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• Everything you need to know about Federated EGA Affiliates: Q&A

  Addressing common questions about Federated EGA (FEGA) Affiliates and providing answers. FEGA Affiliates have recently been defined as the third tier within the newly approved “Federated EGA Structure and Organisation” document, alongside Central EGA (CEGA) and the FEGA Nodes. In this blog post, we aim to answer the questions that may arise on this topic. For more general information about FEGA Affiliates, you can refer to this blog post. Let's now start with the questions and answers! What is the difference between a FEGA Affiliate and a FEGA Node? FEGA Nodes A FEGA Node is a national-level service that accepts submissions and provides archiving and access services within a single country's jurisdiction. Nodes provide end-to-end services for submitters in that jurisdiction, including submission support, processing, permissions management, and distribution. FEGA Affiliates A FEGA Affiliate is not a national submission service. Instead, it archives data from its own legal entity and/or selected partner institutions (for example, consortium partners). Affiliates are designed for organisations and consortia that need to keep data stewardship and access decisions within their own governance model, while still enabling discovery through the broader FEGA ecosystem. What do Affiliates commit to? Here is a practical checklist of the core expectations for a FEGA Affiliate. FEGA Affiliate checklist Discovery and metadata Submit non-personal metadata to CEGA to obtain EGA accessions and enable discovery (with metadata validation handled by the CEGA Helpdesk). Operations and resilience Maintain a data storage system and a defined backup/recovery approach. Ensure operational capacity (personnel and infrastructure) to deliver Affiliate services. Maintain systems and practices that support local data security and align with EGA best-practices. Access and user support Provide data distribution or access (e.g in a trusted research environment) to authorised users to datasets hosted at the Affiliate. Provide permissions management for datasets archived by the Affiliate (the CEGA DAC (Data Access Committee) Portal is always at your disposal to use). Provide a minimal helpdesk with sufficient capacity to support relevant DACs and approved users. Membership term Commit to a minimum membership term of four years. Governance and participation (lightweight by design) Affiliates integrate into the FEGA network operationally, but without the committee obligations associated with Nodes. When is becoming an Affiliate the right fit? Consider the Affiliate tier if: You host (or plan to host) controlled-access datasets that must be managed under your organisation’s or consortium’s governance, you want studies to be discoverable through EGA, but need access control and/or distribution to remain local, and you are not aiming to operate a national submission service tier.. What if a FEGA Node already exists in my jurisdiction? We encourage any potential Affiliate to reach out to their national FEGA Node to explore collaboration at the national level. Why? Federated models within a country already exist in FEGA, where a national Node operates like a Central EGA for their country. FEGA Nodes can also represent the interests of any Affiliates within their jurisdiction at the FEGA Committees. FEGA Nodes have experience and can support you on your FEGA journey. Ready to join as a FEGA Affiliate? We’re excited to open this formally defined pathway for organisations and consortia to participate in the federation. If you think the FEGA Affiliate tier fits your needs, start by assessing: Your scope (organisation/consortium-held data rather than public external submissions), Your ability to provide the core services (permissions, distribution/access, helpdesk, monitoring), and Your readiness to submit non-personal metadata to CEGA for accessioning and discovery. To express interest, please contact us here, and we'll help you understand the onboarding steps and how Affiliates integrate into the FEGA network.

  Blog fega-affiliates-q&a

• Rare Cancer Tumors Project

  A large proportion of common cancers affecting patients around the world have been selected for comprehensive cancer genome studies. Further efforts will be needed to tackle the remaining tumor types, including the rare forms of cancers. Although rare, these cancers tend to be more aggressive and fast growing with an early recurrence following initial chemotherapy and poor prognosis. Besides, patients diagnosed with rare cancers may have difficulty finding a physician knowledgeable in treating their type of cancer. While sample collection is a major challenge, the integrated genomic analyses would identify novel causative genes in these rare cancers, shed new light on the biology of the rare cancers, as well as guide novel targeted cancer therapies. Through efficient collaboration, the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine (BCM) has collected/is expected to collect 20 different types of rare cancers, 15-30 cases each. Whole-exome sequencing and high-resolution SNP array analysis were/will be performed for all cases and whole-genome sequencing was designed for a selected subset of the cases. The Rare Cancer Tumors Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in this sub-study, please click on the following sub-study below or in the "Sub-studies" section of this top-level study page phs000725 Rare Cancer Tumors Cohort. phs000754 Intracranial Germ Cell Tumors phs000861 Craniopharyngioma Tumors phs000859 Sezary Syndrome Genomic Analysis

