performed in order to correlate DNA methylation with gene expression as well as genotyping on the Illumina OmniExpress chip

  Dataset EGAD00001000394

• Somatic mutation and clonal evolution in premalignant lung disease - WGS (2020-01-15)

  Cancer is a genetic disease caused by an accumulations 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 the lung tissue of individuals with a variety of lung diseases (COPD, UIP, IPF, Emphysema, pulmonary hypertension). This will allow us to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. Smoking is a large risk factor for developing many of these lung diseases so we are particularly keen to determining whether there is evidence of a smoking signature in these patients. . This dataset contains all the data available for this study on 2020-01-15.

  Dataset EGAD00001005786

• Single-cell genome-wide concurrent haplotyping and copy-number profiling through genotyping-by-sequencing

  scGBS is a single-cell sequencing-based methodology to haplotype and copy-number profile single cells. Genomic size and complexity is reduced through restriction enzyme digestion and DNA is genotyped through sequencing of the restriction fragments. scGBS data serves as the input for haplarithmisis, an algorithm we previously developed for SNP array-based single-cell haplotyping (Zamani Esteki et al., 2015). We established technical parameters and developed an analysis pipeline enabling accurate concurrent haplotyping and copy-number profiling of single cells with the use of a HapMap cell line pedigree (7 single cells). A clinical validation of the methodology with a total of 14 single blastomeres and 3 trophectoderm samples biopsies from human preimplantation embryos for 6 PGT-M families were processed with scGBS and were previously haploptyped via SNP array.

  Dataset EGAD00001007794

• WGS dataset of Mutational Mechanisms in Multiply Relapsed Pediatric Acute Lymphoblastic Leukemia

  Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. The elevated mutational load at relapse can partly be explained by at least two therapy-related effects and a combination of therapy and underlying mismatch repair deficiency. However, our understanding of the type and timing of mutational mechanisms in relapsed ALL is limited, and it is unclear to what extent mutational processes contribute to disease progression. We collected a cohort of 29 Dutch ALL patients across multiple treatment protocols who had multiple relapses. Using whole genome sequencing of the sequential tumor samples of each patient we were able to distinguish the mutational processes active in relapsed ALL and could track the activity of mutational processes over time. This allowed us to investigate whether subtype-specific mutational processes at diagnosis can continue in relapse or emerge at relapse if absent in initial diagnosis. Furthermore, we assessed whether the activity of mutational processes contributed to disease development and relapse.

  Dataset EGAD00001015401

• A spatiotemporal cancer cell trajectory underlies glioblastoma heterogeneity

  Abstract: Cancer cells display highly heterogeneous and plastic states in glioblastoma, an incurable brain tumour. However, how these malignant states arise and whether they follow a tractable cellular trajectory across tumours is poorly understood. Here, we generated a deep single cell and spatial multi-omic atlas of human glioblastoma that pairs transcriptomic, epigenomic and genomic profiling of 12 tumours across multiple regions. We identify that glioblastoma heterogeneity is driven by spatially-patterned transitions of cancer cells from developmental-like states towards those defined by a glial injury response and hypoxia. This cancer cell trajectory regionalizes tumours into distinct tissue niches and manifests in a conserved manner across tumours as well as genetically distinct tumour subclones. Moreover, using a new deep learning framework to jointly map cancer cell states and clones in situ, we show that tumour subclones are finely spatially intermixed through glioblastoma tissue niches. Finally, we show that this cancer cell trajectory is intimately linked to myeloid heterogeneity and unfolds across regionalised myeloid signalling environments. Our findings define a stereotyped trajectory of cancer cells in glioblastoma and unify glioblastoma tumour heterogeneity into a tractable cellular and tissue framework.

