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• Single-cell analysis reveals transcriptomic and epigenomic impacts on the maternal-fetal interface upon SARS-CoV-2 infection

  During pregnancy, the maternal-fetal interface plays vital roles in fetal development. Its disruption is frequently found in pregnancy complications. Recent works show increased incidences of adverse pregnancy outcomes in COVID-19 patients; however, the mechanism remains unclear. Here, we analyzed the molecular impacts of SARS-CoV-2 infection on the maternal-fetal interface. Generating bulk and single-nucleus transcriptomic and epigenomic profiles from COVID-19 patients and control samples, we discovered aberrant immune activation and angiogenesis patterns in distinct cells from patients. Surprisingly, retrotransposons were also dysregulated in specific cell types. Notably, reduced enhancer activities of LTR8B elements were functionally linked to the downregulation of Pregnancy-Specific Glycoprotein genes in syncytiotrophoblasts. Our findings revealed that SARS-CoV-2 infection induced significant changes to the epigenome and transcriptome at the maternal-fetal interface, which may be associated with pregnancy complications.

  Study EGAS00001006263

• Single-cell Transcriptome Profiling of Treatment-naïve and Post-treatment Colorectal Cancer: Insights into Putative Mechanisms of Chemoresistance

  Drug resistance remains a major clinical challenge in the treatment of colorectal cancer (CRC) with conventional chemotherapy. Investigation of cancer cells and tumor microenvironment (TME) following chemotherapy is critical for unraveling the mechanisms of resistance. In this study, we analyzed scRNA-Seq data from 56 CRCs including treatment-naïve tumors (25 microsatellite stable (MSS) tumors and 7 tumors with microsatellite instability (MSI)); and tumors treated with standard chemotherapy with the known response status (18 responders and 6 progressors). We observed in treatment-naïve MSS CRC that right-sided tumors are more immunogenic with higher numbers of B cells and CD8+ T memory effector cells than left-sided tumors. MSI CRC were even more immunogenic then MSS CRC and were characterized by elevated Tregs in their TME. In the post-treatment CRC there was a high prevalence of dendritic cells (DC) in the TME in the response group. The DC-derived signature was associated with better survival in a large CRC cohort from the TCGA. We also observed two fibroblast subtypes in CRC, one of which was enriched in progressors and was associated with poor survival in a CRC-TCGA cohort. Progressors also showed elevated exhausted CD8+ T memory cells and monocytes suggesting a pro-inflammatory TME. In tumor cells in progressor group we identified specific expression of chemo-protective markers MTRNR2L1 and CDX1; and their co-expression with stemness-related marker CD24. In summary, scRNA-Seq provides a valuable information for the discovery of prognostic markers, and reveals distinct features of CRC based on location, metastasis status, MSI status and treatment response status.

  Study EGAS50000000830

• Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids

  Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n¼54), genome/exome (n¼44) and transcriptome (n¼69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40 and 22.2% of the cases, respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumors but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatinremodelling genes is sufficient to drive transformation in pulmonary carcinoids.

  Study EGAS00001000650

• RNA-seq of M-CSF differentiated human peripheral monocyte-derived macrophages (MDMs) - Validation macIDR

  Macrophages represent multifunctional leukocytes defined by their stimulus-specific transcriptional reprogramming. As in vivo macrophages are often difficult to obtain, in vitro macrophage models are often used. We aggregated public expression data to define consensus expression profiles for eight commonly-used in vitro macrophage models and built the classifier macIDR, capable of distinguishing macrophage subsets with high accuracy (>0.95). Classification of in vivo macrophages suggested that alveolar macrophages resembled interleukin-10 activated macrophages in general whereas chronic obstructive pulmonary disease patients displayed decreased similarity to interferon-γ stimulated macrophages. Adipose tissue-derived macrophages were classified as unstimulated macrophages, but would resemble LPS-stimulated macrophages more in diabetic-obese patients. Rheumatoid arthritic synovial macrophages were similar to macrophages stimulated with interleukin-10 or interferon-γ. Altogether, our results suggest that macIDR is capable of identifying in vitro macrophages. By projecting in vivo macrophages onto the in vitro macrophages, we were capable of elucidating macrophage-specific changes as a result of tissue and disease.

  Study EGAS00001003451

• Phase II trial of targeted immune-depleting chemotherapy and reduced-intensity allogeneic hematopoietic stem cell transplantation using 8/8 and 7/8 HLA-matched unrelated donors and utilizing two graft-versus-host disease prophylaxis regimens for the treatment of leukemias, lymphomas, and pre-malignant blood disorders

  Background: Major problems with stem cell transplantation (SCT) for cancer treatment are a lack of suitable donors for patients without an HLA tissue-matched sibling and graft-versus-host disease (GVHD), a serious side effects of immune-suppressing chemotherapy that is given to bring the cancer under control before SCT. In GVHD, the patient's immune system attacks the transplanted donor cells. This study will try to improve the results of SCT from unrelated HLA-matched donors using targeted immune-depleting chemotherapy to bring the cancer under control before transplantation and to lower the chance of graft rejection, followed by reduced-intensity transplant chemotherapy to make the procedure less toxic. Objectives: To evaluate the safety and effectiveness of targeted immune-depleting chemotherapy followed by reduced-intensity transplant chemotherapy in patients with advanced cancers of the blood and immune system. To evaluate the safety and effectiveness of two different drug combinations to prevent GVHD. Both regimens have been successful in preventing GVHD, but they work by different mechanisms and affect the rebuilding of the immune system after the transplant. Eligibility: People 18 to 74 years of age with advanced or high-risk cancers of the blood and immune system who do not have a suitable HLA-matched sibling. Design: All patients receive chemotherapy before transplant to treat the cancer and suppress immune function. All patients receive a conditioning regimen of cyclophosphamide for 4 days and fludarabine for 4 days before SCT to prepare for the transplant. Patients are randomly assigned to one of two combination drug treatments to prevent GHVD as follows: Group 1: Tacrolimus starting 3 days before SCT and continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the SCT and continuing through day 14 following SCT. Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1 day before SCT and continuing for 6 months. Patients receive the donor's stem cells and immune cells 2 days after the conditioning regimen. Patients are followed at the clinic regularly for the first 6 months after SCT, and then less often for at least 5 years. Some visits may include bone marrow aspirates and biopsies, blood draws, and other tests to monitor disease status. A skin biopsy, oral mucosa biopsy, and saliva collection are done to study chronic GVHD.

  Study phs002021

• Whole exome profiling of spatial biopsies of high grade serous epithelial ovarian cancer patients

  This data set is comprised of data from seven distinct high grade serous epithelial ovarian cancer (HGS-EOC) partients, from whom multiple biopsies were taken at the time of surgery, from the ovary and from different locations in the peritoneal cavity. This data set contains 28 samples, sequenced with a whole exome sequencing approach.

  Dataset EGAD00001004154

• mFAST-SeqS

  mFAST‑SeqS, or modified Fast Aneuploidy Screening Test‑Sequencing System, is a streamlined and cost-effective approach to estimate the fraction of ctDNA in blood samples by detecting genome-wide aneuploidy in cfDNA

  Dataset EGAD50000001670

• Genetic factors underlying premature MI in Greek families without vessel disease

  The study will analyse by exome sequencing 8 Greek family members with an excess of potentially damaging mutations relating to premature MI and no vessel disease, to identify genetic factors underlying this condition. This is a follow on from project GPMI-NVD

  Dataset EGAD00001002178

• TCRab sequencing of T-LGLL patients

  TCRab sequencing was performed on viably frozen cells from 11 T-LGLL samples from 9 T-LGLL patients and 6 age-matched healthy samples. The raw data is available as fastq files.