  Study phs000725

• Cell-free DNA Methylome Analysis Enables Early Preeclampsia Prediction

  This dataset contains in solution target-enrichment bisulfite sequencing of placental tissue, buffy coat and plasma DNA from pregnant women. Blood samples were taken for cell-free DNA (cfDNA) DNA extraction from 64 women at the time of early-onset preeclampsia (PE) diagnosis, or from 38 controls (uncomplicated pregnancies) at a similar gestational age that did not develop preeclampsia subsequently. Among these subjects, plasma samples from 7 PE patients and 6 controls were also subjected to oxidative bisulfite sequencing. Placental tissues from 11 PE and 26 control subjects after delivery, and buffy coat from 16 PE and 16 control subjects at the same time of cfDNA sampling were profiled. A discovery cohort for early PE assessment in the first trimester was collected. In this cohort, cfDNA from 75 pregnancies that went on to develop early-onset PE and from 124 matched controls were collected and methylome sequencing were carried out. An independent validation cohort to validate early PE assessment with methylome profiling was collected as well. This validation cohort includes cfDNA samples from 61 PE and 136 control pregnancies.

  Dataset EGAD00001010159

• Versatile workflow for cell-type resolved transcriptional and epigenetic profiles from cryopreserved human lung

  The complexity of the lung microenvironment and changes in cellular composition during disease progression make it exceptionally hard to understand molecular mechanisms leading to the development of chronic lung diseases. Although recent advances in cell-type resolved and single-cell sequencing approaches hold great promise for studying complex diseases, their implementation relies on local access to fresh tissue, as traditional tissue storage methods do not allow viable cell isolation. To overcome these hurdles, we developed a novel, versatile workflow that allows long-term storage of human lung tissue with high cell viability, permits thorough sample quality check before cell isolation, and is compatible with sequencing-based profiling, including single-cell approaches. We demonstrate that cryopreservation is suitable for the isolation of multiple cell types from human lung and is applicable to both healthy and diseased tissue, including COPD and tumour samples. Basal cells isolated from cryopreserved airways retain the ability to differentiate, indicating that cellular identity is not altered by cryopreservation. Importantly, using RNA sequencing and EPIC Array, we show that genome-wide gene expression and DNA methylation signatures are preserved upon cryopreservation, emphasizing the suitability of our workflow for -omics profiling of human lung cells. In addition, we obtained high-quality single-cell RNA sequencing data of cells isolated from the cryopreserved human lung, demonstrating that cryopreservation empowers single-cell approaches. Overall, thanks to its simplicity, our cryopreservation workflow is well-suited for prospective tissue collection by academic collaborators and biobanks, opening worldwide access to human tissue.

  Study EGAS00001004477

• Neuroblastoma Smart-Seq2 Single Nuclei Sequencing Data

  Heterogeneity of tumors, including the presence of resistant clones, represents a great challenge for high-risk neuroblastoma (NB). Currently, there are no treatments that address cancer heterogeneity. Classification of bulk tumors and corresponding predictions are poor and too general. Understanding heterogeneity will provide critical insight for the development of targeted therapeutic strategies. In this study, we collected 10 human neuroblastoma tumor samples and performed whole-transcriptome profiling at single-nucleus resolution using SMART-Seq2 technology. This approach enables comprehensive characterization of transcriptional diversity within individual tumors, allowing us to identify distinct cellular subpopulations.

  Study EGAS50000001103

• The epigenomic response of skeletal muscle in life-long high-level trained and untrained men and women after acute exercise

  To investigate the influence of lifelong exercise training on the response of skeletal muscle to a bout of acute exercise we generated targeted epigenomic data from long-term endurance (8 men) and strength (8 men) trained individuals and healthy age-matched untrained controls (8 men). Skeletal muscle biopsies were taken from M. vastus lateralis before, directly after, and 3hrs following acute exercise. Control subjects completed one bout of acute endurance exercise and one bout of acute resistance exercise, separated by 4-8 weeks, athletes completed one bout in their respective form of sports. All 96 samples were used for DNA extraction and targeted library construction using a custom Twist Biosciences panel and following EM-methylation tranformation were sequenced (2x150bp paired end) on the Illumina NovaSeq 6000.