  Dataset EGAD00001015516

• Unrelated Donor Reduced Intensity Bone Marrow Transplant for Children with Severe Sickle Cell Disease (BMT CTN-0601-BioLINCC)

  ObjectivesThe primary objective is to determine event-free survival (EFS) at 1 year after unrelated donor (URD) hematopoietic stem cell transplantation (HCT) using bone marrow (BM) in patients with sickle cell disease (SCD).BackgroundSickle cell disease (SCD), also known as sickle cell anemia, is an inherited blood disease that can cause organ damage, stroke, and intense pain episodes. Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. A blood stem cell transplant is a treatment option for someone with a severe form of the disease. Prior to undergoing a transplant, people typically receive a conditioning regimen of high doses of chemotherapy and other medications to prepare the body to accept the transplant. This type of conditioning regimen is known as a myeloablative conditioning regimen, but it can result in toxicities and sterility. A conditioning regimen that uses lower doses of chemotherapy and medications may be safer for transplant recipients. This type of regimen is known as reduced intensity conditioning (RIC) regimen. RIC has a more favorable toxicity profile but is associated with higher rates of graft rejection (GR), especially with graft sources such as umbilical cord blood This study evaluated the safety and effectiveness of blood stem cell transplants, using bone marrow from unrelated donors, in children with severe SCD who receive a RIC regimen prior to the transplant.SubjectsPatients 3.0-19.75 years old with symptomatic SCD AND one or more of the following complications: (1)-(i) a clinically significant neurologic event (stroke) or any neurologic defect lasting > 24 hours and accompanied by an infarct on cerebral magnetic resonance imaging (MRI); OR, (ii) patients who have a Transcranial Doppler (TCD) velocity that exceeds 200 cm/sec by the non-imaging technique (or TCD measurement of >185 cm/sec by the imaging technique) measured at a minimum of 2 separate occasions one month or more apart; OR, (2) Minimum of two episodes of acute chest syndrome within the preceding 2-year period defined as new pulmonary alveolar consolidation involving at least one complete lung segment (associated with acute symptoms including fever, chest pain, tachypnea, wheezing, rales, or cough that is not attributed to asthma or bronchiolitis) despite adequate supportive care measures; OR, (3) History of 3 or more severe pain events (defined as new onset of pain that lasts for at least 2 hours for which there is no other explanation) per year in the 2 years prior to enrollment despite adequate supportive care measures (if patients are receiving hydroxyurea and compliant with therapy, being symptomatic is an indication for transplantation; however, if patients decline hydroxyurea or non-compliant with this therapy, they would still remain eligible for study if pain criteria as described above are met). Lansky/Karnofsky performance score must be ≥ 40. Hemoglobin S must be ≤ 45%. Patients must have an unrelated adult bone marrow donor who is HLA-matched at 8 of 8 HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing. Patients with bridging fibrosis or cirrhosis of the liver, with uncontrolled bacterial, viral, or fungal infection in the past month, or seropositivity for HIV are excluded. Patients with HLA-matched family donors, or who have received prior HCT, and females who are pregnant or breast feeding are excluded. Thirty patients were enrolled on this study and of these, 29 patients met the criteria and proceeded to the study transplant.DesignParticipants attended a study visit prior to the transplant to undergo a blood collection, neurocognitive testing to measure learning and brain function, magnetic resonance angiogram (MRA) and magnetic resonance imaging (MRI) scans. Questionnaires to assess quality of life were also completed. All patients received erythrocyte transfusions before transplant. Twenty-two days (-22) before the transplant, participants began receiving a reduced intensity conditioning regimen of chemotherapy and medications. On days -21, -20, and -19 participants weighing 10 kg or more received 10 mg, 15 mg, and then 20 mg of Alemtuzumab intravenously (IV) followed by 30 mg/m2/day IV on days -8 through -4 of Fludarabine. Eight days (-8) before the transplant, participants were admitted to the hospital to continue the conditioning regimen which included 140 mg/m2 IV of Melphalan on day -3. Participants received the bone marrow transplant on day 0. Prophylaxis for GVHD consisted of a calcineurin inhibitor (tacrolimus or cyclosporine) administered from day -3 through day 100 after graft infusion, with subsequent taper through day 180; methotrexate 7.5 mg/m2 on days 1, 3, and 6; and methylprednisolone 1 mg/kg per day from days 7 through 28, with subsequent taper by 20% per week. One week after the transplant continuing until the WBC is normal, participants received granulocyte-colony-stimulating factor (G-CSF). After leaving the hospital, participants attended study visits weekly during weeks 1 to 8, at day 60, weekly during weeks 9 to 14, at Day 100, at month 6, and at years 1 and 2. At all study visits, a blood collection, medical history review, and physical exam occurred. In addition, at day 100, month 6, and years 1 and 2, questionnaires to assess quality of life were completed. At select visits the following procedures were conducted: lung function testing, heart function testing, MRA and MRI scans, and neurocognitive testing.The primary outcome was 1-year EFS. Death, disease recurrence or graft rejection by 1 year were considered events for this endpoint.ConclusionsThe trial met its prespecified 1-year EFS, and significantly improved HRQL was reported posttransplant. However, although the Reduced-intensity conditioning (RIC) provided successful engraftment in most patients, the regimen cannot be considered safe for widespread adoption without modification due to the regimen-related toxicity (RRT) and high rate of chronic GVHD, which was the predominant cause of mortality.