  Dataset EGAD00001008691

• Whole Exome Sequencing of Congenital Diaphragmatic Hernia Patients and Trios

  Congenital diaphragmatic hernia (CDH) is a common and severe birth defect characterized by structural defects of the diaphragm and by pulmonary hypoplasia. Congenital diaphragmatic hernia patient may present either as an isolated phenotype or together with other congenital anomalies in a complex phenotype. Despite the clinical significance of CDH, the underlying genetic and developmental pathways are incompletely understood. In order to establish a catalog of human genetic variation for this condition, we performed whole exome sequencing (WES) on 275 carefully phenotyped individuals with CDH in the Pediatric Surgical Research Laboratories at the Massachusetts General Hospital (Boston, MA, USA) and Boston Children's Hospital (Boston, MA, USA). The exome data generated are valuable for comparison of candidate genes derived from WES of other CDH cohorts or affected kindreds, and to provide ideal candidates for further functional studies with the ultimate goal of enhancing our understanding of the heterogeneous and, possibly, oligogenic molecular etiology of CDH. While familial clustering has been reported in rare kindreds, the majority of probands with CDH have no family history of CDH leading to the hypothesis that de novo variants are an important and relatively frequent etiological mechanism. In the second version of the study, we performed WES analysis on 87 trios, to assess the contribution of de novo mutations in the etiology of diaphragmatic and pulmonary defects and to identify previously unknown candidate genes. This dbGaP submission includes WES data on: (a) 20 new probands, (b) 9 probands also reported in the previous version (dbGaP accession no. phs000783.v1.p1), (c) 174 unaffected parents, including the parents of 67 previously reported probands. Combined analysis with other available cohorts of congenital diaphragmatic hernia revealed a genome-wide enrichment of likely gene-disrupting de novo variants (i.e., nonsense, frameshift or splice site), and missense de novo variants predicted in silico to be damaging.

  Study phs000783

• Full blood mRNA sequencing of myotonic dystrophy type 1 patients after cognitive behavioural therapy

  This dataset consists of 60 mRNA sequencing runs from full blood of 31 myotonic dystrophy type 1 patients, of which for 27 patients reliable data is available before and after 10 months of cognitive behavioural therapy. >30 million 150 bp paired end reads were obtained with UMI-labeled adapters to facilitate filtering of PCR duplicates. Via UMI-analysis we found samples with the aliases sample_01 and sample_02 to contain a very high number of PCR duplicates and recommend the use of these samples only with highest caution or not at all.

  Dataset EGAD00001008383

• Enrichment of oral-derived bacteria in inflamed colorectal tumors and distinct associations of Fusobacterium in the mesenchymal subtype

  The association between colorectal cancer (CRC) clinical variables and Fusobacterium, but not other intra-tumoral bacteria, has been extensively studied. Here we leveraged whole-transcriptome sequencing from 807 CRC tumor samples from the AVANT phase III trial to dually characterize tumor gene expression and intra-tumoral bacteria. After stringent filtering, 74 high-confidence taxa were identified. 17 of these species, including 4 Fusobacterium spp., were classified as orally-derived and had a robust signal within right-sided, MSI-H, and BRAF mutant tumors. Across consensus molecular subtypes (CMS), integration of Fusobacterium animalis presence and tumor gene expression revealed that F. animalis had the greatest number of associations in mesenchymal CMS4 tumors, despite an overall lower prevalence than in immune CMS1 tumors. Pathway analysis within CMS4 revealed that F. animalis, but not other highly prevalent species, was uniquely associated with pathways for collagen degradation and formation as well as IL-6 and IL-1 cytokine signaling. These associations could explain in part why Fusobacterium has been previously associated with reduced survival in mesenchymal populations. Overall, this study identified oral-derived bacteria, including Fusobacterium, as broadly more prevalent in inflamed CRC tumors compared to the other subtypes, and the association of intra-tumoral bacteria on tumor gene expression is context- and species-specific.

  Study EGAS00001006757

• NHLBI TOPMed: Coronary Artery Risk Development in Young Adults (CARDIA)

  CARDIA is a study examining the etiology and natural history of cardiovascular disease beginning in young adulthood. In 1985-1986, a cohort of 5115 healthy black and white men and women, aged 18-30 years, were selected to have approximately the same number of people in subgroups of age (18-24 and 25-30), sex, race, and education (high school or less, and more than high school) within each of four US Field Centers. These same participants were asked to participate in follow-up examinations during 1987-1988 (Year 2), 1990-1991 (Year 5), 1992-1993 (Year 7), 1995-1996 (Year 10), 2000-2001 (Year 15), 2005-2006 (Year 20), 2010-2011 (Year 25) and 2015-2016 (Year 30). In addition to the follow-up examinations, participants are contacted regularly for the ascertainment of information on out-patient procedures and hospitalizations experienced between contacts. Within the past five years, 95% of the original surviving cohort has been contacted. While the specifics of each examination have differed somewhat, data have been collected on a variety of factors believed to be related to heart disease. These include conditions with clear links to heart disease, such as blood pressure, cholesterol and other lipids. Data have also been collected on physical measurements, such as weight and skinfold fat, as well as lifestyle factors such as substance use (tobacco and alcohol), dietary and exercise patterns, behavioral and psychological variables, medical and family history, and other chemistries (e.g., insulin and glucose). In addition, subclinical atherosclerosis was measured via echocardiography during Years 5, 10, and 25, computed tomography during Years 15 and 20, and carotid ultrasound during Year 20.Comprehensive phenotypic data for study participants are available through dbGaP phs000285.

  Study phs001612

• National Cancer Institute (NCI) TARGET: Therapeutically Applicable Research to Generate Effective Treatments

  The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative seeks to accelerate research in novel marker and drug development, along with understanding the molecular basis of pediatric malignancy, through identification of genomic changes associated with the following childhood cancers: Acute Lymphoblastic Leukemia (ALL) - A fast-growing type of blood cancer in which too many immature white blood cells are found in the blood and bone marrow. Acute Myeloid Leukemia (AML), including AML Induction Failure cases (AML-IF) - Another type of blood cancer marked by too many myeloblasts, an alternate type of immature white blood cell, are found in the blood and bone marrow. Upon diagnosis, AML patients without high-risk genetic markers undergo standard chemotherapy regimen, called the primary induction phase, to eliminate most cancer cells and induce a remission state. Clear Cell Sarcoma of the Kidney (CCSK) - A rare type of kidney cancer, in which the inside of the cells looks clear when viewed under a microscope. Clear cell sarcoma can spread from the kidney to other organs, most commonly the bone, but also including the lungs, brain, and soft tissues of the body. Neuroblastoma (NBL) - Cancer of cells of the sympathetic nervous system. Cancer Model Systems (MDLS), including PPTP - MDLS includes acute leukemia cell lines and xenografts with matched primary and/or relapsed tumor information, NBL cell lines and xenografts with matched controls, kidney tumor cell lines, normal brain tissues, and embryonic stem cell lines that were sequenced for some TARGET disease projects. Osteosarcoma (OS) - A cancer of the bone that primarily affects children and adolescents. Rhabdoid Tumor (RT) - A rare, fast-growing cancer that usually forms in the kidney or central nervous system (the brain and spinal cord) but can also form in soft tissues in other areas of the body. Rhabdoid tumors tend to spread quickly, are hard to treat, and have a poor prognosis. Wilms' Tumor (WT) - A cancer of cells in the kidney that can spread to the liver, lung and lymph nodes. More information can be found about each TARGET subproject by following the links on the top of this page. Together these cancers account for the majority of the more than 10,000 childhood cancer cases diagnosed in the United States each year. TARGET has employed a set of advanced and complementary genome analysis technologies, including large scale 2nd and 3rd generation genome sequencing, to strategically characterize alterations in both gene expression and in genomic structure (such as deletions and amplification) that are involved in childhood cancers. The goal of this coordinated effort has been to create a comprehensive genomic and transcriptomic profile of each cancer. Integrated analysis of the TARGET data has identified those genes that are either altered in their expression level or mapped to the chromosome regions of deletion/amplification/translocation, as these genes represent strong candidates for therapeutic targeting. To learn more about the TARGET project, which is now completed, visit the website at https://www.cancer.gov/ccg/research/genome-sequencing/target. TARGET data is accessible at the NCI's Genomic Data Commons (GDC) via the GDC's Data Portal and from each of the TARGET Publication Pages at the GDC (Please see the "Supplemental Links" section of any TARGET publication's "Publication Information and Associated Data Files page" at the GDC.). Available datasets include raw sequencing data, datasets generated by the original TARGET research teams (fully annotated clinical information and higher-level/analyzed molecular characterization data - gene expression, copy number variation, epigenetics, targeted sequencing), as well as higher level data generated by the GDC. Please see the TARGET Use and Publication Guidelines for updated details on the sharing of any TARGET substudy data, including how to cite TARGET.