  Dataset EGAD50000000512

• Intraductal transplantation models of human pancreatic ductal adenocarcinoma reveal progressive transition of molecular subtypes

  Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past few decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated. However, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present an orthotopic xenotransplantation model of human patient-derived PDAC organoids in which organoids are grafted via direct injection into the pancreatic duct of immunocompromised (NSG) mice. Tumors that arise from these intraductally grafted organoids (IGOs) enable the distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively, depending on which organoid they originate from. RNA-sequencing was used to characterize the tumors that resulted from IGO xenografts, and to compare the fast- and slow-progressing IGO tumors. Tumors generated using a traditional orthotopic xenograft model, in which organoids are injected into the parenchyma of the pancreas (i.e. orthotopically grafted organoids, or OGOs), were also sequenced for comparison with the IGO tumors. To further characterize the model, laser-capture microdissection followed by RNA-sequencing was used to compare intraductal to invasive lesions resulting from IGOs. To better understand the connection between KRAS signaling and the fast-progressing phenotype, RNA-sequencing was used to compare cultured organoids in which oncogenic KRAS (GeneID: 3845) was hyperactivated to control organoids, and to compare laser-capture microdissected lesions derived from IGOs of KRAS-hyperactivated organoids to lesions derived from control organoids. To ascertain copy number, low-coverage, whole genome DNA-sequencing was performed on organoids cultured in vitro, and on laser-capture microdissected lesions derived from IGO tumors.

  Study phs002045

• Genetic analysis of HLA and immune escape genes in Diffuse Large B-cell Lymphoma

  Fifty percent of diffuse large B-cell lymphoma (DLBCL) cases lack cell-surface expression of the class-I major histocompatibility complex (MHC-I), thereby escaping immune recognition by cytotoxic T cells. In order to comprehensively identify the mechanisms involved in MHC-I loss, we first performed immunophenotypic analysis of both MHC class-I and -II in 657 cases across the spectrum of B-NHL, revealing that loss of MHC-I, but not MHC-II, is preferentially restricted to DLBCL. We then used whole exome and targeted deep-sequencing to examine genes involved in MHC-I expression in 74 DLBCL samples representative of MHC-I positive and negative cases. We show here that somatic biallelic or monoallelic inactivation of B2M and/or HLA-I is present in 80.9% (34/42) of MHC-I negative tumors. Furthermore, 68.8% (22/32) of MHC-I positive DLBCLs also harbored monoallelic HLA-I genetic alterations (MHC-I positivemono) that lead to allelic imbalance, suggesting allele-specific inactivation. Both MHC-I negative and MHC-I positivemono cases showed a significantly higher mutational burden as well as a higher number of inferred neo-antigens, suggesting co-selection of HLA-I loss and sustained neo-antigen production. Interestingly, the analysis of > 500.000 individuals in two databases revealed homozygosity of germline HLA-I genes in 26-38% of DLBCL patients, a frequency significantly higher than that observed in any other cancer type. In mice, germinal-center B cells lacking HLA-I expression did not progress to lymphoma and were counterselected in the context of oncogene-driven lymphomagenesis, suggesting that additional events are needed to license immune evasion. These results suggest a multi-step process of HLA-I loss including both germ-line and somatic events in DLBCL development, and have direct implications for the pathogenesis and immunotherapeutic targeting of this disease.

  Study EGAS00001005054

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

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

  Study EGAS00001007027

• Single Cell Analysis of Sporadic Human Basal Cell Carcinomas

  To explore tumor heterogeneity in sporadic human basal cell carcinoma tumors, we profiled three individual patient tumors by scRNA-Seq and scATAC-Seq. Basal cell carcinomas (BCCs) are driven by hedgehog signaling with GLI1 representing the key downstream transcription factor that drives tumor growth. GLI1 as such is a readout of active hedgehog signaling. We identified that LY6D can mark squamous populations such as in squamous cell carcinomas (SCCs) that are negative for GIL1 and hedgehog signaling. As such, both GLI1 and LY6D can be used as biomarkers of BCCs and SCCs and their related states.

