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• CPTAC: Proteogenomic Studies of Ovarian Tumor Responses to Agents Targeting the DNA Damage Response

  There is a critical unmet need for predictors of chemo-refractory High-grade serous ovarian cancer (HGSOC). Despite over 3 decades of research on platinum responses in cancer, no predictive biomarker has been translated into clinical use. Predictors of refractory disease could spare these patients the unnecessary toxicity of a platinum-based regimen and provide a means to triage these patients to clinical trials to identify effective therapies for refractory disease. This study has approached the development of a predictor in a novel way enabling detection of a multi-analyte panel biomarker capable of detecting a subset of refractory HGSOCs with high specificity and implicating potential treatment vulnerabilities for refractory disease. We reported the first proteogenomic analysis of platinum refractoriness in HGSOC and made the novel dataset available as a resource to the community, including a ProTrack portal: http://ptrc.cptac-data-view.org/. Detailed proteogenomic profiles were generated for this study from a retrospective cohort of 242 treatment-naive HGSOCs with enriched representation of "exceptional non-responders" (i.e., patients with chemo-refractory disease). Whole genome sequence (WGS) and RNA seq FASTQ files are available through dbGaP. Proteomic data are available through the NCI Proteomic Data Commons (PDC): https://pdc.cancer.gov/pdc/.

  Study phs003152

• IMPRESS: Improved methylation profiling using restriction enzymes and smMIP sequencing, combined with a new biomarker panel, creating a multi-cancer detection assay

  Background Despite the worldwide progress in cancer diagnostics, more sensitive diagnostic biomarkers are needed. The methylome has been extensively investigated in the last decades, but a low-cost, bisulfite-free detection method for multiplex analysis is still lacking. Methods We developed a methylation detection technique called IMPRESS, which combines methylation-sensitive restriction enzymes and single-molecule Molecular Inversion Probes. We used this technique for the development of a multi-cancer detection assay for eight of the most lethal cancer types worldwide. We selected 1791 CpG sites that can distinguish tumor from normal tissue based on DNA methylation. These sites were analysed with IMPRESS in 35 blood, 111 tumor and 114 normal samples. Finally, a classifier model was built. Results We present the successful development of IMPRESS and validated it with ddPCR. The final classifier model discriminating tumor from normal samples was built with 358 CpG target sites and reached a sensitivity of 0.95 and a specificity of 0.91. Moreover, we provide data that highlight IMPRESS’s potential for liquid biopsies. Conclusions We successfully created an innovative DNA methylation detection technique. By combining this method with a new multi-cancer biomarker panel, we developed a sensitive and specific multi-cancer assay, with potential use in liquid biopsies.

  Study EGAS50000000624

• Benchmarking for alignment and variant calling

  Background: Lung cancer is a heterogeneous disease and the primary cause of cancer-related mortality worldwide. Somatic mutations, including large structural variants, are important biomarkers in lung cancer for selecting targeted therapy. Genomic studies in lung cancer have been conducted using short-read sequencing. Emerging long-read sequencing technologies are a promising alternative to study somatic structural variants, however there is no current consensus on how to process data and call somatic events. In this study, we preformed whole genome sequencing of lung cancer and matched non-tumour samples using long and short read sequencing to comprehensively benchmark three sequence aligners and six structural variant callers comprised of four generic callers (Sniffles2, cuteSV, SVIM and DELLY in generic mode) and two somatic callers (nanomonsv and DELLY in somatic modes). Results: Different combinations of aligners and variant callers influenced somatic structural variant detection. The choice of caller had a significant influence on somatic structural variant detection in terms of variant type, size, sensitivity, and accuracy. The performance of each variant caller was assessed by comparing to somatic structural variants identified by short read sequencing. When compared to somatic structural variants detected with short read sequencing, more events were detected with long read sequencing. The mean recall of somatic variant events identified by short read sequencing was higher for the somatic callers (64%) than generic callers (52%), with nanomonsv (69%) showing the best performance. Conclusion: Long read sequencing can identify somatic structural variants. The longer reads have the potential to improve our understanding of cancer development and inform personalized cancer treatment.

  Study EGAS00001007819

• CyTOF of 27 DLBCLs

  Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma and is notorious for its clinical heterogeneity. Patient outcomes can be predicted by cell-of-origin (COO) classification, demonstrating that the underlying transcriptional signature of malignant B-cells informs biological behavior in the context of standard combination chemotherapy regimens. In the current study, we used mass cytometry (CyTOF) to examine tumor phenotypes at the protein level with single cell resolution in a collection of 27 diagnostic DLBCL biopsy specimens from treatment naïve patients. We found that malignant B-cells from each patient occupied unique regions in 37-dimensional phenotypic space with no apparent clustering of samples into discrete subtypes. Interestingly, variable MHC class II expression was found to be the greatest contributor to phenotypic diversity. Within individual tumors, a subset of cases showed multiple phenotypic subpopulations, and in one case we were able to demonstrate direct correspondence between protein-level phenotypic subsets and DNA mutation-defined subclones. In summary, CyTOF analysis can resolve both inter- and intra-tumoral heterogeneity among primary samples, and reveals that each case of DLBCL is unique and may be comprised of multiple, genetically distinct subclones.

  Dataset EGAD00001005419

• ESGI - Molecular diagnosis for mitochondrial disorders (2017-08-29)

  The MITOEXME project aims to improve protocols for molecular diagnosis of patients with OXPHOS disorders with a focus on a next generation sequencing methods and to increase the knowledge of pahtophysiological mechanisms by identification of new targets and cellular studies. In this project we will sequence the exomes fo 120 patients. This dataset contains all the data available for this study on 2017-08-29.

  Dataset EGAD00001003596

• RNA-Seq of novel miR (nmiR-1 and nmiR-2) overexpression and knockdown in BL

  After overexpression and knockdown of both described novel miRs nmiR-1 and nmiR-2 in BL cell lines (SU-DHL4 for nmiR-1 and Raji for nmiR-2), we performed regular RNA-Seq (including Mock controls for all cell lines) to identify their direct and indirect downstream mRNA targets.

  Dataset EGAD00001001612

• RNA sequencing of high hyperdiploid and ETV6/RUNX1-positive pediatric acute lymphoblastic leukemia

  We performed RNA-sequencing of high hyperdiploid and ETV6/RUNX1-positive ALL cases by using the Human Ribo-Zero rRNA Removal Kit to investigate the gene expression in high hyperdiploid ALL.