  Study phs000218

• TIGIT is the central player in T-cell suppression associated with CAR T-cell relapse in mantle cell lymphoma

  Study EGAS00001007113

• Sequencing probands and families with severe insulin resistance syndromes

  This is an ongoing project and continuation to all the sequencing we have been doing over the last few years. We have some additional families and probands with syndromes of insulin resistance not previously sequenced within uk10k or other core funded projects. We would like to complete the sequencing in all of the good quality families and probands we have, this would require another ~50 samples to be WES sequenced. This cohort has already proven to be a rich source of interesting findings with papers in Science and Nature genetics.

  Dataset EGAD00001000694

• Whole Genome and Exon Capture Sequencing of Bladder Cancers

  One primary bladder cancer and paired peripheral blood sample were subjected to whole genome sequencing on an Illumina HiSeq 2000 platform. This technology was utilized to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations found was a loss-of-function mutation in TSC1 (Tuberous Sclerosis Complex 1), a regulator of mTOR pathway activation. Targeted sequencing using an exon capture and sequencing assay was performed on 13 tumors derived from patients on the same everolimus trial as the index patient and the sequencing data from these tumors is included. TSC1 mutation status was correlated with response to everolimus. The index patient responder tumor and peripheral blood DNA were also subjected to exon capture and sequencing.

  Study phs000535

• Loss of LGR4/GPR48 causes severe neonatal salt-wasting due to disrupted WNT signaling altering adrenal zonation

  Disorders of isolated mineralocorticoid deficiency causing potentially life-threatening salt-wasting crisis early in life have been associated with gene variants of aldosterone biosynthesis or resistance, but in some patients no such variants are found. WNT/β-catenin signaling is crucial for differentiation and maintenance of the aldosterone producing adrenal zona glomerulosa (zG). We describe a highly consanguineous family with multiple perinatal deaths or infants presenting at birth with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Whole exome sequencing revealed a homozygous splice variant in the R-SPONDIN receptor LGR4 gene (c.618-1G>C) regulating WNT signaling. The resulting transcripts affected protein function and stability, and resulted in loss of Wnt/β-catenin signaling in vitro. The impact of LGR4 inactivation was analyzed by adrenal cortex specific ablation of Lgr4, using Lgr4Flox/Flox mated with Sf1:Cre mice. Inactivation of Lgr4 within the adrenal cortex in the mouse model caused decreased WNT signaling, aberrant zonation with deficient zG and reduced aldosterone production. Thus, human LGR4 mutations establish a direct link between LGR4 inactivation and decreased canonical WNT signaling with abnormal zG differentiation and endocrine function. Therefore, variants in WNT signaling and its regulators should systematically be considered in familial hyperreninemic hypoaldosteronism.

  Study EGAS00001006808

• Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT-BioLINCC)

  Data Access NOTEPlease refer to the "Authorized Access" section below for information about how access to the data from this accession. Access differs from many other dbGaP accessions. BiospecimensAccess to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from TOPCAT include Buffy Coat, DNA, Plasma, Serum, Urine, and Whole Blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives The TOPCAT trial evaluated the effectiveness of aldosterone antagonist therapy in reducing cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization in patients who have heart failure with preserved systolic function. Background Many patients with heart failure have a normal, or near-normal, left ventricular ejection fraction (LVEF). Such patients share similar signs and symptoms as patients who have heart failure and a reduced LVEF, as well as an impaired quality of life and a poor prognosis. However, at the time of TOPCAT, the benefit of medical therapies for heart failure were limited to those with a reduced LVEF. Due to a lack of favorable evidence from clinical trials, clinical guidelines offered no specific recommendations for the management of heart failure in patients with preserved LVEF, except for attention to coexisting conditions. Among patients with heart failure and a reduced LVEF and those with myocardial infarction complicated by heart failure and left ventricular dysfunction, mineralocorticoid receptor antagonists have been shown to be effective in reducing overall mortality and hospitalizations for heart failure. In small mechanistic studies involving patients with heart failure and preserved left ventricular function, mineralocorticoid receptor antagonists improved measures of diastolic function. However, rigorous testing was needed regarding their effect on clinical outcomes in patients with preserved LVEF. Therefore, the TOPCAT trial was initiated to determine whether treatment with spironolactone, an aldosterone antagonist, would improve clinical outcomes in patients with symptomatic heart failure and a relatively preserved LVEF. Participants A total of 3445 participants were enrolled, with 1722 assigned to the spironolactone group and 1723 assigned to the placebo group. Among these, 2464 participants were enrolled via the hospitalization stratum and 981 were enrolled via the BNP stratum. Design TOPCAT was a phase 3, multicenter, international, randomized, double-blind, and placebo controlled trial. Eligible participants were randomly assigned to receive either spironolactone or placebo in a 1:1 ratio. Randomization was stratified according to whether the patient met the criterion for previous hospitalization or BNP elevation. The baseline visit included assessment of socio-demographics, physical characteristics, medical history, lifestyle factors, laboratory measures, electrocardiography variables and health-related quality of life and functional status. Study drugs were initially administered at a dose of 15 mg once daily, which was increased as tolerated to a maximum of 45 mg daily during the first four months after randomization. Subsequent dose adjustments were made as required and subjects continued to receive other treatments for heart failure and co-existing illnesses. Measurement of potassium and creatinine levels was required within 1 week after a change in the study-drug dose and at each scheduled study visit. Follow-up visits to monitor symptoms, medications, and events and to dispense study drug were scheduled every four months during the subject's first year on the study, and every six months thereafter. The mean follow-up interval was 3.3 years in each study group. Repository blood and urine samples were collected at the baseline and 1 year visits from consenting subjects. The primary endpoint was a composite of cardiovascular mortality, aborted cardiac arrest or hospitalization for the management of heart failure. Secondary endpoints included all-cause mortality, hospitalization for heart failure management, new onset of diabetes mellitus or atrial fibrillation, and quality of life. A subset of subjects also participated in the Echocardiography or Echocardiography and Vascular Stiffness ancillary studies. Echocardiography, and additionally tonometry in the Echocardiography and Vascular Stiffness study, were performed at baseline and at either 12 or 18 months following randomization. If the subject was already enrolled in the TOPCAT trial at the time the ancillary study was initiated, but had not yet reached the 18 month visit, baseline was determined via a retrospective analysis performed on any echocardiographic images completed within 60 days prior to TOPCAT enrollment and no tonometry was performed if applicable. Conclusions In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. However, the drug reduced the secondary endpoint of heart failure hospitalization incidence.