  Study phs003103

• The tissue origin of highly elevated cell-free DNA in patients with and without cancer

  Forty years ago, the first measurements of cell free DNA (cfDNA) from cancer patients revealed that its total concentration was often elevated compared to healthy controls. The basis for this increase, and in particular the source of the extra cfDNA in such patients, has never been determined. To address this issue, we assessed methylation patterns of cfDNA from 57 individuals, 34 of whom had unequivocally elevated cfDNA concentrations (i.e., >15 ng/mL of plasma). We found that the excess cfDNA in cancer patients did not come from either neoplastic cells or surrounding cells from the tumor's tissue of origin. Instead, 80% of the cfDNA was derived from neutrophils, B cells or T cells, with neutrophils accounting for ~2/3. B cells contributed more than T cells despite the great excess of T cells over B cells in the blood. To see if this result was generalizable to other clinical situations in which elevated cfDNA concentrations have been described, we evaluated nine patients before and one day following surgery. After surgical resection, cfDNA concentration increased by an average of 16.1-fold, as expected. The majority of this increase (55%) was contributed by leukocytes, though damaged hepatocytes contributed a substantial minority (31% of increase). These data suggest that the elevated concentrations of cfDNA in cancer patients, as with patients after surgery, arises largely from dying leukocytes—not from the neoplastic cells or the tissue of origin of the cancer.

  Study EGAS00001005400

• Variability in immune response genes and prediction of severe SARS-CoV-2 infection (INMUNGEN-Cov2 project)

  Genetic factors may contribute to explain the variable clinical response to SARS-CoV-2 infection. To this end we sequenced the DNA of 392 COVID-19 patients from Spain. Whole Exome Sequencing (WES) was performed at two different sequencing centers. Half of the samples were sequenced at a commercial service, NIMGenetics, whereas the other half were sequenced by the EASI-Genomics consortium. Finally, Variant Call Format (VCF) files for each sample was also obtained.

  Study EGAS50000000066

• Single-nucleus RNA-sequencing data of kidney biopsies from patients with primary FSGS, maladaptive FSGS, proteinuric controls and healthy controls

  This dataset includes FASTQ files of single-nucleus RNA sequencing of cryopreserved kidney biopsy cores from adult patients with diagnosed primary FSGS (n = 9, all nephrotic), maladaptive FSGS (n = 9, not nephrotic), proteinuric controls (PLA2R-positive membranous nephropathy, n = 3), and healthy controls (n = 4). A total of 120,751 high-quality nuclei were identified, including 2,471 podocytes and 1,574 parietal epithelial cells (PECs). In addition to the raw FASTQ files, the dataset includes processed data files from all 25 samples, generated using Seurat in R: barcode files, features, count matrices, and associated metadata. Details regarding the bioinformatics pipeline can be found at https://github.com/lambrechtslab/FSGS_Deleersnijder_et_al

  Dataset EGAD50000001557

• Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) - germline whole genome sequencing

  This study consists of whole genome sequencing (target: average 30x coverage) of 110 European-ancestry (EA), early-onset, family-history-positive breast cancer cases, 21 Asian cases, 25 African-American cases, and 24 controls from six studies participating in the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) consortium, part of the NCI's Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative ( http://epi.grants.cancer.gov/gameon/ )

  Study phs001483

• Spatiotemporal Charting of Human Esophageal Development for Epidermolysis Bullosa Cell Therapy

  Human fetal esophageal development is not well understood. We present a spatio-temporal single-cell multi-omics atlas to close such a long-standing knowledge gap. With such an atlas, we describe the cellular heterogeneity and lineage transitions of esophageal epithelium and stroma. We delineate the cellular dynamics of both epithelial and stromal populations during the establishment of esophageal tissue architecture. We identify niche paracrine signals that drive the development of the epithelium. We develop an in silico perturbation deep learning algorithm to further enlighten the in vitro derivation of esophageal basal cells (eBCs) and we use the algorithm to screen for effective and efficient signaling pathway perturbations that could guide in vitro eBC differentiation. We observe that chemically perturbing prioritized pathways yields functional eBCs. Such success sheds light on cell replacement therapy of eBC dysfunction, such as Epidermolysis Bullosa.