  Study phs003470

• DAC Johns Hopkins University - AML scRNAseq study

  This is the Data Access Committee (DAC) from Johns Hopkins University for the study scRNAseq of acute myeloid leukemia

  Dac EGAC50000000242

• CNCD Recall by Genotypes

  This is a DAC to handle recall by genotype studies by the conducted by the Center for Non-Communicable Disease Karachi, Pakistan.

  Dac EGAC50000000937

• MPNST exome and genome

  This is the complete dataset (exome and genome) for the EGAS00001000974 study.

  Dataset EGAD00001001040

• 108 WGS of epileptic patients from the CENet cohort

  Dataset is described in doi: https://doi.org/10.1101/2022.12.13.22283363

  Dataset EGAD00001011301

• The molecular basis of T-PLL is an actionable perturbation of TCL1/ATM- and epigenetically instructed damage responses

  T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. To address its incomplete molecular concept, we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identified novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM towards a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

  Study EGAS00001002744

• Long-Term Outcome in Offspring and Mothers of Dexamethasone-Treated Pregnancies at Risk for Classical Congenital Adrenal Hyperplasia Owing to 21-Hydroxylase Deficiency

  Summary The purpose of this study is to perform the first long-term follow up study both of adolescents and young adults with a history of prenatal treatment with dexamethasone and of their mothers and to test for adverse medical or behavioral side effects. The emphasis will be on the outcome of this prenatal treatment in those fetuses who are not affected with steroid 21-hydroxylase deficiency (21OHD) form of congenital adrenal hyperplasia (CAH) and are either heterozygotes or homozygote-unaffected. Prenatal treatment of 46,XX fetuses with 21OHD (via administration of dexamethasone to the pregnant mother) has been shown to reduce the masculinization of the genitalia and, thereby, the later need for 'corrective' feminizing genital surgery and potential impairment of sexual functioning. Along with the suppression of excess prenatal androgen production and reduction of prenatal masculinization of the genitalia in 46,XX fetuses with 21OHD, prenatal dexamethasone treatment may reduce the behavioral masculinization that is well documented in untreated 46, XX patients with 21OHD. Those fetuses who are partially treated until diagnosis of an unaffected status (heterozygous or homozygous-unaffected) will be studied as well. This latter group is of importance because these fetuses are being unnecessarily treated, but we have no way of diagnosing the unaffected status before the 8th week of gestation when treatment must begin for the female fetus who is affected. As treatment is necessary only until term in the female fetus affected with classical CAH, male fetuses and unaffected or heterozygous female fetuses do not require treatment. Thus, only one out of eight fetuses will require prenatal treatment until term. Findings of adverse effects of glucocorticoid treatment in non-human mammals [1, 2] have raised concerns among other clinicians and investigators about potential adverse side effects of such treatment on the developing human. Thus, this study will address this concern and investigate the potential adverse side effects of prenatal treatment. Detailed Description Females with classical CAH owing to 21-hydroxylase deficiency are born with ambiguous genitalia due to the production of excess androgens in utero. Prenatal treatment with dexamethasone was inaugurated in 1978 by Maguelone Forest and has been the standard of practice in the United States since 1986. Dexamethasone, which crosses the placental barrier, suppresses the fetal adrenal gland production of androgens, thus preventing ambiguous genitalia in the affected female. Children of both sexes are prenatally treated as soon as pregnancies at risk are confirmed. Treatment in females with 21OHD continues to term, but is discontinued in males and unaffected females. To date, 685 pregnancies have been diagnosed, of which 366 fetuses were treated. These investigators will study prenatally treated adolescents and adults 12 years and older with respect to medical and behavioral outcomes (see Table 5). In addition, mothers of children prenatally treated for varying periods of time for suspected 21OHD will be studied for long-term side effects of dexamethasone treatment administered during pregnancy. The long-term outcome in these children and their mothers has never before been studied.