  Study phs003665

• Evaluation of triple negative breast cancer with heterogeneous immune infiltration

  This dataset contains the raw RNA-seq data (FASTQ files) of the samples used in the study title: "Evaluation of triple negative breast cancer with heterogeneous immune infiltration". The dataset is composed of 3 patients with 6 samples per patient (3 with high TILs and 3 with low TILs).

  Dataset EGAD00001010280

• IDH-wildtype untreated human glioblastoma samples (GB-UK cohort), published in Noorani & Haughey et al 2025.

  Extrachromosomal DNA (ecDNA) oncogene amplification is associated with treatment resistance and shorter survival in cancer. Currently, the spatial dynamics of ecDNA, and their evolutionary impact, are poorly understood. Here, we investigate the spatiotemporal evolution of ecDNA by integrating computational modeling with samples from 94 treatment-naive human IDH wild-type glioblastoma patients. Random ecDNA segregation combined with ecDNA-conferred fitness advantages induce distinct spatial ecDNA copy number patterns which depend on ecDNA oncogenic makeup. EGFR-ecDNAs often reach high copy numbers and confer strong fitness advantages. In contrast, PDGFRA-ecDNAs reach lower copy numbers and confer weaker fitness advantages. EGFR structural variants occur exclusively on ecDNA, arise from and are intermixed with wild-type EGFR-ecDNAs. Computational modeling suggests wild-type and variant EGFR-ecDNAs often accumulate before clonal expansion. Using a genetically engineered mouse model, we confirm that the accumulation of oncogenic ecDNA prior to clonal expansion under strong positive selection is observable both in vivo and in vitro in mouse neural stem cells. Intermixed wild-type and variant ecDNAs remain prevalent at diagnosis, as less fit wild-type ecDNAs hitchhike on strongly selected variant EGFR-ecDNAs. A dN/dS analysis in the Genomics England cohort further suggests positive selection of variants on EGFR-ecDNAs but not PDGFRA-ecDNAs in glioblastoma. Overall, our results suggest ecDNA oncogenic makeup determines unique evolutionary trajectories in glioblastoma. New concepts like ecDNA tumor clonality, ecDNA heteroplasmy and multi-species ecDNAs require a refined evolutionary interpretation of genomic data in a large subset of glioblastoma patients and likely other solid cancers.

  Study EGAS00001008126

• RNAseq of primary mesothelioma cell lines

  Mesothelioma is an aggressive cancer associated with previous exposure to asbestos and dismal prognosis. Since a pemetrexed/cisplatin combination was introduced for treatment of mesothelioma, no new first- or second-line therapies have been discovered. Thus, to better understand what drives mesothelioma carcinogenesis and to identify potential targets for therapy, in this project we aim at performing RNAseq analysis of a panel of mesothelioma cells lines.

  Dataset EGAD00001009642

• Mullighan - PAX5-driven Subtypes

  Using integrated genomic analysis of 1.988 childhood and adult cases, we describe a revised taxonomy of B-cell acute lymphoblastic leukemia, which incorporates 23 subtypes defined by chromosomal rearrangements, sequence mutations, or heterogeneous genomic alterations. Two subtypes have frequent alterations of the B lymphoid transcription factor gene PAX5. One, PAX5alt, has diverse PAX5 alterations, and a second subtype is defined by a single mutation, PAX5 P80R. We show that P80R impairs B lymphoid development and promotes the development of B-ALL in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.

  Study EGAS00001003266

• Separation of chronic myeloid leukemia stem cells from normal hematopoietic stem cells at single-cell resolution

  Chronic myeloid leukemia (CML) is a clonal disease, initiated and sustained by a subpopulation of CML stem cells (CML-SC) containing the BCR::ABL1 oncogene. Genetic markers that enrich for CML-SC have been identified, including CD26 being most specific. Genome sequencing analysis remain yet to be performed at single cell level in order to determine differences and heterogeneity in the genetic profile of CML-SC versus normal hematopoietic stem cells (HSC). Here we show that CD26 and CD33 separate CML-SC from normal HSC in freshly isolated bone marrow samples from newly diagnosed CML patients. DNA sequencing confirms that single CML-SC derived colonies are positive for BCR::ABL1 and harbor a recurrent set of patient-specific clonal somatic mutations across different CML-SC derived colonies. In contrast, marker-negative (CD26-CD33-) HSC from the same patients are negative for the BCR::ABL1 oncogene and do not carry recurrent, clonal mutation across different colonies. These results support the concept that CD26/CD33 expression separates genetically defined, clonal mutant CML-SC from normal HSC that carry individual sets of random mutations in CML patients. We provide whole exome DNA sequencing data for 23 clinical samples of CML-SC plus two buccal swipes derived normal samples. CML samples are comprised of 4 to 8 replicates from two patients, at diagnosis and after treatment. Single CML stem cells before treatment and single non-transformed HSC at remission were selected from bone marrow samples by FACS, according to genetic markers CD33+CD26+ at diagnosis and CD33+CD26-/CD33-CD26- at remission. WES libraries of colony forming assays derived CML-SC and HSC populations were prepared using Agilent SureSelect Human All Exon V6 kit and sequenced running 150 cycles (2x 75bp paired-end) on an Illumina NextSeq 500 platform. Following GATK best practices for somatic mutation calling, novel CML variants and random mutation events during remission phase were obtained.

  Study EGAS00001006904

• EMBARCAM BC360 PROJECT

  This dataset is related to the EMBARCAM BC360 PROJECT. A total of 106 breast cancer samples, from Pregnancy-Associated Breast Cancer (PABC) (n=57) and non-PABC (n=49) patients, were analysed using the nCounter Breast Cancer 360 V2 panel on the NanoString platform. All samples were FFPE tumor samples from breast cancer patients, derived from GEICAM/2012-03, GEICAM/2017-07, and EpiGEICAM studies, sponsored by GEICAM.

  Dataset EGAD00010002709

• Naive B-cell receptor heavy chain repertoire of celiac patients and healthy controls

  High throughput sequencing dataset of antibody repertoires from naive B-cells, taken from blood samples of 100 individuals from Norway. 48 healthy controls and 52 patients with celiac disease. Sequencing was performed using a 300*2 paired-end kit by Illumina MiSeq. The sequences were processed using pRESTO. Each fastq file in the dataset is the repertoire of a single individual.

  Dataset EGAD00001004512

• Resistance to MAPK-inhibitor induces internal duplication in BRAF_Oscar Krijsman

  2 BRAFV600E cell lines that have been made resistance to 1. the BRAF inhibitor PLX4720 and 2. the combination therapy of dabrafenib and trametinib seem to have a internal duplication in the kinase domain. We would like to know if this is caused by a translocation.