  Study EGAS00001003079

• Single-nucleus brain transcriptomics reveals microglia dysfunction in Multiple System Atrophy

  Multiple System Atrophy (MSA) is a rare, age-related neurodegenerative disease that shares clinical and pathological features with Parkinson’s disease (PD) but presents a more devastating disease course. To elucidate the distinct cellular pathophysiology underlying multiple system atrophy (MSA) or Parkinson's disease (PD), we performed single-nucleus RNA sequencing on postmortem striatal brain tissue from 7 MSA and 12 PD patients, and 10 non-neurological cases. Using 10x Genomics Chromium Next GEM Single Cell 3' Reagent Kits v3.1, we isolated 130k nuclei covering all major cell types of the striatum. We performed state-of-the-art bioinformatic analyses on the data followed by orthogonal analyses to validate our findings. We identified a disease-specific activation of microglia cells distinguishing the two diseases and possibly explaining some of the detrimental effects observed in both.

  Study EGAS50000001406

• Deregulation of FOXF1/FENDRR from t(14;16)(q32;q24) defines a subtype of high risk lineage ambiguous leukemia

  Despite great progress in understanding the genomic basis of immature T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL) and acute leukemias of ambiguous lineage (ALAL), there are still cases that lack defining genetic markers, complicating risk stratification and limiting targeted therapeutic options. Here, we describe a subtype of leukemia defined by the t(14;16)(q32;q24) translocation, which places the FOXF1 gene and its antisense long noncoding RNA gene FENDRR under the regulatory control of the BCL11B enhancer, leading to their ectopic transcriptional activation. Analysis of different high-throughput sequencing data, including WGS, RNA-seq, scDNA-seq, scRNA-seq, ChIP-seq, ATAC-seq, and HiChIP-seq, identified BCL11B-enhancer mediated deregulation of FOXF1/FENDRR as a hallmark of a subtype of high-risk lineage ambiguous leukemia that is potentially amenable to targeted therapeutic intervention.

  Study EGAS50000001255

• CIRdb: Array genotype data

  The current inhabitants of the Canary Islands have a unique genetic makeup in the European diversity landscape due to the existence of African footprints from recent admixture events, especially of North African components (>20%). The underrepresentation of non-Europeans in genetic studies and the sizable North African ancestry, which is nearly absent from all existing catalogs of worldwide genetic diversity, justify the need to develop CIRdb, a population-specific reference catalog of natural genetic variation in the Canary Islanders. Based on array genotyping of the selected unrelated donors and comparisons against available datasets from European, sub-Saharan, and North African populations, we illustrate the intermediate genetic differentiation of Canary Islanders between Europeans and North Africans and the existence of within-population differences that are likely driven by genetic isolation. In addition, here we describe the overall design and the methods that are being implemented to develop CIRdb.

  Study EGAS00001006050

• Pangenomic classification of pituitary adenomas

  Pituitary neuroendocrine tumors (PitNETs) are common. They are classified in five main histological types: PitNETs of POU1F1 (Pit1) lineage -lactotroph, somatotroph and thyrotroph -, gonadotroph, and corticotroph PitNETs. Pituitary tumorigenesis is poorly understood. We report here a pangenomic characterization of 134 PitNETs from all types, based on exome, genome, transcriptome, miRnome and methylome. Pit1 lineage was associated with a specific epigenetic signature of diffuse DNA hypomethylation, and correlated with expression of Pit1 markers and chromosomal instability. 45% of somatotroph PitNETs showed GNAS mutations. GNAS-wild type somatotroph showed a distinct transcriptome profile, expressing gonadotroph transcription factor NR5A1 (SF1). Sparsely granulated somatotroph PitNETs was classified apart from somatotroph, owing to a thyrotroph transcriptome signature. 43% of corticotroph PitNETs showed USP8 mutations, sharing a low epithelial-mesenchimal transition (EMT) transcriptome signature. Silent corticotroph PitNETs showed a gonadotroph transcriptome signature evoking transdifferentiation, and lost somatostatin target SSTR5 expression.

  Study EGAS00001003642

• Whole exome sequencing reveals the mutational spectrum of testicular germ cell tumours

  Testicular germ cell tumours (TGCTs) are the most common cancer in young men. Here we perform whole exome sequencing of 42 TGCTs to comprehensively study the mutational profile of TGCT. The mutation rate is uniformly low in all of the tumours (mean 0.5 mutations per megabase [Mb]) as compared to the common cancers, consistent with the embryological origin of TGCT. In addition to expected copy number gain of chromosome 12p and mutation of KIT we identify recurrent mutations in the tumour suppressor gene CDC27 (11.9%). Copy number analysis reveals recurring amplification of the spermatocyte development gene FSIP2 (15.3%) and a 0.4Mb region at Xq28 (15.3%). Two treatment-refractory patients are shown to harbour XRCC2 mutations, a gene strongly implicated in defining cisplatin resistance. Our findings provide further insights into genes involved in the development and progression of TGCT.

  Study EGAS00001001084

• Genotype data of human CD4 Treg cell

  Genotype data obtained using the coreExome Illumina SNP chip array for all the individuals included in the study of gene expression regulation in human primary regulatory CD4+ T cells (Tregs)

  Dataset EGAD00010001848

• Low input LC (WGS) (2019-04-01)

  R&D project to develop low input library construction methods. . This dataset contains all the data available for this study on 2019-04-01.

  Dataset EGAD00001004878

• RNA-seq

  This dataset contains the raw sequencing data (Runs) for all 10x Genomics single-cell RNA-seq Experiments.

  Dataset EGAD00001009823

• RNAseq - Colorectal organoids and tumoroids (2015-08-05)

  Transcriptome sequencing of tumour tissue, adjacent normal tissue and derived organoids/tumoroids from colorectal cancer. This dataset contains all the data available for this study on 2015-08-05.

  Dataset EGAD00001001459

• Pilot Fetal Cell Atlas_RNAseq (2018-08-20)

  As part of the Human Cell Atlas we will study fetal tissue. . This dataset contains all the data available for this study on 2018-08-20.

  Dataset EGAD00001004305

• Dataset for WES PCNSL

  WES sequencing of 23 samples from PCNSL tumor and blood control samples. Sequencing was performed on a NovaSeq 6000 and NextSeq 500 using Agilent SureSelectXT HS Human All Exon V7 and V8. Sequencing was always paired.