  Study phs001317

• NHLBI TOPMed: My Life Our Future (MLOF) Research Repository of Patients with Hemophilia A (Factor VIII Deficiency) or Hemophilia B (Factor IX Deficiency)

  Hemophilia A and B are X-linked bleeding disorders resulting from a deficiency in coagulation factor VIII (FVIII) or factor IX (FIX), respectively. Hemophilia affects approximately 1/5000 male births worldwide, and results in premature death and disability due to bleeding if coagulation factor replacement therapy is not used effectively. Hemophilia is clinically categorized by coagulation factor activity levels and ranges in severity from mild (6% to 30%) to moderate (1-5%) to severe (<1%). Many female "carriers" of hemophilia also have decreased factor activity and morbidity from bleeding. Hemophilia A and B are almost always caused by identifiable mutations in the F8 and F9 genes, respectively, and these mutations are found throughout the structural genes. Although the hemophilias are monogenic disorders, there are wide variations in disease severity and therapeutic outcomes which are not readily explained by the disease causing mutations alone. The My Life Our Future (MLOF) project (www.mylifeourfuture.org) is a national resource developed by a partnership of BloodworksNW (BWNW, formerly the Puget Sound Blood Center), the American Thrombosis and Hemostasis Network (ATHN), the National Hemophilia Foundation (NHF) and Bioverativ, to provide free F8 and F9 gene variant analysis to patients with hemophilia A or B, and to establish a research repository of DNA sequence, DNA, RNA, buffy coat, serum and plasma. The sequence analysis and serum samples are linked to a phenotypic database hosted by ATHN, with samples submitted and clinical data entered at ~100 hemophilia treatment centers (HTCs) nationwide. (See ATHN Research Report Brief in the resource center at www.athn.org). MLOF has become the largest hemophilia genetic project worldwide. The roles of the MLOF partners are: BWNW, to serve as the central laboratory for the project and house the research repository; ATHN, to support and provide the administrative link with HTCs, to facilitate the collection of accurate phenotypic data, to conduct research review and approval for use of the repository and with BWNW to provide samples and data for research projects; NHF, to provide consumer education and facilitate consumer input into the project; and Bioverativ, to provide financial support and scientific input. The project is governed by a Steering Committee consisting of one representative from each organization. Subject samples chosen from the MLOF parent study for TOPMed and WGS were drawn from those who gave (or parents gave) informed consent for the Research Repository and included patients of all severities and type, but with an emphasis on those with severe hemophilia and others at increased risk of neutralizing antibody (inhibitor) formation and who had samples in the Research Repository (plasma, serum, RNA) for potential additional -omic studies. Also included were samples from subjects where a likely causative variant for hemophilia was not found in the F8 or F9 coding region, intron-exon boundaries or immediate upstream and downstream regions. Since hemophilia is an X-linked disorder, the majority of subjects are male. Racial distribution is similar to the overall population distribution.

