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• Tumor Profiler Melanoma Study

  The Tumor Profiler Study is an observational trial combining a prospective diagnostic approach to assess the relevance of in-depth tumor profiling to support clinical decision-making with an exploratory approach to improve the biological understanding of the disease. Technologies used are digital pathology, targeted NGS, single-cell RNA, single-cell DNA, bulk RNA, bulk proteotyping, single-cell CyTOF, imaging mass cytometry, pharmacoscopy, 4i Drug Response Profiling, and cell-free DNA. These technologies were applied to 240 tumor samples collected over 3 years across three cancer indications: metastatic melanoma, metastatic epithelial ovarian cancer, and acute myeloid leukemia (AML). Here, we publish the scRNA, scDNA, and bkRNA data of the melanoma cohort.

  Study EGAS50000000599

• Multi-omic analysis of SDHB-related PCPG

  Hereditary SDHB-mutant pheochromocytomas (PC) and paragangliomas (PG) are rare tumours with a high propensity to metastasize although their clinical behaviour is unpredictable. To characterize the genomic landscape of these tumours and identify metastasis biomarkers, we performed multi-omic analysis on 94 tumours from 79 patients using six molecular methods including: whole-genome sequencing (WGS) of tumour and matched blood (n=94), whole transcriptome sequencing (RNA-seq) (n=91), small-RNA seq (n=90), DNA methylation profiling (n=93). Droplet-based (10x) single nuclei (sn)RNA-seq and snATAC-seq was applied to 9 and 7 cases, respectively. Additionally snATAC-seq was applied to one sample of normal adrenal medulla.

  Study EGAS50000000346

• Tumor Profiler Ovarian Study

  The Tumor Profiler Study is an observational trial combining a prospective diagnostic approach to assess the relevance of in-depth tumor profiling to support clinical decision-making with an exploratory approach to improve the biological understanding of the disease. Technologies used are digital pathology, targeted NGS, single-cell RNA, single-cell DNA, bulk RNA, bulk proteotyping, single-cell CyTOF, imaging mass cytometry, pharmacoscopy, 4i Drug Response Profiling, and cell-free DNA. These technologies were applied to 240 tumor samples collected over 3 years across three cancer indications: metastatic melanoma, metastatic epithelial ovarian cancer, and acute myeloid leukemia (AML). Here, we publish the scRNA and scDNA data of the ovarian cancer cohort.

  Study EGAS50000000885

• CSER: North Carolina Clinical Genomic Evaluation by Next-Gen Exome Sequencing 2

  The North Carolina Clinical Genomic Evaluation by Next-gen Exome Sequencing, 2 (NCGENES 2) study is part of a larger consortium project investigating the clinical utility, or net benefit of an intervention on patient and family well-being as well as diagnostic efficacy, management planning, and medical outcomes. A clinical trial will be implemented to compare (1) first-line exome sequencing to usual care and (2) participant pre-visit preparation to no pre-visit preparation. The study will use a randomized controlled design, with 2x2 factorial design, coupled with patient-reported outcomes and comprehensive clinical data collection addressing key outcomes, to determine the net impact of diagnostic results and secondary findings.

  Study phs002110

• Identification_of_rare_variants_associated_with_cardiovascular_traits_in_Cilento_isolates

  The aim of this project is to identify rare genetic variants of large effect implicated in complex diseases by focusing on the study of cardiovascular diseases and related quantitative traits in a well characterized isolated population in Cilento area, Italy.The reference panel has been selected carefully in order to maximize the imputation coverage and quality on the all population samples. The selected individuals should meet three criteria: selected individuals should be chip-genotyped and closely related to the maximum number of chip-genotyped individuals so as to maximize imputation coverage; relatedness between selected individuals should be minimal, so as to minimize redundancy in genetic information of the reference panel.We perform exome sequencing on samples from 250 individuals from the Campora and Gioi-Cardile populations.

  Study EGAS00001000620

• Data generated by the Drier Lab at HUJI

  This Data Access Committee is responsible to all data generated by and deposited by the Drier Lab at the Faculty of Medicine of the Hebrew University of Jerusalem (http://yotamdrier.ekmd.huji.ac.il/)

  Dac EGAC50000000060

• Prediction and quantification of splice events from RNA-seq data

  Analysis of splice variants from short read RNA-seq data remains a challenging problem. Here we present a novel method for the genome-guided prediction and quantification of splice events from RNA-seq data, which enables the analysis of unannotated and complex splice events. Splice junctions and exons are predicted from reads mapped to a reference genome and are assembled into a genome-wide splice graph. Splice events are identified recursively from the graph and are quantified locally based on reads extending across the start or end of each splice variant. We assess prediction accuracy based on simulated and real RNA-seq data, and illustrate how different read aligners (GSNAP, HISAT2, STAR, TopHat2) affect prediction results. We validate our approach for quantification based on simulated data, and compare local estimates of relative splice variant usage with those from other methods (MISO, Cufflinks) based on simulated and real RNA-seq data. In a proof-of-concept study of splice variants in 16 normal human tissues (Illumina Body Map 2.0) we identify 249 internal exons that belong to known genes but are not related to annotated exons. Using independent RNA samples from 14 matched normal human tissues, we validate 9/9 of these exons by RT-PCR and 216/249 by paired-end RNA-seq (2 x 250 bp). These results indicate that de novo prediction of splice variants remains beneficial even in well-studied systems. An implementation of our method is freely available as an R/Bioconductor package SGSeq.