  Dataset EGAD00001010847

• The Role of E2F4 in Controlling Resistance to Irinotecan (CPT-11) in Human Colon Cancer

  This study reports the results of RNA sequencing (RNA-seq) experiments performed on three isogenic clones of the human HT29 colon cancer cell line, genetically engineered to achieve the selective inactivation of the adenovirus early 2 (E2) gene transcription factor 4 (E2F4) protein, a key functional component of the multimeric transcriptional repression complex known as the dimerization partner (DP), retinoblastoma-like (RB-like), E2F and multi-vulva class B (MuvB) complex (DREAM). In previous studies, we identified E2F4 as a key regulator of colorectal cancer (CRC) resistance to irinotecan (CPT-11), a cytotoxic agent that stands at the backbone of multiple chemotherapy regimens for the treatment of metastatic CRCs. The molecular mechanisms linking E2F4 to irinotecan resistance, however, remain poorly understood. The present study was designed to identify which genes are under the transcriptional control of E2F4, either at baseline or following exposure to SN38 (i.e., the active metabolite of irinotecan, generated in vivo by biotransformation in the liver) in order to clarify the role played by E2F4 in shaping colon cancer resistance to chemotherapy. The cell line used for this study (HT29) is aneuploid and contains three copies of the E2F4 gene, because of a trisomy of chromosome 16, where the E2F4 gene is located (Kawai et al., Genes, Chromosomes & Cancer, 34:1-8, 2002; PMID: 11921276). HT29 cells were infected with lentivirus vectors encoding for CRISPR/Cas9 constructs designed to selectively inactivate the E2F4 gene, using three distinct guide-RNAs (gRNAs), each targeting a different sequence within the proximal exons of the E2F4 gene (exon 1, exon 2). Lentivirus-infected cells were sub-cloned by single-cell fluorescence-activated cell sorting (FACS), based on the differential expression of a fluorescent reporter (EGFP) expressed in tandem with the gRNAs. Isogenic clones (EGFP+) were then screened to identify those with a tri-allelic knock-out, as revealed by both genetic sequencing of the E2F4 gene (revealing the presence of three distinct frameshift mutations) and Western blot (revealing complete loss of E2F4 protein expression). The study includes twelve (n=12) RNA-seq experiments, representative of 3 experimental replicates (i.e., three distinct isogenic clones of the HT29 cell line, each displaying complete loss of E2F4 expression) and 3 negative controls (i.e., three independent preparations of the parent HT29 cell line, infected with a lentivirus vector encoding for a non-targeting gRNA) exposed to 2 distinct in vitro cell culture conditions: a) treatment with SN38 resuspended in dimethyl sulfoxide (DMSO); or b) treatment with DMSO alone (negative control). The in vitro treatment regimen used for SN38 (32 nM, 24 hours) was designed so that the exposure to SN38 experienced in vitro by HT29 cells would mirror the exposure to SN38 experienced in vivo by malignant tissues, as measured, for example, in metastatic CRC patients receiving a standard dose of irinotecan (180 mg/m2) administered by intravenous infusion over 90 minutes (Deyme et al., Cancer Chemotherapy and Pharmacology, 88:247-258, 2021; PMID: 33912999).

  Study phs003560

• Single cell transcriptomic landscape of pediatric B-cell acute lymphoblastic leukemia: dissection of transcriptional heterogeneity and B-cell developmental state

  Introduction: Genomic analyses of bulk ALL samples have improved our understanding of the genetic basis and risk stratification of B-ALL, but do not directly examine intratumor heterogeneity or enable inference of leukemia developmental state and cell of origin. Methods: We profiled 89 B-ALL samples by single-cell RNA-seq (scRNA-seq) (10X Genomics 5’v2) and compared them to a scRNA-seq reference map of normal human B-cell development. Results: Analysis of heterogeneity of inferred DNA copy number alterations at single cell level showed that aneuploid ALL with near haploidy and hyperdiploid harbor chromosomal losses or gains in all blasts, consistent with early, synchronous origin rather than sequential accumulation. Intra-sample heterogeneity was driven by five gene expression signatures: cell cycle, metabolism, differentiation, inflammation, refining leukemic subtyping. An atlas of B cell development was established to map B-ALL samples to specific developmental states. Hyperdiploid samples resembled pro-B cells, while MEF2D-r and TCF3::PBX1 showed high pre-B abundance. Patients with high early lymphoid abundance had poorer outcomes. Conclusions: Understanding variation in transcriptional programs and developmental states of B-ALL blasts by sc transcriptome refines existing clinical and genomic classifications and provides novel prognostic markers.

  Study EGAS00001007512

• Neuroblastoma relapse trio series from the AMC

  The majority of neuroblastoma patients have tumors that initially respond to chemotherapy, but a large proportion of patients will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole genome sequencing of 23 paired diagnostic and relapsed neuroblastomas showed clonal evolution from the diagnostic tumor with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed RAS-MAPK pathway mutations. Seven events were detected only in the relapse tumor while the others showed clonal enrichment. In neuroblastoma cell lines we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18, 61%) and these lesions predicted for sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastoma and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.

  Dataset EGAD00001001360

• Transdisciplinary Studies of Genetic Variation in Colorectal Cancer(CORECT): Axiom GWAS

  This study is part 1 of 2 for Schumacher et al, Nat Commun. 2015 Jul 7;6:7138. Part 1 is the original GWAS data for 9,259 participants on the Affymetrix Axiom platform of the studies listed below in the Inclusion Criteria.

  Study phs001856

• National Cancer Institute (NCI) Biospecimen Pre-analytical Variables (BPV) Analysis