  Study phs003281

• Exome sequencing of uterine leiomyosarcomas

  Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%), alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%), and mediator complex subunit 12 (MED12; 4/19; 21%). Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52%) showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT), and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX), another gene previously associated with ALT, and the tumor showed ALT positivity. Aberrant expression of both TP53 and ATRX were associated with poor overall survival. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.

  Study EGAS00001001612

• SINGLE_CELL_ANALYSIS_OF_IN_VITRO_ERYTHROPOIESIS

  We are developing a protocol to differentiate mouse and human induced pluripotent stem (IPS) and embryonic stem (ES) cells towards the haematopoietic pathway to generate erythrocytes in vitro. This system has many applications such as the study of the role of specific genes and human polymorphisms in infectious diseases such as malaria, as well as haematological diseases such as myelodysplastic syndrome. The nature of the in vitro differentiation process means that a heterogeneous population of cells is generated. In order to understand the types of cells produced with our protocol, we have performed a single cell analysis, which has the power to reveal the different populations of cells and their characteristics. For this, a cDNA library has been made that needs to be sequenced to obtain the gene expression profiles of the different cells. With this information we will be able to assess the quality of the differentiation protocol and improve it in order to produce better cells for the downstream applications.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001000764

• Resuscitation Outcomes Consortium (ROC) Trauma Epidemiologic Registry (Trauma Epistry) (ROC-Trauma Epistry-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions.Available Data: This dataset only includes traumatic injury participants. For ROC cardiac arrest Epistry data please see: ROC-Cardiac Epistry 1 and 2 and ROC-Cardiac Epistry 3.Objectives: To build a prospective population-based registry of participants with out-of-hospital traumatic injury responded to by Emergency Medical Services (EMS). Specific aims included: to establish whether the results of Resuscitation Outcomes Consortium (ROC) trials can be generalized to the larger population of people that experience traumatic injury; to more fully establish the burden of traumatic injury; and to examine the relationships between variation in EMS structure and process, regional and periodic factors, and participant outcomes.Background: Traumatic injury is a major public health problem generating substantial morbidity, mortality, and economic burden on society. The majority of seriously injured persons are initially evaluated and cared for by prehospital providers, however the effect of EMS systems, EMS clinical care, and EMS interventions on trauma patient outcomes is largely unknown. EMS factors such as service level, number of responding providers, use of procedures or drugs in the field, training, quality assurance/feedback, and response time intervals also vary significantly by region.The Resuscitation Outcomes Consortium (ROC) was established in 2004 to conduct clinical research in the areas of cardiopulmonary arrest and life-threatening traumatic injury with the overall goal of improving resuscitation outcomes. Previous trauma registries have generally focused primarily on hospitalized patients with limited prehospital information. Registries may also exclude trauma cases at far ends of the spectrum, such as those who die in the field or in a non-trauma center and/or patients that are treated and released. These limitations do not allow for detailed, outcome-based assessments of EMS system factors necessary to define prehospital resuscitation best practices. Therefore there was a need for standardized data collection of out-of-hospital traumatic injuries matched to hospital-based outcomes in diverse geographic locations in order to identify the independent effects of prognostic or treatment factors accounting for variations in survival. Participants: The registry included 13,830 traumatic events from 264 EMS agencies transporting to 287 acute care hospitals from the following regional centers: Birmingham, Alabama; Dallas, Texas; Iowa City, Iowa; Milwaukee, Wisconsin; Pittsburgh, Pennsylvania; Portland, Oregon; San Diego, California; Seattle/King County, Washington; Ottawa, Ontario; Toronto, Ontario; and Vancouver, British Columbia.Design: ROC Epistry collected standardized data regarding episode-specific factors, participant demographics, clinical information, pre-hospital interventions and disposition, hospital information, and participant outcome for all out-of-hospital traumatic injuries in the ROC regions. Cases were identified through review of emergency response system records including dispatch centers, EMS ground agencies, and air medical services. Out-of-hospital data were extracted from existing databases whenever possible and augmented with targeted review of EMS reports. Hospital data were abstracted directly from the hospital file in most cases. Sites submitted data using a web-based interface or batch uploads (Newgard, et al., 2008, PMID: 18482792).