  Study EGAS00001001026

• The University of Hong Kong Gastric Cancer Organoids RHO Signaling Study

  Objective: Cell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells. Design: We explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix, or both, to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers: ARHGAP fusions, RHOA, and CDH1, in modulating CC (CCi) or CM (CMi) adhesion independence. Results: 97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to 3 public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling via RHOA mutation or ARHGAP fusions. Inducible knockout of ARHGAP fusions in CCi/CMi tumour organoids led to re-sensitization to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype, and inhibited xenograft formation. Normal gastric organoids engineered with CDH1 or RHOA mutations became CMi or CCi, respectively. Conclusions: The CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.

  Study EGAS00001006252

• Intra-tumor heterogeneity and clonal evolution patterns towards platinum-resistant high-grade serous ovarian cancer

  Although many high-grade serous ovarian carcinoma (HGSOC) patients are initially sensitive to the standard-of-care platinum-based therapy, intra-tumor heterogeneity may fuel selection towards platinum-resistant clones over subsequent lines of therapy. We performed whole-exome coupled to ultra-deep re-sequencing and copy number alteration (CNA) profiling on 31 matched diagnosis and relapse tumors from HGSOC patients treated with platinum. Genetic heterogeneity within tumor pairs varied extremely, with some recurrent tumors being identical and others completely different from the primary tumor. All primary tumors showed evidence of homologous recombination (HR)-deficiency, but none of them carried reactivating mutations in the HR pathway at relapse, also not when becoming resistant to subsequent lines of platinum. We did also not identify other mutations, CNAs or pathways that were enriched in platinum-resistant clones. However, a platinum score consisting of 13 CNAs correlated significantly with platinum-free interval (PFI) after first-line therapy in multiple cohorts of >450 primary HGSOCs. A relative increase of this score in the relapsed tumor correlated with a change in PFI during subsequent therapy. Clonal evolution under platinum therapy contributes to genetic heterogeneity within tumor pairs, implicating that genetic tests linked to targeted treatment options for recurrent HGSOC need to be performed on biopsies collected at relapse. Platinum resistance of an initially platinum-sensitive HR-deficient HGSOC at relapse is not caused by reactivation of the HR pathway, suggesting that these tumors are still responsive to PARP inhibitors, instead, several chromosomal aberrations contribute to a score predictive of disease outcome under platinum therapy, both in first and subsequent lines of platinum therapy.

  Study EGAS00001001244

• ENOC WGS for the study Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes

  For ENOC cohorts, OvCaRe cases were reviewed, including frozen material, by at least two expert gynecopathologists prior to inclusion in the sequencing cohort who provided the confirmation on final selected cohort. Frozen H&E from Tokyo were also used for evaluation along with representative H&E photos and review done at the Jikei School of Medicine. For ENOC, DAH985 and DG1288 are recurrent and both were treated with chemotherapy after their first surgery. DAH123 is a untreated sample, metastasis from an primary endometrial tumour. All HGSC, GCT, CCOC and the rest ENOC tumours are primary tumour samples. Library construction and sequencing Frozen specimens with >50% tumour cellularity (based on initial slide review) were used for cryosectioning and subsequent nucleic acid extraction. Patient tumour and normal blood samples derived from primary, untreated fresh frozen tumour specimens harvested at diagnosis during standard of care debulking surgery. Germline DNA was provided from peripheral blood buffy coat on all specimens except 13 from Tokyo, where non-cancer frozen tissue was used as a germline source. DNA extraction from both matched normal (blood) and tumour samples (frozen tissue) were performed using the QIAamp Blood and Tissue DNA kit (Qiagen) and quantified using a Qbit fluorometer and reagents (high-sensitivity assay). Three lanes of Illumina HiSeq 2500 v4 chemistry for normal samples and five lanes for tumour samples were obtained. The PCR-free protocol was adopted to eliminate the PCR-induced bias and improve coverage across the genome.

  Dataset EGAD00001003266

• Human liver mtDNA sequencing

  BAM files containing paired-end mtDNA sequencing data from morphologically normal human liver. Clonal CCO-deficient patches of hepatocytes were identified in human liver samples, and samples were taken along a line spanning approximately from the portal triad to the central hepatic vein. Individual BAM files are named according to their patch, line and cut, where cut 1 is nearest to the portal triad, and cuts 2, 3 etc. lying further from the portal triad. Other file types include "Bulk" samples, contain sequencing data of the remaining CCO-deficient cells that were not sampled as part of the line of cuts, and "Stroma" control samples (used for identifying germ-line variants). Sequenced on NextSeq 500 platform.