  The Biospecimen Pre-analytical Variables (BPV) Program is a National Cancer Institute-sponsored study to systematically assess the effects of pre-analytical factors on the molecular profile of biospecimens. A robust biospecimen collection infrastructure was established to prospectively collect biospecimens using rigorous standard operating procedures to control for most variables while introducing experimental conditions to study specific biospecimen handling issues, including the cold ischemic time (delay to formalin fixation), time in formalin, freezing methods, and storage temperatures and durations. RNA and DNA from biospecimens collected under these conditions was analyzed on multiple molecular platforms. The potential effects of these pre-analytical conditions on protein integrity and detection of metabolites were also examined. Data from this study will be used to develop evidence-based biospecimen standard operating procedures and best practices for fit-for-purpose collection, processing, and storage of biospecimens. The BPV Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following sub-studies below or in the "Substudies" box located on the right hand side of this top-level study page phs001304 BPV Cohort. The substudy links will be active once they are released by dbGaP. Preanalytical Impacts on Global Metabolite Profiling - plasma (MassSpec by Metabolon) This study was to evaluate the impact of the storage temperature (s) (-80°C and LN2 vapor) and the length of storage on human plasma quality using LC-MS/MS (liquid-chromatography-mass spectrometry/mass spectrometry) based global metabolite profiling. The study includes 240 plasma samples collected from 40 donors. Investigate the effect of the delay to fixation on the proteome and phosphoproteome -FFPE (MassSpec by Caprion). The study is to do proteome and phosphoproteome analysis on Delay to fixation was carried out using FFPE tumor samples from colon and ovarian cancer patients comparing 2, 3, and 12hr delay to fixation to the 1hr time point. The study includes 100 samples 20 donors. Investigate the effect of storage conditions of tumor specimens on the proteome and phosphoproteome profiling- Frozen tissue and plasma (MassSpec by Caprion). The study was to evaluate the effects of storage conditions on tumor specimens. Plasma samples from 40 cancer patients stored at two different temperatures (-80°C and LN2) for a given period (0-2, 6-8, and 12-14 months) were evaluated. Frozen kidney tumor samples from 20 patients were compared for effects of different snap frozen (dry ice vs. LN2) and storage temperatures (-80°C and LN2). The study includes 100 tissue and 240 plasma samples from 60 donors. Preanalytical Impacts on Genomic Sequencing by Next Generation Sequencing (NGS) technology (mRNA/miRNA and WES by Expression Analysis). The goal of the study is to determine the effects of cold ischemic delay-to-fixation (4 time points) and formalin preservation (FFPE) on the nature and quality of genomic profiles using the matched freshly frozen sample as the gold standard, which including WES, RNAseq. The study includes 395 samples from 37 donors. Preanalytical Impacts on Copy Number Variation (CNV) Detection by aCGH technology (aCGH by Georgetown University). This study was to use aCGH to evaluate the effect of variation in cold ischemia time and time in formalin fixation on CNV in DNA extracted from kidney cancer specimens. The study includes 235 samples from 40 donors. Evaluation of frozen conditions on mRNA profiling by TaqMan assay (mRNA expression by Georgetown University). This study was to utilize gene expression profiling, using custom TaqMan arrays, to compare the molecular profiles of RNA from frozen tumor samples collected using two freezing methods (dry ice or LN2), two storage temperatures (-80°C or LN2 vapor), as well as Optimal Cutting Temperature (OCT) compound and non-OCT embedded. The study includes 100 samples from 20 donors. mRNA signature for stratification by cold ischemia time (mRNA expression by IBBL). The study was to determine the effects of cold ischemic time (delay-to-fixation) and formalin preservation (FFPE) on mRNA detection by Taqman assay using tumor tissue specimens from kidney, colon and ovarian cancer patients. There are160 samples from 40 donors. The Biospecimen PV cohort is utilized in the following dbGaP individual studies. To view molecular data, and derived variables collected in these individual studies, please click on the following individual studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs001304 Biospecimen PV cohort. phs001634 CIT mRNA phs001635 CNV aCGH phs001636 Fixation Delay phs001637 Global Metabolite Profiling phs001638 mRNA TaqMan phs001639 NGS phs001640 Tumor Storage

  Study phs001304

• Acute Respiratory Distress Network (ARDSNet) Studies 10 and 12 Statins for Acutely Injured Lungs from Sepsis (SAILS) (ARDSNet-SAILS-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. Biospecimens Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-SAILS include Plasma, DNA, and Urine. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives The SAILS trial was intended to assess the efficacy and safety of oral rosuvastatin in participants with sepsis-induced Acute Lung Injury (ALI) and test the hypothesis that rosuvastatin therapy would improve the clinical outcomes of critically ill participants with sepsis-associated acute respiratory distress syndrome (ARDS). Background In ARDS, inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in participants with sepsis. Participants There were 745 participants. Design Participants were randomly assigned in permuted blocks to receive either enteral rosuvastatin or placebo. A 40 mg loading dose of the study drug was administered within four hours after randomization. Subsequently, maintenance doses of 20 mg were administered daily until the third day after discharge from the intensive care unit, study day 28, hospital discharge, or death, whichever came first. The primary outcome measure was mortality before hospital discharge home or until study day 60 if the participant was still in a health care facility. Secondary outcome measures included the number of ventilator-free days to day 28, organ-failure-free days to day 14, and ICU-free days to day 28. Conclusions The study was stopped because of futility after 745 of an estimated 1000 participants had been enrolled. There was no significant difference between study groups in 60 day in-hospital mortality or in mean ventilator-free days. The rosuvastatin group had fewer days free of hepatic or renal failure. Thus, rosuvastatin therapy did not improve clinical outcomes in participants with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction.

  Study phs003736

• Acral Melanoma PDXs from the admixed Brazilian Population - Patient Derived Xenograft samples VCF files with somatic SNV and INDELs - Whole exome sequencing data

  Raw, flagged and annotated VCF files with somatic calls made with CavEMan and Pindel for Patient Derived Xenograft samples. Variant effect prediction was run with Ensembl VEP v103. Acral melanoma (AM) is an aggressive melanoma subtype with limited therapeutic options and poor outcomes. In non-European descent and admixed populations, like in Latin America, it can account for a significant proportion of cutaneous melanoma cases. Here, we performed comprehensive genomic and functional profiling of AM from a uniquely diverse Brazilian cohort. Whole-exome and transcriptome sequencing was performed on both tumours and patient-derived xenograft (PDX) samples. The PDX were obtained from a comprehensive collection of patient-derived xenograft (AM-PDX) models that we established which faithfully retained the histopathological and genomic features of the original tumours.

  Dataset EGAD00001015749

• single nuclei multiomics (ATAC-RNA) of KOLF2.1J human induced pluripotent stem cells-derived differentiated dopaminergic neurons

  We processed nuclei from hIPSCs differentiated optimized protocols for generating dopaminergic neurons. Cells differentiated with a first iteration were RNA and ATAC-sequenced, to understand our protocol caveats to address for optimization. Cells differentiated with a second protocol and in vivo were RNA-sequenced to validate the identities of our cells.

  Study EGAS50000001418

• Age related Macular Degeneration (AMD) - Michigan, Mayo, AREDS, Pennsylvania (MMAP) Cohort Study: Association and Sequencing Studies

  Age-related Macular Degeneration (AMD) is a leading cause of incurable blindness in people over the age of 65. AMD is a late-onset multi-factorial neurodegenerative disease and its pathogenesis involves interaction of genetic and environmental factors. Several chromosomal regions have been associated with AMD susceptibility through linkage analysis (Swaroop et al., 2009). More recent studies provide strong evidence that variants within the CFH gene cluster on chromosome 1 and at/near LOC387715/ARMS2 on chromosome 10 are strongly associated with the disease. Variants at other genes including C2/BF, C3, CFI and APOE4, also contribute to AMD susceptibility. Our primary goals are to identify genetic variants and haplotypes that are associated with AMD. The underlying hypothesis is that DNA variation(s) in multiple genetic susceptibility loci will predispose individuals to AMD pathogenesis, and comparison of DNA of cases and controls should identify these susceptibility variants. Our studies are focused on the genetic analysis of advanced AMD and should provide novel insights into disease diagnosis, progression and pathology. We have assembled a collaborative group of researchers from the University of Michigan, Mayo Clinic, University of Pennsylvania, and the AREDS group including National Eye Institute intramural investigators, who collected clinical data and DNA from a large number of patients affected with AMD and from unaffected controls. The primary source of funding was National Eye Institute. Study 1: To identify genetic variants and haplotypes that are associated with AMD, we submitted and obtained usable genotyping data on 2185 patients and 1155 controls from the Center for Inherited Disease Research (CIDR). Study 2: To identify rare coding variants associated with a large increase in risk of AMD, 10 candidate loci spanning 57 genes were sequenced in 2,335 cases and 789 controls. Probes were designed to capture 96.5% of the coding sequence and 35% of total locus sequence, generating an average 123Mb of on-target sequence per individual at 127x average depth. Substudies: phs000182 AMD-MMAP Cohort Study: A Joint Genome-Wide Asscociation Study phs000246 Fuchs' Corneal Dystrophy GWAS phs000457 MMAP Methylation in AMD phs000685 Age-Related Macular Degeneration Targeted Sequencing Study