  Dataset EGAD00001001846

• mRNA capture sequencing and RT-qPCR for the detection of pathognomonic, novel and secondary fusion transcripts in formalin-fixed paraffin-embedded tissue: a sarcoma showcase

  RNA sequencing is widely used to study gene abundance patterns, but less frequently to assess structural alterations such as fusion transcripts. In this study, we assess the performance of messenger RNA (mRNA) capture sequencing to identify fusion transcripts in formalin-fixed paraffin-embedded (FFPE) tissue of different types of sarcoma, followed by orthogonal confirmation using RT-qPCR. To validate our workflow, we used the TruSight RNA Pan-Cancer Panel to analyze a first cohort of 6 positive control tumors for which the diagnostic workup demonstrated the presence of a specific chromosomal rearrangement. Fusion transcript calling by FusionCatcher confirmed all known aberrations and enabled the identification of both fusion gene partners and breakpoints. Next, whole transcriptome TruSeq RNA Exome sequencing was applied to a second cohort of 17 patients, diagnosed with fusion gene-negative alveolar rhabdomyosarcoma (ARMS) or undifferentiated round cell sarcoma (URCS), for whom fluorescence in situ hybridization (FISH) did not identify the classical pathognomonic rearrangements. Remarkably, for 6 out of 17 patients, mRNA capture sequencing readily detected a pathognomonic fusion transcript, i.e. PAX3-FOXO1 in 2 ARMS patients, and EWSR1-FLI1, EWSR1-ERG or EWSR1-NFATC2 in 4 URCS patients. These data show that RNA capture sequencing may enhance the detection rate of pathognomonic fusion genes in sarcoma. For the 11 patients with no known pathognomonic fusion transcript, 11 newly identified fusion transcripts were confirmed by RT-qPCR, including COPS3-TOM1L2, NCOA1-DTNB, WWTR1-LINC01986, PLAA-MOB3B, AP1B1-CHEK2 and BRD4-LEUTX fusion transcripts in ARMS patients. Additionally, recurrently detected secondary fusion transcripts in two patients diagnosed with EWSR1-NFATC2-positive sarcoma were confirmed (COPS4-TBC1D9, PICALM-SYTL2, SMG6-VPS53 and UBE2F-ALS2). Our results provide new insights into the underlying genetic causes of these malignancies.

  Study EGAS00001005202

• Genetic landscape of SMM

  Identifying high risk smoldering myeloma patients and progression mechanism is a prerequisite to implement effective inception strategies and curve myeloma related morbidity and mortality. We hypothesize that genomics may help identify determinants of progression that may help predict outcome and offer effective chemo preventive targets. Eighty-two patients underwent a custom targeted panel sequencing with an additional capture for the translocation loci. These results were compared to 223 newly diagnosed patients (EGAS00001003223 and EGAD00001004117) and 17 MGUS and 10 early myeloma patients. DNA was obtained from either CD138+ cells from the bone marrow of multiple myeloma patients (tumor) or from stem cell harvests or peripheral blood cells from the same patient (control). 100 ng of DNA was fragmented, end-repaired, and adapters ligated using the HyperPlus kit (KAPA Biosystems). After PCR amplification the libraries were hybridized with probes against either a targeted panel consisting of 140 genes and chromosomal regions (Nimblegen) using SeqCap reagents (Nimblegen). Hybridized libraries underwent further amplification before being sequenced on a NextSeq500 (Illumina) using 75 bp paired end reads. Overall, these data highlight the importance of dysregulation of the MAPK pathway in the progression to MM.

  Dataset EGAD00001005285

• Deciphering Developmental Disorders (DDD)

  The Deciphering Developmental Disorders (DDD) study is a research collaboration between the Wellcome Trust Sanger Institute, the NHS clinical genetics services and families across the UK and Ireland. The project aims to improve the diagnosis of children with developmental disorders by using high-resolution microarray and massively parallel sequencing technologies on 12,000 children and their parents. Genetic changes that explain the child's symptoms will be displayed in the DECIPHER database (https://decipher.sanger.ac.uk). Extended datasets generated by the DDD project will be available in the European Genome-Phenome Archive with access carefully managed by a Data Access Committee.

  Study EGAS00001000775

• Human Pancreatic Islet RNAseq - Lund

  Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, many key tissues and cell-types required for appropriate functional inference are absent from large-scale resources such as ENCODE and GTEx. We explored the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using RNA-Seq and genotyping data from 420 islet donors. We find: (a) eQTLs have a variable replication rate across the 44 GTEx tissues (<73%), indicating that our study captured islet-specific cis-eQTL signals; (b) islet eQTL signals show marked overlap with islet epigenome annotation, though eQTL effect size is reduced in the stretch enhancers most strongly implicated in GWAS signal location; (c) selective enrichment of islet eQTL overlap with the subset of T2D variants implicated in islet dysfunction; and (d) colocalization between islet eQTLs and variants influencing T2D or related glycemic traits, delivering candidate effector transcripts at 23 loci, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in tissues of greatest disease-relevance while expanding our mechanistic insights into complex traits association loci activity with an expanded list of putative transcripts implicated in T2D development.

  Study EGAS00001004042

• Phenotyping data on human pancreatic islets from 191 donors - Lund

  Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, many key tissues and cell-types required for appropriate functional inference are absent from large-scale resources such as ENCODE and GTEx. We explored the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using RNA-Seq and genotyping data from 420 islet donors. We find: (a) eQTLs have a variable replication rate across the 44 GTEx tissues (<73%), indicating that our study captured islet-specific cis-eQTL signals; (b) islet eQTL signals show marked overlap with islet epigenome annotation, though eQTL effect size is reduced in the stretch enhancers most strongly implicated in GWAS signal location; (c) selective enrichment of islet eQTL overlap with the subset of T2D variants implicated in islet dysfunction; and (d) colocalization between islet eQTLs and variants influencing T2D or related glycemic traits, delivering candidate effector transcripts at 23 loci, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in tissues of greatest disease-relevance while expanding our mechanistic insights into complex traits association loci activity with an expanded list of putative transcripts implicated in T2D development.

  Study EGAS00001004056

• GWAS data on human pancreatic islets from 191 donors - Lund

  Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, many key tissues and cell-types required for appropriate functional inference are absent from large-scale resources such as ENCODE and GTEx. We explored the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using RNA-Seq and genotyping data from 420 islet donors. We find: (a) eQTLs have a variable replication rate across the 44 GTEx tissues (<73%), indicating that our study captured islet-specific cis-eQTL signals; (b) islet eQTL signals show marked overlap with islet epigenome annotation, though eQTL effect size is reduced in the stretch enhancers most strongly implicated in GWAS signal location; (c) selective enrichment of islet eQTL overlap with the subset of T2D variants implicated in islet dysfunction; and (d) colocalization between islet eQTLs and variants influencing T2D or related glycemic traits, delivering candidate effector transcripts at 23 loci, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in tissues of greatest disease-relevance while expanding our mechanistic insights into complex traits association loci activity with an expanded list of putative transcripts implicated in T2D development.

  Study EGAS00001004044

• Carbamazepine-induced hypersensitivity reactions in Europeans

  An antiepileptic drug carbamazepine is well tolerated by the majority of patients, but can cause severe and potentialy fatal hypersensitivity reactions in a small number of individuals. The aim of this study was to identify genetic predictors of hypersensitivity reactions to carbamazepine. We undertook a genome-wide association study (GWAS) in 22 patients of European ancestry with carbamazepine-induced hypersensitivity syndrome (HSS) and compared our data with genotypes from a healthy population within the WTCCC. We performed imputation of classical HLA alleles according to a recently described method (Science. 2010 Dec 10;330(6010):1551-7. Epub 2010 Nov 4). GWAS statistical analysis was performed using logistic regression with an additive model of inheritance.