  Dataset EGAD00001007991

• Heart Failure Network: Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF (HFN INDIE-BioLINCC)

  Data Access NOTEPlease refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.ObjectiveTo determine the effect of inhaled, nebulized inorganic nitrite on exercise capacity in patients with heart failure with preserved ejection fraction. Background Approximately half of patients with heart failure have a preserved ejection fraction (HFpEF). However, there are no proven effective medical treatments for this syndrome. Evidence suggests that impairments in nitric oxide availability have a potentially important role in the pathophysiology of HFpEF. Unlike organic nitrates, inorganic nitrite is converted to nitric oxide in the presence of hypoxia and acidosis, conditions that develop during exercise. Because the cardiac, vascular, and skeletal muscle abnormalities that limit physical capacity and contribute to symptoms in patients with HFpEF characteristically develop during exercise, inorganic nitrite may provide the best way to target nitric oxide delivery precisely at the time of greatest need. The HFN-INDIE trial was initiated to test the hypothesis that compared to placebo, longer-term use of inhaled, nebulized inorganic nitrite would enhance peak exercise capacity in patients with HFpEF. Participants A total of 105 participants were randomized. 53 were randomized to receive nitrite first and 52 were randomized to receive placebo first. Design HFN-INDIE was a multicenter, randomized, double-blind, placebo-controlled, crossover study. After enrollment, patients underwent baseline studies to determine eligibility. All patients were required to display objective exercise limitation, evidenced by reduced peak oxygen consumption (V̇O2) on cardiopulmonary exercise testing of less than 75% predicted, with a respiratory exchange ratio indicative of maximal effort (≥1.0). Following qualifying exercise testing, eligible participants received an open-label, single-dose run-in of inhaled, nebulized sodium nitrite (80 mg) to assess tolerability, symptoms, and orthostatic vital signs. Patients developing hypotension (systolic blood pressure The prespecified primary end point was peak V̇o2, measured as the highest 30-second average during upright cycle ergometry, during the 4-week period in which patients were receiving inorganic nitrite as compared with placebo. Accelerometry, health-related quality-of-life scores on the self-administered Kansas City Cardiomyopathy Questionnaire (score range, 0-100, with higher scores indicating better quality of life), echocardiographic indicators of cardiac filling pressures measured at trough drug levels (E/e' ratio, estimated pulmonary artery systolic pressure, and left atrial volume index; lower scores indicate better health for all), ventilatory efficiency (VE/V̇co2, lower indicating better health), exercise time (higher indicating better health), and NT-proBNP levels (lower indicating better health) were also collected. Conclusions Among patients with HFpEF, administration of inhaled inorganic nitrite for 4 weeks, compared with placebo, did not result in significant improvement in exercise capacity. Borlaug et al., 2018, PMID: 30398602.

  Study phs003667

• The Spatial Heterogeneity in Multiple Myeloma - from the Subclonal Architecture to the Immune Microenvironment (partly hipo_K08K)

  Multiple myeloma (MM) cells show pronounced heterogeneity not only within a given patient but also between spatially separated tumor loci in the bone marrow. Understanding this spatial heterogeneity is emerging as a critical challenge for the successful treatment of the disease. Yet, our understanding of spatial differences in the subclonal architecture, molecular signatures and interactions with the tumor microenvironment remains very limited. To address this shortcoming, we performed bulk and single-cell multi-region sequencing, including random bone marrow samples from the iliac crest and paired imaging-guided focal lesion specimens from 15 newly diagnosed MM patients. We found a median of 5 subclones per patient and unique subclones in focal lesions. Central features of spatial heterogeneity included a consistent down-regulation of the chemoattractant cytokines CXCL7 and CXCL12 in focal lesion tumor cells as well as a significant depletion of macrophages in the focal lesion microenvironment. In contrast, a site-specific expansion of T-cell clones was not detected in focal lesions. In conclusion, our results demonstrate the relevance of considering spatial heterogeneity with potential implications for immunotherapies and molecular studies analyzing the role of gene signatures and MM-microenvironment interactions in disease progression.

  Study EGAS00001006090

• DAC for study CMMRD–associated high-grade glioma

  This Data Access Committee (DAC) is responsible for de-identified, summarized somatic variant call data derived from paired tumor–blood Whole-exome sequencing of human samples in a glioma research study. Access requests are approved without additional restrictions and are granted solely for health-related research purposes.