  Study phs000684

• Genome-wide Association Study of Myasthenia Gravis

  The purpose of this project was to conduct a genome-wide associate study to search for the genetic factors that predispose to myasthenia gravis. The rationale for this study lies in the fact that, although the immunological and physiological processes affecting the neuromuscular junctions of myasthenia gravis patients are well understood, the spectrum of genetic factors that predispose to myasthenia gravis and influence its disease manifestations are not well known. Identification of the myasthenia gravis-related genes will shed light on the fundamental cellular events underlying myasthenia gravis, and will provide focus for research aimed at developing therapies that alter the natural course of the disease. A consortium of fourteen institutions in North America collected DNA samples from 1028 people diagnosed with autoimmune myasthenia gravis. Relevant clinical data have been collected for each patient, including age of onset, severity of disease, response to drug therapy, personal and family history of other autoimmune diseases. Genotyping of the case cohort was performed in the Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD. Genotyping of the case cohort was performed using the HumanOmniExpress-12v1_C SNP array manufactured by Illumina Inc. For the control cohort, we downloaded genotype data from dbGAP (accession phs000196.v2.p1) for 1,998 US neurologically normal individuals. The control cohort had been previously genotyped at the Center for Inherited Disease Research at Johns Hopkins University on HumanOmni1-Quad version 1.0B beadchips (Illumina) as part of the NeuroGenetics Research Consortium GWAS of Parkinson's disease. Analyses were confined to the 677,673 autosomal SNPs that were common to both chips. Of the 1028 samples which were genotyped, 21 samples were excluded due to mismatched genders, 9 were excluded due to low genotype call rate, 5 samples were excluded as duplicates, and 25 samples were excluded as ethnic outliers. The remaining 972 samples were used in analysis.

  Study phs000726

• Whole genome sequencing of adult glioblastoma nuclei

  Three primary adult glioblastoma specimens were dissociated and nuclei were extracted. A portion of the nuclei was used for single-cell ATAC seq and the remainder were submitted for whole genome sequencing, to provide orthogonal validation of copy number variations in the samples compared to single-cell ATAC seq. Samples were sequenced on the Illumina NovaSeq 6000 in paired-end mode.

  Dataset EGAD00001007651

• Genetic profiling of mucosal melanoma

  Primary mucosal melanomas (MMs) arise from melanocytes located in mucosal membranes lining the respiratory, gastrointestinal and urogenital tracts. MMs frequently present late and have a poor prognosis; the 5-year survival rate is only 14%. MM makes up only ~1.4% of all melanomas and it is this rarity that makes knowledge of the genetic changes that contribute to its pathogenesis limited to a small number of exome/genome studies and other targeted studies. Thus to investigate the somatic alterations and mutation spectra in MM genomes, we have extracted genomic DNA from formalin-fixed, paraffin-embedded (FFPE) human MMs, and subjected them to whole exome sequencing. Given the propensity of MM to metastasize, we will also be sequencing metastatic MM lesions; primary and metastatic lesions from the same individual represent an excellent opportunity to identify potential drivers of metastasis in MM. Finally we will sequence 'normal' DNA from the same individual, where possible, to exclude germline variations.

  Dataset EGAD00001003237

• Nasal epithelial cells of PCD and non-PCD patients grown at air-liquid interface for RNAseq analysis

  Raw RNAseq data files of genetically unsolved PCD patients used for transcriptomic analysis aming to uplift the diagnostic rate. The non-PCD patients were used as a clinical comparator to the PCD patients. Majority of the nasal epithelial cells used for RNAseq were cultured at an air-liquid interface for 21 days, unless the data file name indicates a different air-liquid-culture time-point.

  Study EGAS00001006632

• Matching of actionable mutations with therapies in cancer patients: comparison of three commercial decision support platforms

  Purpose: In oncology, precision medicine centers on tailoring the most appropriate therapy to a patient according to their tumor molecular profile. We addressed the question whether there is a consensus in the classification of actionability of somatic variants and their alignment to treatment recommendations. To this end, we evaluated three commercial clinical decision support tools to assess their variant classification and drug matching strategies.Methods: In this two centers study 48 patients with metastatic breast (n=12), colorectal (n=17) or non-small cell lung cancer (n=19) were recruited based on circulating tumor DNA levels in peripheral blood. In individual patients’ plasma samples, we established somatic copy number alterations and somatic mutations across a 77 cancer-associated gene panel and exposed the obtained molecular profiles to the decision support packages NAVIFY Mutation Profiler (NMP; Roche), Qiagen Clinical Insight (QCI) Interpret (Qiagen) and CureMatch Bionov (CureMatch).Results: In the plasma samples, altogether 492 somatic alterations were assessed. Each decision support platform varied in their format of data input, mode of variant classification and strategies for identifying druggable targets and clinical trials, which resulted in discrepancies in tier classification as well as designations of actionability. The frequency of concordant actionable events for tier I-A or tier I-B classifications, i.e. those with the strongest clinical evidence, was only 4.3%, 9.5% and 28.4% when comparing NMP with QCI, NMP with CureMatch, and CureMatch with QCI, respectively. As a consequence, the obtained treatment recommendations differed drastically, and alignment of treatment recommendations was limited to established predictive markers.Conclusions: The lack of standards for the extraction of treatment recommendations from comprehensive tumor molecular profiling data challenge the promising concepts of precision oncology.