  Study phs003809

• Kids First: Genetic Basis of Fetal Alcohol Spectrum Disorders

  Fetal Alcohol Spectrum Disorder (FASD) is estimated to occur in at least 1-5% of all children in the USA and is a major public health issue. However, in addition to alcohol, other susceptibility factors, such as maternal or fetal genetic variation, must play a role as not all children prenatally exposed to alcohol are similarly affected. The proposed study will examine the role of genetic susceptibility for FASD. This work will help to inform more effective intervention efforts for this common congenital disorder.

  Study phs002594

• Real-time analysis of the cancer genome and fragmentome from plasma and urine short and long cell-free DNA using Nanopore sequencing

  Cell-free DNA (cfDNA) can be isolated from blood and/or urine of cancer patients and analyzed with sequencing. Unfortunately, most conventional short-read sequencing methods are technically challenging, labor intensive and time consuming, requiring several days but more typically weeks to obtain interpretable data which are limited by a bias for short cfDNA fragments. Here, we demonstrate that with Oxford Nanopore Technologies sequencing  we can achieve economical and ultra-fast delivery of clinical data from liquid biopsies.   Our ‘ITSFASTR’ approach is able to deliver copy number aberrations, and cfDNA fragmentation profiles in less than 24 hours from sample collection. The tumor-derived cfDNA fraction calculated from lung cancer patient plasma and urine from bladder cancer patients was highly correlated (R=0.98) to the tumor fraction calculated from conventional short-read sequencing of the same samples. cfDNA size profile and fragmentation patterns in plasma and urine exhibited the typical cfDNA features yet with a significantly higher proportion of informative fragments that exceed 300bp, exhibiting similar tumor fraction than shorter size fragments. Notably, comprehensive fragment-end composition and nucleosome profiling near transcription start sites can be determined from the same data.  We propose that ITSFASTR is the first point-of-care solution for obtaining genomic and fragmentomic results from liquid biopsies.

  Study EGAS00001006591

• Clonal selection after gene therapy in sickle cell disease

  While gene therapy (GT) provides a potentially curative treatment option for patients with sickle cell disease (SCD), the occurrence of myeloid malignancies in clinical trials has prompted concern. To interrogate potential mechanisms underlying increased cancer risk, we used hematopoietic stem cell (HSC) clonal tracking by whole genome sequencing (WGS) to map the somatic mutation and clonal landscape of 2,592 gene modified as well as unmodified single stem and progenitor cells from six SCD patients undergoing gene therapy (7-26 years old, average 12.7× depth). Pre-GT phylogenetic trees in SCD were highly polyclonal and mutation burdens per cell were elevated in some, but not all, patients. Post-GT, no clonal expansions were identified. However, an increased frequency of driver mutations associated with myeloid neoplasms or clonal hematopoiesis (DNMT3A- and EZH2-mutated clones in particular) were seen in both genetically modified and unmodified cells suggested positive selection of mutant clones during gene therapy. This work sheds light on the mutation landscape and HSC clonal dynamics in gene therapy for SCD and highlights enhanced fitness of some HSCs harboring pre-existing driver mutations following gene therapy. Future studies should define the long-term fate of mutant clones including any contribution to expansions associated with myeloid neoplasms.

  Dataset EGAD00001010914

• Transcriptome analysis of Williams syndrome

  Williams syndrome (WS) is a neurodevelopmental disorder caused by microdeletion on chromosome 7q11.23, and has attracted much attention for its distinctive features, such as hypersociability. However, it remains unclear which genes are involved in the complex phenotypes of their condition. Here, we performed transcriptome analysis of peripheral blood to identify genes associated with WS.