  Dac EGAC50000000855

• Starr County Health Studies' Genetics of Diabetes Study

  An initial observation in the 1970s that Starr County, Texas, had the highest diabetes-specific mortality of any of the 254 Texas counties led to the establishment of a field office in Rio Grande City, Texas (the county seat of Starr County) and the initiation of a series of studies to understand the epidemiology and genetics of type 2 diabetes, its complications and related conditions in this predominantly (97%) Mexican American population. The field office opened in February 1981 and has operated continuously since then. During this time, three systematic surveys of the population have been conducted as well as family and longitudinal studies. Culturally sensitive diabetes education programs have been developed and implemented and also a weight loss intervention. In total, more than 23,000 Mexican American individuals have been examined with more than 200,000 aliquots of biological specimens stored. Collectively, these studies are known as the Starr County Health Studies. The present Genetics of Diabetes Study has the goal of identifying loci/alleles that underlie susceptibility to type 2 diabetes in this high risk population using genome wide markers and association testing. The study makes use of two primary resources that have been developed in order to identify 1,000 type 2 diabetes cases and 1,000 disease free controls. In the first instance we have identified a subset of unrelated cases from the total cases that we have identified. Where multiply affected sibships were available, the youngest onset case with detailed phenotyping (including assessment of diabetic retinopathy) was selected. Controls came from a recent survey to establish a representative sample of the Starr County population. Blocks were randomly selected, households on selected blocks enumerated and one individual randomly selected from each household for a detailed examination. The examination included an oral glucose tolerance test. Those included as controls are those with no prior diagnosis of diabetes and a negative oral glucose tolerance test. This collection of cases and controls provides the opportunity to identify susceptibility loci for type 2 diabetes and its complications, specifically diabetic retinopathy and albuminuria. The data set also allows the examination of impaired fasting glucose and impaired glucose tolerance. The samples are split between those born in the United States and those born in Mexico and this gives a natural contrast for examining genotype and environmental interactions. It is anticipated that the understanding that will come will lead to strategies for delaying and preventing the onset of diabetes and its complications.

  Study phs000143

• Proteomic Biomarkers of Progressive Fibrosing Interstitial Lung Disease: a Multicentre Cohort Analysis (PF-ILD Proteomics-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. Objectives: To identify novel plasma biomarkers of progressive fibrosing interstitial lung disease and develop a proteomic signature to predict this phenotype. Background: Progressive fibrosing interstitial lung disease (ILD) is a devastating condition characterized by parenchymal scar formation, leading to deteriorating lung function and early death. Whereas almost all patients with idiopathic pulmonary fibrosis (IPF) progress, a variable proportion of patients with other common ILDs, including connective tissue disease associated ILD, chronic hypersensitivity pneumonitis, and unclassifiable ILD, develop progressive fibrosing ILD. There are criteria that effectively identify those experiencing ILD progression. However, the criteria do not allow patients who are at risk to be identified before progression occurs. Several blood-based biomarkers have been linked to differential progression in patients with IPF and other fibrosing ILDs. Inflammatory signaling also appears to have a prominent role in fibrotic-predominant ILDs. As such, cytokines, interleukins, and other immune mediators might serve as useful biomarkers of progressive fibrosing ILD. The PF-ILD Proteomics study was a targeted investigation of inflammation-related proteins to identify and validate novel biomarkers of progressive fibrosing ILD in patients with fibrotic connective tissue disease-associated ILD, chronic hypersensitivity pneumonitis, and unclassifiable ILD. Participants: There were 589 participants. The discovery cohort comprised 385 participants and the validation cohort comprised 204 participants. Design: PF-ILD Proteomics was a multicenter cohort analysis study. Peripheral blood was collected from consenting patients and plasma was isolated according to center-specific protocols. Relative plasma concentrations for 368 biomarkers were determined with use of a semi-quantitative, targeted proteomic platform. Patients from UC Davis and UCSF comprised the discovery cohort and those from UTSW comprised the validation cohort. Participants who were alive with less than 10% relative decline in forced vital capacity (FVC) at 12 months-after blood draw were considered to have non-progressive ILD. Participants who died of any cause, underwent lung transplant, or experienced 10% or greater relative FVC decline within 12 months of blood draw were deemed to have progressive fibrosing ILD. Conclusions: 17 plasma biomarkers of progressive fibrosing interstitial lung disease were identified and showed consistent associations across ILD subtypes.

  Study phs003954

• Monocyte and macrophage lipid accumulation results in downregulated type-I interferon responses

  Macrophages are critical components of atherosclerotic lesions and their pro- and anti-inflammatory responses influence atherogenesis. Type-I interferons (IFNs) are cytokines that play an essential role in antiviral responses and inflammatory activation and have been shown to promote atherosclerosis. Although the impact of type-I IFNs on macrophage foam cell formation is well-documented, the effect of lipid accumulation in monocytes and macrophages on type-I IFN responses remains unknown. Here we examined IFN stimulated (ISG) and non-ISG inflammatory gene expression in mouse and human macrophages that were loaded with acetylated LDL (acLDL), as a model for foam cell formation. We found that acLDL loading in mouse and human macrophages specifically suppressed expression of ISGs and IFN-β secretion, but not other pro-inflammatory genes. The downregulation of ISGs could be rescued by exogenous IFN-β supplementation. Activation of the cholesterol-sensing nuclear liver X receptor (LXR) recapitulated the cholesterol-initiated type-I IFN suppression. Additional analyses of murine in vitro and in vivo generated foam cells confirmed the suppressed IFN signalling pathways and suggest that this phenotype is mediated via downregulation of interferon regulatory factor binding at gene promoters. Finally, RNA-seq analysis of monocytes of familial hypercholesterolemia (FH) patients also showed type-I IFN suppression which was restored by lipid-lowering therapy and not present in monocytes of healthy donors. Taken together, we define type-I IFN suppression as an athero-protective characteristic of foamy macrophages. These data provide new insights into the mechanisms that control inflammatory responses in hyperlipidaemic settings and can support future therapeutic approaches focusing on reprogramming of macrophages to reduce atherosclerotic plaque progression and improve stability.