  Study EGAS00001004383

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

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

  Study phs002205

• Studying Glioblastoma in a Human Organoid Tumor Transplantation Model

  This study comprises two complementary investigations that leverage innovative human model systems and cutting-edge molecular profiling to dissect glioblastoma (GBM) heterogeneity and tumor-microenvironment interactions. The first study uses a novel Human Organoid Tumor Transplantation (HOTT) model, in which freshly dissociated GBM tumor cells from five patients were transplanted into human embryonic stem cell-derived cortical organoids. This system enables the interrogation of tumor and microenvironment interactions in a human-specific, developmentally relevant context. Using single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA-seq (snRNA-seq), the authors profiled over 216,000 cells, analyzing tumor heterogeneity across multiple media conditions. Ligand-receptor analysis (CellChat), immunofluorescence, and RNAScope were used to validate findings. The study revealed that the HOTT model faithfully recapitulates primary GBM cell types and microenvironmental components, and uncovered a novel bidirectional signaling axis mediated by PTPRZ1 that influences both tumor migration and cell fate in a context-dependent manner. PTPRZ1 is identified to be important for intercellular communication between tumor and microenvironmental cells, while PDGFRB, NOTCH3, HOPX, FAM107A, CLDN5, RGS5, FOXC1, SOX18 are key markers of the neurovascular progenitor that we identify to be a multipotent, restricted progenitor in GBM. Related datasets include the inclusion of immune cells in the HOTT system, termed “iHOTT”. The second study focuses on identifying and characterizing a rare but functionally potent neurovascular progenitor (NVP) population within GBM tumors. By generating a meta-atlas from seven publicly available GBM scRNA-seq datasets, the authors identified a unique tumor-derived cell population co-expressing neural progenitor and vascular markers. This population was validated in situ and in vivo through immunostaining and lineage tracing via DNA barcoding in the HOTT system. Functional knockdown of NVPs in a murine GBM model resulted in reduced cycling cells, altered tumor composition, and increased survival. Clonal analysis showed NVPs have dual potency to give rise to both neuronal and vascular-like tumor cells, contributing significantly to tumor cell diversity. Molecular technologies used across the studies include: Single-cell and single-nucleus RNA sequencing DNA barcoding and clonal lineage tracing (CellTag) Population information: Tumor samples were obtained directly from multiple GBM patients (all IDH1 wild-type, adult), including core and peripheral tumor regions. Human cortical organoids derived from human embryonic stem cells (hESCs) served as the microenvironment in the HOTT model. Principal findings include: HOTT recapitulates the heterogeneity and cell type fidelity of GBM, while enabling the study of tumor–microenvironment signaling. PTPRZ1 has opposing roles in tumor and microenvironment, influencing GBM cell migration and fate via non-catalytic mechanisms. A novel GBM neurovascular progenitor population (NVP) was identified, validated, and shown to contribute clonally to distinct tumor cell types. Elimination of NVPs in vivo reduces tumor aggressiveness and improves survival. Data to be available through dbGaP: Raw and processed single-cell and single-nucleus RNA-seq data (HOTT model and NVP studies) CellTag barcode-labeled scRNA-seq clonal lineage data Associated metadata including patient of origin, experimental condition, and sample annotations.

  Study phs003936

• Identifying causative mutations for Thrombocytopenia with Absent Radii

  Thrombocytopenia with Absent Radii is an inherited disorder that manifests itself with major limb skeletal abnormalities and low platelet count (and therefore a bleeding diathesis). The syndrome is well-characterised and defined phenotypically and there is a well-established database of UK-based families affected with ths disorder. The causative mutation for the disorder is yet to be identified. If known, it would allow for pre-natal screening and counselling avoiding life-long care for patients who are affected and are therefore severely disabled. We postulate that exon sequencing of 4 unrelated affected individuals would give enough power to narrow down potential candidate mutations which would thereafter be confirmed using DNA from other affected families.

  Study EGAS00001000054

• Human tumor ChIP-seq.

  We profiled 15 patient brain tumor samples by ChIP-seq. Inputs are provided for 16 samples, H3K27ac is provided for 15 samples, H3K27me3 is provided for 10 samples and H3K27me3 is provided for 5 samples. The raw bam files are provided.

  Dataset EGAD00001008350

• Deep amplicon sequencing to infer malignant clonal populations for The interface of malignant and immunologic clonal dynamics in high-grade serous ovarian cancer

  A total of 192 positions per patient were deeply sequenced in each corresponding tumor sample (including 4 experimental controls and SNVs predicted to originate at each node of the sample phylogeny, see Zhang et al. for details). Genomic DNA templates were used as starting material to generate PCR products. PCR was set up using Phusion DNA polymerase according to the manufacturer’s specifications. The standard PCR conditions used were an initial denaturation at 98C for 30 seconds, followed by 35 cycles of 98C for 10 seconds, 60C for 15 seconds and 72C for 8 seconds, and a final extension at 72C for 10 minutes. PCR products were cleaned up using PCRClean DX beads. Amplicons were pooled by template for sequencing sample preparation. Sample preparation involved a second round of amplification using Phusion DNA polymerase with 6 PCR cycles, with primers specified in Zhang et al. DNA quality was assessed using the Caliper LabChip GX HighSensitivity Assay and DNA quantity was measured using a Qubit dsDNA HS assay kit on a Qubit fluorometer. The indexed libraries were pooled together and sequenced on the Illumina NextSeq500 platform with paired-end 150bp reads using v2 chemistry reagents.

  Dataset EGAD00001003986

• Short-term fasting before living kidney donation has an immune-modulatory effect