  Study EGAS00000000037

• Resuscitation Outcomes Consortium (ROC) Amiodarone, Lidocaine or Neither for Out-Of-Hospital Cardiac Arrest Due to Ventricular Fibrillation or Ventricular Tachycardia (ALPS)(ROC-ALPS-BioLINCC)

  Accessing Data Please refer to “Authorized Access” below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP. Objective To compare the effects of amiodarone, lidocaine, and placebo on survival to hospital discharge after out-of-hospital cardiac arrest due to shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. Background Ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) are common causes of out-of-hospital cardiac arrest, but are considered the most responsive to shock and therefore the most treatable. Nonetheless, most defibrillation attempts do not result in sustained return of spontaneous circulation, and VF or VT may persist or recur after shock. There is also evidence that longer durations of VF or VT are associated with decreases in the likelihood of resuscitation. Amiodarone and lidocaine are commonly used to promote successful defibrillation of shock-refractory VF or VT and prevent recurrences. Previous trials have shown amiodarone to be more effective than placebo or lidocaine for return of spontaneous circulation and survival at hospital admittance. This study sought to further extend the research and examine whether amiodarone would improve survival to hospital discharge and neurologic outcomes, as compared to placebo or lidocaine. Participants 3,026 eligible participants were enrolled, with 974 assigned to amiodarone, 993 assigned to lidocaine, and 1,059 assigned to placebo. An additional 1,627 participants that received a study intervention, but did not meet eligibility criteria, were included in analysis of the intention-to-treat population. Design The study interventions (amiodarone, lidocaine, and saline) were packaged in indistinguishable sealed kits and randomly distributed in to Emergency Medical Services (EMS) providers in a 1:1:1 ratio, stratified by participating site and agency. Each kit contained three syringes, and each syringe held 3 ml of colorless fluid containing 150 mg of amiodarone, 60 mg of lidocaine, or normal saline. Participants with out-of-hospital cardiac arrest were treated in accordance with local EMS protocols, in compliance with American Heart Association (AHA) guidelines. If VF or VT persisted or recurred after one or more shocks, eligible participants received a vasopressor and the masked kit containing amiodarone, lidocaine, or placebo. Approximating current clinical practice, the initial dose consisted of two syringes administered by rapid bolus. If the estimated body weight of the patient was less than 100 lbs., then one syringe was used. If VF or VT persisted, standard resuscitation measures, additional shocks, and an additional syringe of the study drug were administered. At that point the trial interventions were completed and standard interventions for advanced life support were employed. Upon arrival at the hospital, providers were notified of the patient's enrollment in the trial and encouraged to provide usual care in accordance with AHA guidelines, including open-label amiodarone or lidocaine if necessary. Components of hospital care were monitored but not standardized by the trial protocol. Participants, providers, and trial personnel were blinded to the trial drug assignments, with the exception of treating physicians if emergency un-blinding was required for care. Data from pre-hospital patient care records, CPR process measures, and hospital medical records were collected. The primary outcome of the trial was survival to hospital discharge, and the secondary outcome was survival with favorable neurologic status at discharge, defined as a score on the modified Rankin scale of 3 or less. Conclusions Neither amiodarone nor lidocaine resulted in a significantly higher rate of survival to hospital discharge or favorable neurologic outcome, as compared to placebo, among participants with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia.

  Study phs003784

• POPCOL: population-based colonoscopy.

  PopCol is a cohort study in Stockholm, Sweden that includes a data-rich set of individuals with data available from bowel symptoms questionnaires, gastroenterology visits and biospecimens (genotype and 16S sequencing from blood and stool samples, respectively). Genotyping was carried out using the Illumina HumanOmniExpressExome-8v1 arrays at the SciLifeLab NGI facility in Uppsala, Sweden. Fecal DNA was extracted from samples kept at -80°C using Qiagen 5 QIAamp DNA Stool Mini Kits and analyzed using 16S rRNA gene amplicon sequencing (in the V1-V2 hypervariable region). This was performed on the Illumina MiSeq platform at the Institute of Clinical Molecular Biology (IKMB) in Kiel, Germany. Of these, six PopCol participants were PPI users and 12 used antibiotics. The study was approved by the local Committee of Research Ethics (Forskningskommitté Syd) at Karolinska Institutet, Stockholm, in November 2001. Written informed consent was obtained from all participants

  Study EGAS00001004869

• Prediction of HLA genotypes using NGS data

  High-precision human leukocyte antigen (HLA) genotyping is crucial for anti-cancer immunotherapy, but existing tools predicting HLA genotypes using next-generation sequencing (NGS) data are insufficiently accurate. We compared the availability and accuracy of eight HLA genotyping tools (OptiType, HLA-HD, PHLAT, seq2HLA, arcasHLA, HLAscan, HLA*LA, and Kourami) using 1,275 cases from the 1000 Genomes Project data and created a new HLA-genotyping algorithm combining tools. Then, we assessed the new algorithm’s performance in 39 in-house samples with normal whole-exome sequencing (WES) data and polymerase chain reaction–sequencing-based typing (PCR-SBT) results.

  Dataset EGAD00001007733

• Tumor-derived cell lines as pharmacogenomic models to predict therapeutic vulnerabilities in hepatocellular carcinoma

  Hepatocellular carcinoma (HCC) is a heterogeneous aggressive malignancy with low efficacy of current therapies at advanced stages. We integrated molecular and pharmacological profiling of a large panel of liver cancer cell lines (LCCL) to assess their clinical relevance as HCC preclinical models and identify new effective therapies and biomarkers of response. We performed multi-omic analysis including whole-exome, RNA and miRNA sequencing and quantification of 126 proteins in a series 34 LCCL coupled with a screening of 29 anti-cancer agents. Molecular profiles of LCCL and primary HCC were compared and we searched for molecular features associated with drug response. Our panel of LCCL faithfully recapitulated the most aggressive molecular "proliferation class" of HCC. Genomic alterations of the RAS-MAPK pathway correlated with trametinib sensitivity that was more potent than FGFR4 inhibitors in tumor cells depending on the FGF19/FGFR4 pathway. Moreover, we showed that FGF19 amplification was only functional in tumor cells that retained a hepatocyte differentiation program with expression of FGFR4, KLB and NR1H4 highlighting the complex interplay between the genomic and transcriptomic context in drug response. We also identified drugs/combination that could target efficiently the transcriptomic "progenitor subclass of HCC", as well as specific genetic contexts such as inactivating mutations in TSC1/TSC2 and TP53 associated with higher sensitivity to the mTOR inhibitor rapamycin and the AURKA inhibitor alisertib, respectively. LCCL represent relevant preclinical models for drug-biomarker discovery in HCC and enabled to identify molecular contexts linked with particular therapeutic vulnerabilities that may be useful to stratify patients in future clinical trials

  Study EGAS00001003536

• Spatial Transcriptomics of Vaccine Therapy With or Without Cyclophosphamide in Treating Patients Undergoing Chemotherapy and Radiation Therapy for Stage I or Stage II Pancreatic Cancer That Can Be Removed by Surgery

  Pancreatic ductal adenocarcinoma (PDAC) is a rapidly progressing cancer that responds poorly to immunotherapies. Intratumoral tertiary lymphoid structures (TLS) have been associated with rare long-term PDAC survivors, but the role of TLS in PDAC and their spatial relationships within the context of the broader tumor microenvironment remain unknown. Here, spatial transcriptomics data were generated from 16 pancreatic cancer patients treated with GVAX, whose tumors presented with induced intratumoral TLS. Resected tumor specimens were embedded in OCT media and freshly frozen. Sections were cut into 6.5 x 6.5 mm dimensions compatible with Visium spatial transcriptomics slides. TLS-positive tumor sections from 14 patients (14 tumor samples in total) and lymph nodes from remaining patients (2 lymph node samples in total) were selected by an expert pathologist for profiling. We used 4 Visium slides and covered the 16 capture areas with sections cut in a cryostat at 10 µm. The fresh frozen Visium protocol was followed according to manufacturer's recommendations (10x Genomics Spatial 3' v1). Tissue permeabilization and library construction was carried out according to the manufacturer's protocols. Permeabilization time was optimized to 30 minutes. The captured tissue sections were permeabilized to allow RNA to be captured onto the slide where it reverse-transcribed to cDNA. The cDNA was then amplified, and sequencing libraries were prepared using the 10x Genomics Visium Spatial Gene Expression Reagent Kit for Library Preparation. The libraries were then sequenced using an Illumina NovaSeq sequencer. The raw data obtained from the sequencing were processed using the SpaceRanger (spaceranger-1.2.0) pipeline for alignment onto the GRCh38-2020-A reference transcriptome quantification of gene expression. Unsupervised learning generated a TLS-specific spatial gene expression signature that significantly associates with improved survival in PDAC patients. These analyses demonstrate TLS-associated intratumoral B cell maturation.