  Study EGAS00001005955

• Primary plasma cell leukemia (pPCL) samples were sequenced using the Nimblegen MedExome hybridization capture to detect translocations, copy number changes, and mutations in 20 pPCL samples and patient matched controls.

  Primary plasma cell leukemia (pPCL) is a rare malignancy related to multiple myeloma. Here we have assembled 20 patient samples and performed whole exome sequencing to determine the differences between multiple myeloma and pPCL. CD138+ cells were purified from bone marrow aspirates from patients with pPCL. Control cells were obtained from CD34+ stem cell harvests or CD3+ T cells. DNA was extracted and processed using the HyperPlus library prep kit (KAPA Biosystems) and sequenced using 75 bp paired end reads on an Illumina NextSeq500.

  Study EGAS00001003104

• TCR Repertoire Sequencing to Evaluate the Diversity of Follicular Helper T Cells in HIV Infected Lymph Nodes

  The TCR repertoire of CD4+ T cells in human lymph nodes is a case-based analysis of the TCR repertoire of CD4+ T cells in human lymph nodes. The study aims to determine how HIV infection alters the repertoire complexity of follicular helper T cells (TFH) in relationship to other T cell subsets in the lymphoid compartment. This study performs TCR repertoire sequencing using Molecular Identifier Clustering-based Immune Repertoire Sequencing (MIDCIRS). We found TFH cells become clonally expanded and convergently selected in LNs from patients with chronic HIV infection.

  Study phs001548

• Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)

  (Excerpted/paraphrased from original grant application): FOCI seeks to expand our understanding of epithelial ovarian cancer through a coordinated and comprehensive approach. Project 1 will focus on discovery, expansion, and replication. By pooling GWAS, we expect to identify new associations and achieve independent replication, explore whether there are risk variants specific for histologic subtypes, and evaluate structural polymorphisms - copy number variants - as risk factors. Finally, Project 1 will leverage the GWAS data to correlate DNA variants with a new endpoint - survival. Project 2 will focus on biological studies designed to help inform interpretation of findings from Project 1. This will include efforts to identify the functional consequences of variants and improve understanding of biological mechanisms. Project 3 will include epidemiologic studies of gene by gene interaction, gene by environment interaction, and development of risk prediction models. The collective effort builds upon the strengths and history of collaboration inherent in the Ovarian Cancer Association Consortium (OCAC), a multidisciplinary group comprised of epidemiologists, genetic epidemiologists, statistical geneticists, molecular and cell biologists and clinicians that was formed in 2005. The FOCI Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs001133 FOCI Cohort. phs001131 Affymetrix Exome Chip phs001132 GWAS Meta Analysis phs001142 Mayo Omni Express phs001150 Mayo 2 5M

  Study phs001133

• TRACERx 100: whole exome data of the first 100 TRACERx tumours

  BACKGROUNDTRACERx (TRAcking Cancer Evolution through therapy (Rx)) is a prospective cohort study designed to investigate intratumor heterogeneity (ITH) in relation to clinical outcome, and to determine the clonal nature of driver events and evolutionary processes in early stage non-small cell lung cancer (NSCLC). METHODSMultiregion high-depth whole-exome sequencing (M-seq) was performed on 100 early stage NSCLC tumors resected prior to systemic therapy. A total of 327 tumor regions were sequenced and analyzed to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between ITH and recurrence-free survival (RFS). RESULTSWidespread ITH was observed for both somatic copy number alterations (median 48% [0.03-88%]) and mutations (median 30% [0.5-93%]). Driver mutations in EGFR, MET, BRAF and TP53 were almost always clonal. However, heterogeneous driver alterations occurring later in evolution were found in over 75% of tumors and were common in PIK3CA, NF1 and genes involved in chromatin modification and DNA response and repair. Genome doubling and ongoing dynamic chromosomal instability (CIN), illustrated by mirrored subclonal allelic imbalance, were identified as causes of ITH resulting in parallel evolution of driver copy number events, including amplifications of CDK4, FOXA1, and BCL11A. Elevated copy number heterogeneity was associated with shorter RFS (HR=4.9, P=0.00044), which remained significant in a multivariate analysis.CONCLUSIONSITH mediated through CIN, rather than point mutational heterogeneity, was associated with increased risk of relapse, supporting its value as a prognostic predictor, and the need to target this high-risk phenotype.