  Study JGAS000132

• scRNA-seq of total bone marrow and T cells from multiple myeloma long-term survivors

  scRNA This dataset contains 50 scRNA-seq samples from bone marrow aspirates of 11 multiple myeloma patients experiencing long-term survival and 3 healthy donors. For each donor, total bone marrow and CD3+ T cells were sequenced. For multiple myeloma patients, paired samples were collected at initial diagnosis and between 7-17 years after first-line therapy. Bone marrow mononuclear cells were isolated by Ficoll density gradient centrifugation. For sorting of total bone marrow cells singlet, live cells were gated and sorted, for sorting of T cells CD45+, CD3+ cells were gated and sorted on either FACSAria Fusion or FACSAria II. Single-cell RNA sequencing were generated using 10x Genomics single-cell RNAseq technology (Chromium Single Cell 3’ Solution v2) according to the manufacturer’s protocol and sequenced on an Illumina HiSeq4000 (paired end, 26 and 74 bp). Bulk RNA Singlet, live CD3+CD4- CXCR3+CD8+ and CD3+CD4- CXCR3-CD8+ cells were sorted from 7 bone marrow and 3 peripheral blood samples of 7 multiple myeloma patients using a FACSAria Fusion machine. Bulk-RNA sequencing libraries were generated using the SMART Seq Stranded Total RNA-Seq kit (Takara) and sequenced using the Illumina NovaSeq 6000 platform (2 x 100 bp).

  Dataset EGAD00001010025

• Genetic characterization of B-cell prolymphocytic leukemia: a hierarchical prognostic model involving MYC and TP53 abnormalities - WXS

  B-PLL is a rare disease, whose molecular pathology is largely unknown. We report here the cytogenetic and molecular findings in a large series of 34 B-PLL. Karyotype (K) was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. The most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (62%), 17p deletion including TP53 gene (38%), trisomy 18/18q (30%), 13q14 deletion (29%), trisomy 3 (24%), trisomy 12 (24%) and 8p deletion (23%). Whole-Exome Sequencing performed in 16 patients revealed recurrent mutations in TP53 (6/16, 38%), MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2) and BCLAF1 (n=2). The main group of patients (21/34, 62%) had a t(MYC) associated with a higher percentage of prolymphocytes (p=0.03), CD38 expression (p<0.001), lower K complexity (p=0.0004), mutations in MYC and in genes involved in RNA metabolism and chromatin remodeling. Principal component analysis of gene expression data showed that patients with t(MYC) clustered together. A second group with MYC gain (5/34, 15%), was associated with HCK≥5 (p=0,01) and trisomy 3 (p=0,008). Altogether, 26/34 patients (76%) had a MYC activation, translocation or gain, that were mutually exclusive. We identified 3 distinct cytogenetic prognostic groups (p=0.0006): lower risk: absence of MYC activation (median not reached); intermediate risk: MYC activation without del17p (125 months); high risk: MYC activation + del17p (11 months). Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification.

  Study EGAS00001003275

• Genetic characterization of B-cell prolymphocytic leukemia: a hierarchical prognostic model involving MYC and TP53 abnormalities - RNA-seq

  B-cell prolymphocytic leukemia (B-PLL) is a rare disease, whose molecular pathology is largely unknown. We report here the cytogenetic and molecular findings in a large series of 34 B-PLL. Karyotype (K) was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. The most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (62%), 17p deletion including TP53 gene (38%), trisomy 18/18q (30%), 13q14 deletion (29%), trisomy 3 (24%), trisomy 12 (24%) and 8p deletion (23%). Whole-Exome Sequencing performed in 16 patients revealed recurrent mutations in TP53 (6/16, 38%), MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2) and BCLAF1 (n=2). The main group of patients (21/34, 62%) had a t(MYC) associated with a higher percentage of prolymphocytes (p=0.03), CD38 expression (p<0.001), lower K complexity (p=0.0004), mutations in MYC and in genes involved in RNA metabolism and chromatin remodeling. Principal component analysis of gene expression data showed that patients with t(MYC) clustered together. A second group with MYC gain (5/34, 15%), was associated with HCK≥5 (p=0,01) and trisomy 3 (p=0,008). Altogether, 26/34 patients (76%) had a MYC activation, translocation or gain, that were mutually exclusive. We identified 3 distinct cytogenetic prognostic groups (p=0.0006): lower risk: absence of MYC activation (median not reached); intermediate risk: MYC activation without del17p (125 months); high risk: MYC activation + del17p (11 months). Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification.

  Study EGAS00001003274