  Study phs003862

• A Scalable, GMP-Compatible, Autologous Organotypic Cell Therapy for Dystrophic Epidermolysis Bullosa

  Gene editing in induced pluripotent stem (iPS) cells has been hailed for enabling new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa (DEB). However, manufacturing, efficacy, and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies. Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), is a new generation, Good Manufacturing Practice-compatible (cGMP), reproducible, and scalable platform to produce autologous clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts to treat incurable wounds of patients lacking type VII collagen (C7). DEBCT uses a single step, combined, high-efficiency reprogramming, and CRISPR-based genetic correction to generate genome scar-free, COL7A1 corrected clonal iPS cells from primary patient fibroblasts. Validated iPS cells are converted into epidermal, dermal, and melanocyte progenitors with a novel 2D organoid differentiation protocol, followed by CD49f enrichment and expansion to minimize maturation heterogeneity. iSC product characterization by single cell transcriptomics was followed by mouse xenografting for disease correcting activity at 1 month and toxicology analysis at 1-6 months. Culture-acquired mutations, potential CRISPR-off target effects, and cancer-driver variants were evaluated by targeted and whole genome sequencing. iPS cell-derived iSC grafts were reproducibly generated from four recessive DEB patients with different pathogenic mutations. Organotypic iSC grafts onto immune-compromised mice developed into stable stratified skin with functional C7 restoration. Single cell transcriptomic characterization of iSCs revealed prominent holoclone stem cell signatures in keratinocytes and the recently described Gibbin-dependent signature in dermal fibroblasts. The latter correlated with enhanced graftability. Multiple orthogonal sequencing and subsequent computational approaches identified random and non-oncogenic mutations introduced by the manufacturing process. Toxicology revealed no detectable tumors after 3-6 months in DEBCT-treated mice. In conclusion, DEBCT successfully overcomes previous roadblocks and establishes a robust, scalable, and safe cGMP manufacturing platform for the production of a CRISPR-corrected autologous organotypic skin graft to heal DEB patient wounds.

  Study phs003271

• GATA6 expression distinguishes classical and basal-like subtypes in advanced pancreatic cancer.

  PURPOSE: To determine the impact of basal-like and classical subtypes in advanced PDAC and to explore GATA6 expression as a surrogate biomarker. EXPERIMENTAL DESIGN: Within the COMPASS trial patients proceeding to chemotherapy for advanced PDAC undergo tumour biopsy for RNA sequencing. Overall response rate (ORR) and overall survival (OS) were stratified by subtypes and according to chemotherapy received. Correlation of GATA6 with the subtypes using gene expression profiling, in situ hybridization (ISH) were explored. RESULTS: Between December 2015-May 2019, 195 patients (95%) had enough tissue for RNA sequencing; 39 (20%) were classified as basal-like and 156 (80%) as classical. RECIST response data were available for 157 patients; 29 basal-like and 128 classical where the ORR was 10% vs. 33% respectively (p=0.02). In patients with basal-like tumours treated with modified FOLFIRINOX (mFFX) (n=22) the progression rate was 60% compared to 15% in classical PDAC (p= 0.0002). Median OS in the intention to treat population (n=195) was 9.3 months for classical vs. 5.9 months for basal-like PDAC (HR 0.47 95% CI 0.32-0.69, p=0.0001). GATA6 expression by RNAseq highly correlated with the classifier (p<0.001) and ISH predicted the subtypes with sensitivity of 89% and specificity of 83%. In a multivariable analysis, GATA6 expression was prognostic (p=0.02). In exploratory analyses, basal-like tumours, could be identified by keratin 5, were more hypoxic and enriched for a T cell inflamed gene expression signature. CONCLUSIONS: The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression.

  Dataset EGAD00001006081

• Evolutionary analysis of pancreatic cancer and coexistent precursor lesions using whole exome sequencing data

  Most adult carcinomas develop from noninvasive precursor lesions, a progression that is supported by genetic analysis. Further, the evolution of these lesions contextualizes the dynamics of advanced stage disease. We analyzed the somatic variants of co-existing pancreatic cancers and precursor lesions sampled from distinct regions of the same pancreas. After inferring evolutionary relationships, we found that the ancestral cell had initiated and clonally expanded to form one or more lesions, and that subsequent driver gene mutations eventually led to a pancreatic cancer. We also found that this multi-step progression generally spans many years. Our data suggest that independent, high-grade pancreatic lesions observed in a histologic cross section often represent a single neoplasm that can spread and colonize the ductal system, accumulating spatial and genetic divergence over time.

  Study EGAS00001002778

• Epigenetics of Cocaine and Nicotine Addiction

  This project characterizes DNA methylation and gene expression changes that occur in the human brain, specifically in neurons from the rostral striatum. Major advances from NIDA funded initiatives for noninvasive neuroimaging studies have made it possible to study neuroanatomical, neurochemical and functional changes in the human brain that contribute to the vulnerability to abuse drugs, together with the neurotoxic consequences of years of drug misuse. Animal models have been developed to explain the fundamental behavioral and biological mechanisms of addiction, including reward, tolerance and dependence. From these studies, we learned that cocaine abuse not only alters the epigenetic status of genes, but also induces particular epigenetic modifications depending on the frequency of the drug's administration. Certain genes are switched on by infrequent (short-term exposure) administration, while others are switched on only after chronic administration (addiction/dependence). Animal studies have also suggested that cocaine-seeking habits modeling chronic cocaine addiction in humans depend upon dopamine-dependent serial connectivity linking the ventral (nucleus accumbens) with the dorsal striatum (caudate nucleus). The primary goal of this study is to identify DNA methylation and gene expression changes that occur in the transition from recreational cocaine use to cocaine addiction. High throughput sequencing studies were designed to investigate unique postmortem human brain specimens from individuals that met criteria for cocaine dependence, as compared to unaffected age-matched controls. Brain biospecimens were available from the University of Miami Brain Endowment BankTM, from a collection of phenotypically well-characterized postmortem tissues sampled from chronic cocaine abusers that came to autopsy. This biobank of postmortem brain specimens and annotated genomic data serve as a research resource to support NIDA's scientific mission.