  Background: Short-Term Fasting (STF) is an intervention reducing the intake of calories, without causing undernutrition or micronutrient-related malnutrition. It aims to systemically improve resilience against acute stress. Several (pre-)clinical studies have suggested protective effects of STF, marking the systemic effects STF can induce in respect to surgery and ischemia-reperfusion injury. In addition, STF also affects the number of circulating immune cells. We aim to determine the effect of STF on the abundance and phenotype of different immune cell populations. Methods: Thirty participants were randomly selected from the FAST clinical trial, including living kidneys donors, randomised to a STF-diet or control arm. In an observational cohort sub-study we prospectively included 30 patients who donated blood samples repeatedly during study runtime. Using flow cytometry analyses, immune cell phenotyping was performed on peripheral blood mononuclear cells. Three panels were designed to investigate the presence and activation status of peripheral T cells, B cells, dendritic cells (DCs) and myeloid cells. Results: Eight participants were excluded due to sample constraints. Baseline characteristics showed no significant differences, except for fasting duration. Weight changes were minimal and non-significant across different time intervals, with slight trends towards long-term weight loss pre-surgery. Glucose, insulin, and β-hydroxybutyrate levels differed significantly between groups, reflecting adherence to the fasting diet. Flow cytometry analysis revealed no baseline differences between groups, with high variability within each group. We observed significant changes in immune cell populations due to fasting, particularly in B cells, T cells, and DCs. Discussion: In this study, we found that STF changes the levels and phenotype of immune cells, reducing abundance and activation of T cells and regulatory T cells, increased presence of (naïve) B cells, and elevation of type 1 conventional DCs. Further research should focus on the clinical implications of the changes in immune cell populations and significance of these observed immunological changes. Background: Short-Term Fasting (STF) is an intervention reducing the intake of calories, without causing undernutrition or micronutrient-related malnutrition. It aims to systemically improve resilience against acute stress. Several (pre-)clinical studies have suggested protective effects of STF, marking the systemic effects STF can induce in respect to surgery and ischemia-reperfusion injury. In addition, STF also affects the number of circulating immune cells. We aim to determine the effect of STF on the abundance and phenotype of different immune cell populations. Methods: Thirty participants were randomly selected from the FAST clinical trial, including living kidneys donors, randomised to a STF-diet or control arm. In an observational cohort sub-study we prospectively included 30 patients who donated blood samples repeatedly during study runtime. Using flow cytometry analyses, immune cell phenotyping was performed on peripheral blood mononuclear cells. Three panels were designed to investigate the presence and activation status of peripheral T cells, B cells, dendritic cells (DCs) and myeloid cells. Results: Eight participants were excluded due to sample constraints. Baseline characteristics showed no significant differences, except for fasting duration. Weight changes were minimal and non-significant across different time intervals, with slight trends towards long-term weight loss pre-surgery. Glucose, insulin, and β-hydroxybutyrate levels differed significantly between groups, reflecting adherence to the fasting diet. Flow cytometry analysis revealed no baseline differences between groups, with high variability within each group. We observed significant changes in immune cell populations due to fasting, particularly in B cells, T cells, and DCs. Discussion: In this study, we found that STF changes the levels and phenotype of immune cells, reducing abundance and activation of T cells and regulatory T cells, increased presence of (naïve) B cells, and elevation of type 1 conventional DCs. Further research should focus on the clinical implications of the changes in immune cell populations and significance of these observed immunological changes.

  Study EGAS00001008034

• Genomic landscape of oral cancers (Illumina RNA-Seq)

  Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCC) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCC, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. By contrast, in HPV-negative OSCC, T>C substitutions in the sequence context 5’-ATN-3’ correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCC. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1 and NFKBIA. Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon and nuclear factor-B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr. 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCC, in contrast to their gains in HPV-negative OSCC. High-ranking variant allele fractions implicated ZNF750, PIK3CA and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

  Study EGAS00001003237

• Genomic landscape of oral cancers (Complete Genomics WGS)

  Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCC) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCC, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. By contrast, in HPV-negative OSCC, T>C substitutions in the sequence context 5’-ATN-3’ correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCC. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1 and NFKBIA. Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon and nuclear factor-B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr. 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCC, in contrast to their gains in HPV-negative OSCC. High-ranking variant allele fractions implicated ZNF750, PIK3CA and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

  Study EGAS00001002393

• Genomic landscape of oral cancers (Illumina WGS)

  Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCC) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCC, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. By contrast, in HPV-negative OSCC, T>C substitutions in the sequence context 5’-ATN-3’ correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCC. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1 and NFKBIA. Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon and nuclear factor-B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr. 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCC, in contrast to their gains in HPV-negative OSCC. High-ranking variant allele fractions implicated ZNF750, PIK3CA and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

  Study EGAS00001003228

• UK10K_NEURO_MUIR

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.The sample selection consists of subjects with schizophrenia (SZ), autism, or other psychoses all with mental retardation (learning disability). The samples were initially collected under the leadership of Walter J Muir (deceased), now with Prof. Blackwood, Dr McKechanie and Prof McIntosh as custodians. These subjects represent the intersection of severe forms of neurodevelopmental disorders, appear to have a higher rate of familiality of SZ than typical, and are likely to have more serious and penetrant forms of mutations.For further information on this cohort please contact Andrew McIntosh (andrew.mcintosh@ed.ac.uk).

  Study EGAS00001000122

• A Somatic Reference Standard for Cancer Genome Sequencing

  In this study, we separately performed PCR-free whole genome sequencing on the paired tumor/normal melanoma COLO-829 and lymphoblastoid COLO-829BL cell lines across three separate institutions (TGen, Illumina, Genome Sciences Centre at the British Columbia Cancer Agency). We performed a meta-analysis of all data, in combination with the originally reported analysis of these cell lines by Pleasance et al., and report a somatic reference standard based on consensus events. This standard can be used as a reference for tumor/normal whole genome analyses.

  Study phs000932

• Y90 radioembolization followed by intravenous Nivolumab for advanced hepatocellular carcinoma

  To evaluate the efficacy of combination therapy with ICI and RT in patients, a Phase II trial (CA209-678) was conducted to investigate the efficacy and safety of Y90-RE followed by nivolumab in patients with advanced HCC (NCT03033446, n = 36). Interestingly, the ORR was found to be 30.6% in all patients and 43.5% when restricted to patients with only intrahepatic tumors, suggesting possible synergism between Y90-RE and ICI. Here we present whole exome sequencing (WES) and RNA-seq data for 33 patients treated with Y90 radioembolization followed with Nivolumab.

  Study EGAS00001006834

• Single-cell transcriptome analysis of B-cell development in the ABO platform

  The dataset includes samples from four individual donors, pooled at each cell-harvesting time point (days 21, 28, and 35). Single-cell RNA sequencing was performed on the 10x Genomics Chromium platform using GEM-X Single Cell 5′ v3 and GEM-X Single Cell V(D)J v3 for BCR profiling. For each timepoint, paired libraries were constructed: a 5′ GEX library and a V(D)J-B library. Per reaction 350,000-400,000 cells were loaded, aiming for 60,000 cells per reaction. Pooled libraries were sequenced on an Illumina NovaSeq X sequencer. 50,000 read pairs per cell for GEX and 5,000 read pairs per cell for V(D)J were targeted.

  Dataset EGAD50000002433

• Whole-genome and transcriptome versus panel sequencing in precision oncology: A translational-clinical comparison

  Precision oncology offers new cancer treatment options. While the use of whole-genome (WGS) and transcriptome (TS) sequencing remains often confined to specific clinical programs, molecular analysis with gene panels is more common clinical practice. Methods: Twenty patients with rare or advanced tumors sequenced by WGS/TS within the DKFZ/NCT/DKTK-MASTER program from 2015 to 2020 (MASTER 1) were additionally sequenced with the TSO500 DNA and TST170 RNA Assay by Illumina. Original Molecular Tumor Board (MTB) therapy recommendations (TR) were juxtaposed with TR from NGS panel data analysis (comparison 1). To mitigate temporal differences between the two sequencings, WGS/TS was bioinformatically reanalyzed (MASTER 2), and new TR were again compared (comparison 2). Results: In comparison 1, 47.1% of the MASTER 1’s TR and 62.8% of the panel’s TR were identical, as were 45.9% of the TR of MASTER 2 and 54.9% of the panel in comparison 2. In both MASTER 1 and MASTER 2, 26.5% and 36.1% of TR, respectively, relied on Biomarkers (BM) which were not covered by the panel. Eight of the ten MTB-derived therapy implementations were also supported in the panel, the two remaining ones being based on BM absent from the panel. Conclusions: About half of the TR in WGS/TS and panel sequencing were identical. Around a third of TR issued by WGS/TS were based on BM which are not covered by the panel, leading to therapy implementations. The presented data underscores the clinical value of comprehensive molecular analyses in individuals with advanced cancers.