  Study EGAS00001002247

• Exome sequencing

  Human telomere biology disorders (TBD), a heterogeneous group of disorders characterized by telomere attrition and premature aging phenotypes, are caused by inherited loss-of-function mutations in telomere-associated genes. Here, we identify three germline heterozygous missense variants in RPA1 gene in four unrelated probands presenting with short telomeres and varying clinical features of TBD including bone marrow failure, myelodysplastic syndrome, T- and B-cell lymphopenia, pulmonary fibrosis, and skin manifestations. All variants cluster to DNA binding domain A of RPA1 protein. RPA1 is an essential single-strand DNA-binding protein essential for DNA replication and repair. RPA1 has been implicated in telomere maintenance but the mechanism remains elusive. Thus far, no genetic disorder had been linked to RPA1. Using FRET assays, we showed that RPA1E240K and RPA1V227A exhibit increased binding to single-strand and telomeric DNA, implying a gain in DNA-binding function while RPA1T270A has binding properties similar to wild type. To study the mutational effect, RPA1E240K, with the highest binding capacity, was knocked-in iPSCs using CRISPR/Cas9, which showed severe telomere shortening and impaired hematopoietic differentiation. Furthermore, in the RPA1E240K patient, stable blood counts over two decades due coincided with clonal rescue hematopoiesis with an RNA-degrading truncating RPA1 mutation and a uniparental isodisomy 17p with loss of RPA1E240K allele. Using single cell DNA sequencing, the two somatic genetic rescue events were proven to be independently acquired in hematopoietic stem cells. In summary, we describe the first human disease caused by germline RPA1 variants in individuals with TBD.

  Study EGAS00001005761

• Ovarian Cancer Organoid Biobank - RNASeq data

  Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of OC are limited and hard to establish. We present a novel protocol that enables efficient derivation and long-term expansion of OC organoids. Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing the spectrum of ovarian neoplasms, including non-malignant borderline tumors, as well as mucinous, clear-cell, endometrioid, low- and high-grade serous carcinomas. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and inter-patient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug screening assays and capture different tumor subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug sensitivity assays. Taken together, this demonstrates their potential application for research and personalized medicine.

  Dataset EGAD00001004509

• Frequent alterations in cytoskeleton remodeling genes in primary and metastatic Chinese lung adenocarcinomas

  The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including themost commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scalesequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.

  Study EGAS00001000982

• Enhanced cortical neural stem cell identity through SMAD/WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells

  Cerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity despite the tremendous upsurge in derivation methods, suggesting inadequate patterning of early neural stem cells (NSCs). Here we show that a short and early dual-SMAD/WNT inhibition course is necessary and sufficient for establishing robust and lasting cortical organoid NSC identity, efficiently suppressing of non-cortical NSC fates, while other widely used methods are inconsistent in their cortical NSC specification capacity. Accordingly, this method selectively enriches for outer radial glia (oRG) NSCs, which cytoarchitecturally demarcate well-defined outer sub-ventricular (oSVZ)-like regions propagating from superiorly radially organized, apical cortical rosette NSCs. Finally, this method culminates in the emergence of molecularly distinct deep and upper cortical layer neurons, and reliably uncovers cortex-specific microcephaly defects. Thus, a short SMAD/WNT inhibition is critical for establishing a rich cortical cell repertoire that enables mirroring fundamental molecular and cytoarchitectural features of cortical development and meaningful disease modeling.

  Study EGAS00001006063

• Exome Sequencing Analysis of Cutaneous Squamous Cell Carcinoma

  The Exome Sequencing Analysis of Cutaneous Squamous Cell Carcinoma (SCC) study is a single-center cohort study. To identify recurrent genomic aberrations that might underlie the development of this malignancy, we performed whole exome sequencing on a series of SCC-normal pairs to distill a list of 336 candidate genes that were subsequently re-sequenced in 100 SCC-normal pairs with an average depth >1200X. This study also included whole-genome copy number analysis on 5 primary SCC with KNSTRN p.Ser24Phe and 5 histologically matched SCC with wild-type KNSTRN.

  Study phs000785

• Whole exome sequencing of 184 unrelated subjects with 22q11.2 deletion syndrome (DiGeorge syndrome/velo-cardio-facial syndrome)

  Our goal is to find genetic modifiers of major phenotypes in patients with 22q11.2 deletion syndrome, also known as DiGeorge syndrome or velo-cardio-facial syndrome. Whole exome sequencing was performed as part of a contract to the NHLBI, Resequencing and Genotyping Service. We have obtained cardiac phenotype information from the de-identified subjects enrolled in the study, either by echocardiography report or medical doctor report. All of the subjects have a 3 million base pair 22q11.2 deletion flanked by low copy repeats, LCR22, A-D.

  Study phs000987

• Prediction of DNA Repair Inhibitor Response in Short Term Patient-Derived Ovarian Cancer Organoids

  In this study, 34 ovarian tumor organoids generated from 23 patients underwent paired DNA damage repair defect functional analyses and whole exome sequencing analysis to compare genetic mutational status to DNA repair functional capacity. 22 of the patients had high grade serous cancer and 1 of the patients had low grade serous cancer. A normal control, fresh parent tumor, and cells from the organoid culture generated from the parent tumor underwent whole exome sequencing analysis and the data from the sequencing analysis is provided here.

  Study phs001685

• In Vivo Cytokine eQTL Interactions from a Lupus Clinical Trial

  The purpose of this study is to discover in vivo cytokine expression quantitative trait locus (eQTL) interactions from a cohort of patients with systemic lupus erythematosus. 157 lupus patients were enrolled in a clinical trial to test the efficacy and safety of an anti-IL-6 monoclonal antibody. At three time points, we measured interferon (IFN) status, anti-IL-6 drug exposure and genome-wide gen expression. We identified 4,818 cis-eQTLs and then observed a statistically significant enrichment of in vivo eQTL interactions with IFN status and anti-IL-6 exposure.