  Study phs001377

• Quantitative analysis of a novel DNA hypermethylation panel for lung cancer diagnosis using bronchial specimens

  Non-diagnostic findings in Transbronchial Lung Biopsy (TBLB) and Endobronchial Ultrasound-guided Transbronchial Lung Biopsy (EBUS-TBLB) are not uncommon. A challenge is to improve lung cancer detection by TBLB/EBUS-TBLB. In order to improve the diagnostic yield of bronchoscopy, we used 850K methylation chip to identify methylation sites that distinguish malignant from benign lung nodules.We found that the combination of HOXA7, SHOX2,and SCT methylation analysis has the best diagnostic yield in 123 bronchial washing (sensitivity: 74·1%; AUC: 0·851) and 172 brushing samples (sensitivity: 86·1%; AUC: 0·915). We developed a kit comprising these three genes and validated the kit in 329 unique bronchial washing samples, 397 unique brushing samples, and 179 unique patients with both washing and brushing samples. The diagnostic accuracy of the panel alone in lung cancer diagnosis was 86·9%, 91·2% and 95% in bronchial washing, brushing, and washing+brushing samples, respectively. The panel's sensitivity in combination with cytology, rapid on-site evaluation (ROSE), and histology in lung cancer diagnosis was 90·8% and 95.8% in bronchial washing and brushing samples, respectively, and 100% in washing+brushing samples. Quantitative analysis of the three-gene panel improves lung cancer diagnosis by bronchoscopy.

  Study EGAS00001007089

• MiR expression profiles of paired primary colorectal cancerand metastases by next-generation sequencing

  MicroRNAs (miRs) have been recognized as promising biomarkers. It is unknown to what extent tumor-derived miRs aredifferentially expressed between primary colorectal cancers (pCRCs) and metastatic lesions, and to what extent the expressionprofiles of tumor tissue differ from the surrounding normal tissue. Next-generation sequencing (NGS) of 220 fresh-frozen samples,including paired primary and metastatic tumor tissue and non-tumorous tissue from 38 patients, revealed expression of 2245known unique mature miRs and 515 novel candidate miRs. Unsupervised clustering of miR expression profiles of pCRC tissue withpaired metastases did not separate the two entities, whereas unsupervised clustering of miR expression profiles of pCRC withnormal colorectal mucosa demonstrated complete separation of the tumor samples from their paired normal mucosa. Twohundred and twenty-two miRs differentiated both pCRC and metastases from normal tissue samples (false discovery rate (FDR)o0.05). The highest expressed tumor-specific miRs were miR-21 and miR-92a, both previously described to be involved in CRC withpotential as circulating biomarker for early detection. Only eight miRs, 0.5% of the analysed miR transcriptome, were differentiallyexpressed between pCRC and the corresponding metastases (FDR o0.1), consisting of five known miRs (miR-320b, miR-320d,miR-3117, miR-1246 and miR-663b) and three novel candidate miRs (chr 1-2552-5p, chr 8-20656-5p and chr 10-25333-3p). Theseresults indicate that previously unrecognized candidate miRs expressed in advanced CRC were identified using NGS. In addition,miR expression profiles of pCRC and metastatic lesions are highly comparable and may be of similar predictive value for prognosisor response to treatment in patients with advanced CRC

  Study EGAS00001001127

• 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

• Whole genome and whole exome sequencing of serial biopsies of relapsed/refractory diffuse large B-cell lymphoma.

  Purpose: Diffuse large B-cell lymphoma (DLBCL) is cured in more than 60% of patients, but outcomes remain poor for patients experiencing disease progression or relapse (refractory or relapsed DLBCL [rrDLBCL]), particularly if these events occur early. Although previous studies examining cohorts of rrDLBCL have identified features that are enriched at relapse, few have directly compared serial biopsies to uncover biological and evolutionary dynamics driving rrDLBCL. Here, we sought to confirm the relationship between relapse timing and outcomes after second-line (immuno)chemotherapy and determine the evolutionary dynamics that underpin that relationship. Patients and methods: Outcomes were examined in a population-based cohort of 221 patients with DLBCL who experienced progression/relapse after frontline treatment and were treated with second-line (immuno)chemotherapy with an intention-to-treat with autologous stem-cell transplantation (ASCT). Serial DLBCL biopsies from a partially overlapping cohort of 129 patients underwent molecular characterization, including whole-genome or whole-exome sequencing in 73 patients. Results: Outcomes to second-line therapy and ASCT are superior for late relapse (>2 years postdiagnosis) versus primary refractory (<9 months) or early relapse (9-24 months). Diagnostic and relapse biopsies were mostly concordant for cell-of-origin classification and genetics-based subgroup. Despite this concordance, the number of mutations exclusive to each biopsy increased with time since diagnosis, and late relapses shared few mutations with their diagnostic counterpart, demonstrating a branching evolution pattern. In patients with highly divergent tumors, many of the same genes acquired new mutations independently in each tumor, suggesting that the earliest mutations in a shared precursor cell constrain tumor evolution toward the same genetics-based subgroups at both diagnosis and relapse. Conclusion: These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naïve disease and have implications for optimal patient management.

  Study EGAS00001007053

• Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection

  SARS-CoV-2 vaccine immunogenicity varies between individuals, and immune responses correlate with vaccine efficacy. Using data from 1,076 participants enrolled in ChAdOx1 nCov-19 vaccine efficacy trials in the United Kingdom, we find that inter-individual variation in normalised antibody responses against SARS-CoV-2 spike (S) and its receptor binding domain (RBD) at 28 days following first vaccination shows genome-wide significant association with major histocompatibility complex (MHC) class II alleles. The most statistically significant association with higher levels of anti-RBD antibody was HLA-DQB1*06 (P=3.2 x 10-9), which we replicate in 1,677 additional vaccinees. Individuals carrying HLA-DQB1*06 alleles were less likely to experience PCR-confirmed breakthrough infection during the Wuhan and Alpha-variant waves compared to non-carriers (HR 0.63, 0.42-0.93, P=0.02). We identify a distinct S-derived peptide that is predicted to bind effectively to HLA-DQB1*06 compared to other equivalent alleles, and find evidence of increased spike-specific memory B-cell responses in HLA-DQB1*06 carriers at 84 days post first vaccination. Our results demonstrate association of HLA type with COVID-19 vaccine antibody response and risk of breakthrough infection, with implications for future vaccine design and implementation.

  Study EGAS00001006909

• Repression of CADM1 transcription by HPV type 18 is mediated by three-dimensional rearrangement of promoter-enhancer interactions

  Repression of CADM1 transcription by HPV type 18 is mediated by three-dimensional rearrangement of promoter-enhancer interactions

  Study EGAS50000000773

• Small-molecule inhibitors in melanoma - Kenski / Kong - WES (2019-04-11)

  Small-molecule inhibitors targeting the most commonly activated pathway in melanoma, MAPK pathway (either alone or in combination) are already given to melanoma patients for few years, and initially reduce tumour burden dramatically, eventually melanomas become resistant and tumours progress while on treatment. Resistance to this treatment occurs by acquisition of additional mutations or other alterations that affect the mitogen-activated protein kinase (MAPK) pathway by either direct or indirect signalling. Many resistance mechanisms somehow lead to reactivation of extracellular signal-regulated kinase (ERK), thereby restoring signalling of the oncogenic BRAF/MEK/ERK pathway. In addition, PI3K pathway activation contributes to resistance to BRAF inhibition. Less frequent but equally important to the phenomenon of targeted drug resistance is the observation that B15-20% of BRAF mutant melanoma patients fail to respond to BRAF inhibition already early on treatment, owing to intrinsic resistance. These patients have little therapeutic options, unless immunotherapy can be given. To better understand the resistance mechanisms in MAPK inhibitor-treated melanoma patients and melanoma biology, our lab generated a big panel of MAPK inhibitor resistant melanoma cell lines by continuous drug exposure. The understanding of the genetic landscape and gene expression as well as cross resistance to other treatment regimens, and other aspects of melanoma biology such as phenotype switch, will allow us to better exploit new therapeutic strategies for melanoma patients. . This dataset contains all the data available for this study on 2019-04-11.

  Dataset EGAD00001004952