  Study EGAS50000000431

• Molecular biomarkers for stratification periheral T cell lymphoma

  Peripheral T cell lymphoma (PTCL) is a diverse group of rare lymphoid malignancies with overall poor prognosis. Diverse biological mchanisms behind these diverse disease groups make targeted treatment challenging. Based on molecular biomarkers, more , the aim is to characterise more specific features for the different clinically defined PTCL for new future prognostic therapies.

  Study EGAS00001006691

• Smoking and the Vaginal Microbiome

  The focus of this study was to better understand the effects of cigarette smoking on the vaginal microbiome. There were two phases of the study, cross-sectional and longitudinal, conducted at the Center for Health Behavior Research at the University of Maryland School of Public Health. In the cross-sectional phase, 20 smokers and 20 non-smokers collected mid-vaginal swabs, measured their vaginal pH, prepared a vaginal smear on a slide for Nugent Gram stain analysis, and completed questionnaires about demographics, tobacco use, and reproductive and sexual health history. Smoking status was confirmed through self-report, carbon monoxide exhalation and saliva cotinine measures. Secretions from the mid-vaginal swabs were tested for presence/absence of HPV strains and GC-MS was used to quantify the levels of over 600 metabolites. In the longitudinal phase, 7 participants who were current smokers and motivated to quit smoking were recruited and followed for up to 12 weeks. On a daily basis, participants collected mid-vaginal swabs, measured their vaginal pH, and prepared a mid-vaginal smear on a slide for Nugent Gram stain analysis, and completed daily diaries on tobacco use and reproductive health. Carbon monoxide exhalation and saliva cotinine measures were collected at weekly clinical visits. In addition, participants had weekly behavioral counseling sessions about smoking cessation and used Nicoderm CQ patches to aid in quitting smoking. The self-collected vaginal swabs were used for DNA extractions,16s rRNA sequencing and measurement of metabolites in vaginal fluid.

  Study phs001386

• Cryptococcosis in Previously Healthy Adults

  Cryptococcus is a fungus that causes infections most commonly in immunocompromised patients, such as those with AIDS and solid organ transplant recipients and is currently responsible for an estimated 15% of all AIDS-related deaths globally. However, in developed countries, approximately one-third of cases fall outside these groups such that cryptococcal meningoencephalitis (CM) has become the most common cause of non-viral meningitis in the U.S. Within the U.S., approximately 15-20% have no readily identifiable immune defect and cryptococcal infection in these hosts has a mortality rate of 30-50% despite optimal antifungal therapy. NIH Clinical Study Protocol 93-I-0106 (NCT00001352). The objectives of this protocol can be broadly categorized as: 1) Characterize the immunologic and genetic mechanisms predisposing to disease acquisition; 2) Understand the post-infectious inflammatory response and distinguish its consequences from those directly due to fungal growth; and 3) Management of post-infectious neuro-inflammatory syndromes associated with cryptococcal meningitis (CM). This protocol recruits patients who have microbiological evidence of cryptococcal neurologic or non-CNS disease (typically pulmonary or bone). Cerebrospinal fluid (CSF) and blood samples collected during clinical care are used to measure serum and CNS cellular and soluble cytokines as well as to perform in-situ immunohistochemistry. CSF and blood samples are also collected to measure transcriptional (gene expression), proteomic (protein), and lipidomic (lipids) changes that occur throughout disease and treatment. Observational data detailing audiological, ophthalmological and neurocognitive deficits in these patients is also recorded. We have recently described a post-infectious inflammatory syndrome (PIIRS) associated with cryptococcal meningoencephalitis (CM) which can be best described as a neuro-inflammatory state during which CM patients present with altered mental status (Montreal Cognitive Assessment Score As part of the protocol, we treat patients for either microbiological failure or neuroinflammatory sequelae by conventional therapies utilizing FDA-approved pharmaceuticals at FDA-approved doses. To understand and identify the predominant biological pathways responsible for PIIRS neuroinflammation, we examined patient CSF at baseline (at time of PIIRS diagnosis) and post-treatment with different FDA-approved pharmaceuticals at FDA-approved doses compared to CSF from non-PIIRS donors. Upstream pathway analysis of differentially expressed genes in the CSF of PIIRS patients revealed a prominent role for the JAK/STAT pathway in the pathogenesis of PIIRS and support the use of the JAK inhibitor, ruxolinib, as a pathway-instructed therapy to treat PIIRS patients. Data available through dbGaP: single cell RNA sequencing (scRNA-seq) data from CSF cells of a patient with PIIRS at the time of diagnosis and following treatment with steroids (1g solumedrol/day) and NanoString transcriptional data from CSF cells of patients with PIIRS at the time of diagnosis compared to CSF cells from non-PIIRS donors.

  Study phs003871

• Germline whole genome sequencing of patients with Li-Fraumeni syndrome

  Five hundred ng to 1 ug of genomic DNA was submitted to The Centre for Applied Genomics (TCAG) at The Hospital for Sick Children for genomic library preparation and whole genome sequencing. DNA samples were quantified using the Qubit High Sensitivity Assay and purity was assessed using the Nanodrop OD 260/280 ratio. Approximately 500-700 ng of DNA was used as input material for library preparation using the Illumina TruSeq PCR-free DNA Library Prep Kit following the manufacturer’s recommended protocol. In brief, DNA was fragmented to 400 bp on average using sonication on a Covaris LE220 instrument. Fragmented DNA was end-repaired, A-tailed and indexed TruSeq Illumina adapters with overhang-T were added to the DNA. Libraries were then validated on a Bioanalyzer DNA High Sensitivity chip to check for size and absence of primer dimers and quantified by qPCR using Kapa Library Quantification Illumina/ABI Prism Kit protocol (KAPA Biosystems). Validated libraries were pooled in equimolar quantities and paired-end sequenced on an Illumina HiSeq X platform following Illumina’s recommended protocol to generate paired-end reads of 150-bases in length and an average depth of 40X. FASTQ files were aligned to the hg19 reference genome using BWA-mem v0.78. PCR duplicates were marked with Picard MarkDuplicates v1.1.08, and base recalibration and realignment was performed using GATK v2.8.1.

  Study EGAS00001007061