  Study phs001515

• HeartShare - Extant Datasets - Harmonized Clinical Trials Collection

  Heart failure with preserved ejection fraction (HFpEF) prevalence is rising with an aging population and contributing comorbidities, such as obesity and diabetes. The Get With The Guidelines - Heart Failure (GWTG-HF) study showed that the proportion of hospitalized HFpEF patients rose from 2005 to 2010, and this trajectory continued to increase through 2020. HFpEF patients have a poor 5-year outcome with a 75% mortality rate. Taken together, these data suggest that HFpEF may be the dominant HF subtype in the future, affecting approximately 1 in 10 adults during their lifetime.In addition to its increasing prevalence, HFpEF is a heterogeneous syndrome with multiple pathophysiological processes and varied clinical presentations. There is an urgent need to improve understanding of different HFpEF phenotypes to match patients with interventions based on their unique subtype. Phenomapping studies have identified between two and six HFpEF clusters/phenogroups with shared features. Of these, three overlapping phenotypes repeatedly arise: an 'older, vascular aging' phenotype, 'metabolic, obese' phenotype, and 'relatively younger, natriuretic peptide (NP) deficiency' phenotype. Continued refinement of these HFpEF subtypes is needed to identify distinct characteristics and underlying biologic and molecular mechanisms towards therapeutic development and future precision trials with improved diagnostic criteria and treatment including prevention.The HeartShare extant datasets collection consists of selected completed trials on HFpEF which have been harmonized for the purpose identifying and defining subtypes. The goal is to identify HFpEF subtypes that have a common pathophysiology. Through the HeartShare extant datasets collection, users can request access to both the harmonized data and the individual trial datasets.To request access to this study collection, select phs003989 in the dbGaP when submitting a data access request. The following clinical trials and harmonized data is available through this collection:Study NameHandleAccessionConsent GroupsSurgical Treatment for Ischemic Heart FailureBioLINCC_STICHphs003493.v1.p1GRUHeart Failure Network Aldosterone Targeted Neurohormonal Combined with Natriuresis TherapyBioLINCC_HFN_ATHENAphs003506.v1.p1GRUHeart Failure Network - Effectiveness of Ultrafiltration in Treating People With Acute Decompensated Heart Failure and Cardiorenal SyndromeBioLINCC_HFN_CARRESSphs003510.v1.p1GRUHeart Failure Network: Diuretic Optimization Strategies Evaluation in Acute Heart FailureBioLINCC_HFN_DOSEphs003524.v1.p1GRUHeart Failure Network - Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure PatientsBioLINCC_EXACT_HFphs003533.v1.p1GRUHeart Failure Network: Functional Impact of GLP-1 for Heart Failure TreatmentBioLINCC_HFN_FIGHTphs003542.v1.p1GRUHeart Failure Network - Nitrate's Effect on Activity Tolerance in Heart Failure with Preserved Ejection FractionBioLINCC_HFN_NEATphs003548.v1.p1GRUHeart Failure Network - Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart FailureBioLINCC_HFN_RELAXphs003565.v1.p1GRUHeart Failure Network - Renal Optimization Strategies Evaluation in Acute Heart Failure and Reliable Evaluation of DyspneaBioLINCC_HFN_ROSEphs003589.v1.p1GRUHeart Failure: A Controlled Trial Investigating Outcomes of Exercise TrainingBioLINCC_HF_ACTIONphs003599.v1.p1HMBHeart Failure: A Controlled Trial Investigating Outcomes of Exercise TrainingBioLINCC_HF_ACTIONphs003599.v1.p1HMB-NPUGuiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart FailureBioLINCC_GUIDE_ITphs003621.v1.p1GRUSudden Cardiac Death in Heart Failure TrialBioLINCC_SCD_HeFTphs003654.v1.p1GRUTreatment of Preserved Cardiac Function Heart Failure With an Aldosterone AntagonistBioLINCC_TOPCATphs003665.v1.p1HMB-MDSHeart Failure Network - Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEFBioLINCC_HFN_INDIEphs003667.v1.p1GRUStudies of Left Ventricular DysfunctionBioLINCC_SOLVDphs003668.v1.p1GRUEvaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization EffectivenessBioLINCC_ESCAPEphs003782.v1.p1GRU

  Study phs003989

• Charles University - Hemminki Lab DAC

  Charles University DAC is described at: https://cuni.cz/UKEN-1958.html#:~:text=Data%20sharing,%2C%20as%20closed%20as%20necessary%E2%80%9D

  Dac EGAC50000000393

• USZ Dermatology and UZH DQBM DAC

  This DAC is responsible for datasets arising from the collaboration between USZ Department of Dermatology and UZH Department of Quantitative Biomedicine.

  Dac EGAC50000000853