  Study phs001702

• Multi-Omics Study of Lung Cancer in Smokers From EAGLE

  EAGLE (Environment And Genetics in Lung cancer Etiology) is a population-based case-control study examining the full spectrum of lung cancer etiology from smoking initiation, smoking dependency to lung cancer development and outcome. It combines a traditional molecular epidemiology design with more integrative approaches by examining epidemiological, molecular, and clinical data together. To comprehensively investigate the effect of tobacco smoking behaviors on genomic or epigenomic alterations, we performed a multi-omics study including whole-genomic, transcriptomic, and epigenomic profiles in a total of 221 individuals from the EAGLE study.

  Study phs002992

• Impact of Genomic Variation on Function (IGVF) Consortium

  The IGVF (Impact of Genomic Variation on Function) Consortium aims to understand how genomic variation affects genome function, which in turn impacts phenotype. The NHGRI is funding this collaborative program that brings together teams of investigators who will use state-of-the-art experimental and computational approaches to model, predict, characterize and map genome function, how genome function shapes phenotype, and how these processes are affected by genomic variation. These joint efforts will produce a catalog of the impact of genomic variants on genome function and phenotypes.

  Study phs003472

• A New CA19-9 Cut-Off Value Identifies Lewis Antigen Status and Refines Prognostic Stratification in PDAC

  This study investigates the clinical utility of serum CA19-9 levels in pancreatic ductal adenocarcinoma (PDAC), with a focus on identifying patients with Lewis antigen–negative status due to germline FUT3 variants. Using data from multicenter prospective cohorts in Taiwan, we analyzed CA19-9 classification, FUT2/FUT3 genotypes, and clinicopathological annotations. The goal of this study is to refine prognostic stratification and reduce false-negative interpretation of CA19-9 in PDAC patients. All participants provided informed consent, and the study was approved by the relevant institutional review boards.

  Study EGAS50000001575

• Exome-seq data of two non-obstructive azoospermia patients

  Azoospermia, characterized by the absence of spermatozoa in the ejaculate is a common cause of male infertility with a poorly characterized etiology. Exome sequencing analysis of two azoospermic brothers allowed the identification of a homozygous splice mutation in SPINK2, encoding a serine protease inhibitor believed to target acrosin, the main sperm acrosomal protease. In accord with these findings we observed that homozygous Spink2 KO male mice had azoospermia. Moreover, despite normal fertility, heterozygous male mice had a high rate of morphologically abnormal spermatozoa and a reduced sperm motility. Further analysis demonstrated that in the absence of Spink2, protease-induced stress initiates Golgi fragmentation and prevents acrosome biogenesis leading to spermatid differentiation arrest. We also observed a deleterious effect of acrosin overexpression in HEK cells, effect that was alleviated by SPINK2 coexpression confirming its role as acrosin inhibitor. These results demonstrate that SPINK2 is necessary to neutralize proteases during their cellular transit towards the acrosome and that its deficiency induces a pathological continuum ranging from oligoasthenoteratozoospermia in heterozygotes to azoospermia in homozygotes.

  Dataset EGAD00001003326

• Genetic sequencing of MODY patients.

  Maturity-onset Diabetes of the young (MODY) is an early-onset, autosomal dominant form of non-insulin dependent diabetes. Genetic diagnosis of MODY can transform patient management. Earlier data on the genetic predisposition to MODY have come primarily from familial studies in populations of European origin. Using next generation sequencing, we carried out a comprehensive genomic analysis of 289 individuals from India that included 152 clinically diagnosed MODY cases to identify variants in known MODY genes. Our findings report that HNF1A and ABCC8 are among the most frequently mutated MODY genes in south India.

  Study EGAS00001001699

• Neuroblastoma and adrenal gland single-cell study

  Neuroblastoma is a pediatric tumor of the developing sympathetic nervous system. However, the cellular origin of neuroblastoma remains to be defined. Here, we study single-cell transcriptomes of neuroblastomas and normal human developing adrenal glands at various stages of embryonic and fetal development. We define normal differentiation trajectories during adrenal medullary development and identify the cellular origin of neuroblastoma. Importantly, adrenergic and mesenchymal neuroblastomas with varying clinical phenotypes match different temporal states along normal differentiation trajectories, with the degree of differentiation corresponding to clinical prognosis.

  Study EGAS00001004388

• Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets

  Untreated prostate cancers rely on androgen receptor (AR) signaling for growth and survival, forming the basis for the initial efficacy of androgen deprivation therapy (ADT). Yet, the disease can relapse and progress to a lethal stage termed castration-resistant prostate cancer (CRPC). Reactivation of AR signaling represents the most common driver of CRPC growth and next generation AR signaling inhibitors (ARSIs) are now used in combination with ADT as a first line therapy. However, ARSIs can result in selective pressure generating AR-independent tumors. The transition from AR-dependence frequently accompanies a change in phenotype resembling developmental trans-differentiation or ‘lineage plasticity’. Neuroendocrine prostate cancer, which lacks a defined pathologic classification, is the most studied type of lineage plasticity. However, most AR-null tumors do not exhibit neuroendocrine features and are classified as ‘double-negative prostate cancer’, the drivers of which are poorly defined. Lineage plasticity studies in CRPC are limited by the lack of genetically defined patient-derived models that recapitulate the disease spectrum. To address this, we developed a biobank of organoids generated from patient biopsies to study the landscape of metastatic CRPC and allow for functional validation assays. Proteins called transcription factors (TFs) are drivers of tumor lineage plasticity. To identify the key TFs that drive the growth of AR-independent tumors, we integrated epigenetic and transcriptomic data generated from CRPC models. By presenting a map of the chromatin accessibility and transcriptomic landscape of CRPC using a diverse biobank of organoids, PDXs and cell lines that recapitulate the heterogeneity of metastatic prostate cancer, we validate CRPC-AR and CRPC-NE subtypes and reveal two subtypes of AR-negative/low samples as well as their respective masterTFs. Additional analysis revealed a model in which YAP, TAZ, TEAD and AP-1 function together and drive oncogenic growth in CRPC-SCL samples. Overall, we show here how an approach to stratify CRPC patients into four subtypes using their transcriptomic signatures can potentially inform upon appropriate clinical decisions.

  Study EGAS00001006059

• Whole genome sequencing data of pediatric B-other subtype acute lymphoblastic leukemia

  For a long time, approximately 70% of childhood B-ALL cases could be classified routinely, and the remaining 30% were classified into the “B-other” group lacking the known genetic features. However, more recently, new genomic tools have uncovered new subtypes among the B-other groups. Approximately 10% of B-ALL cases lack the recurrent genetic abnormalities, and are referred as "B-other". They are typically more heterogeneous than other subtypes of B-ALL, and their prognoses are more variable. In a more recent update of the B-ALL classification, 27 subtypes were identified (Arber et al., 2022). The identification of some of these subtypes is dependent on NGS methods, such as RNA sequencing, which are not routinely used in all clinical laboratories. For example, ETV6::RUNX1-like and DUX4-rearranged subtypes have been identified using RNA sequencing. For this study, subtype predictions for some of the cases is acquired from ALLIUM (Krali et al., NPJ Precis Oncol., 2023) and ALLCatchR (Beder et al., Blood, 2022) based on the RNA-seq profiles.

  Study EGAS50000001497

• Ewings Sarcoma Rearrangement Screen

  Cancer is driven by mutations in the genome. We will uncover the mutations that give rise to Ewing's sarcoma, a bone tumour that largely affects children. We will use second generation Illumina massively parallel sequencing, and bespoke software, to characterise the genomes and transcriptomes of Ewing's sarcoma tumours.

  Dataset EGAD00001000389

• RNAseq of patients with Ewings sarcoma

  Cancer is driven my mutations in the genome. We will uncover the mutations that give rise to Ewing's sarcoma, a bone tumour that largely affects children. We will use second generation Illumina massively parallel sequencing, and bespoke software, to characterise the genomes and transcriptomes of Ewing's sarcoma tumours.

  Dataset EGAD00001000444

• V2 panel bait design test

  This study comprises of three different datasets. 1) 57 samples from the 1243 canapps cell line study,2) 91 FFPE normal samples and 3) 87 samples from the SCORT WS2 dataset. The aim is to sequence these 235 samples in order to test the new V2 Colorectal bait design.

  Dataset EGAD00001003242

• WGS of human colorectal cancer organoid exposed to genotoxic pks+ E. coli

  Organoid cultures were exposed to two different E.Coli strains and a dye control with three biological duplicates. Their original culture was harvested as a control. In total 10 organoid cultures were whole-genome sequenced using the Novaseq6000 platforms. The data is deposited as .bam format.

  Dataset EGAD00001005416

• DAC Johns Hopkins University - AML scRNAseq study

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

  Dac EGAC50000000242

• MPNST exome and genome

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

  Dataset EGAD00001001040

• DAC for "Pyjacker identifies enhancer hijacking events in acute myeloid leukemia including MNX1 activation via deletion 7q"

  This is the DAC for the study "Pyjacker identifies enhancer hijacking events in acute myeloid leukemia including MNX1 activation via deletion 7q" of Christoph Plass (c.plass@dkfz.de).

  Dac EGAC50000000472

• Trio Sequencing results for the AnkyrinG MIPS screening study

  Approximately 1000 trio's with varying degrees of cognitive disorders. All samples have been sequenced for the AnkyrinG interactome using MIPS technology. Data is presented as BAM and unfiltered VCF files.

  Dataset EGAD00001006823

• Developmental Mechanisms of Human Congenital Heart Disease in Subjects with 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome)

  The study is designed to identify genetic modifiers of cardiovascular defects in subjects with 22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome or velo-cardio-facial syndrome. Affymetrix 6.0 arrays were processed on 1,480 subjects with known cardiovascular anomalies or with normal structures, all with 22q11.2DS. One sample is a duplicate so it was removed. There are 1,472 samples total of unrelated, de-identified, probands. Over 90% have the same sized 3 million base pair deletion flanked by low copy repeats (LCR22) A and D, while approximately 6% have nested A to B deletions. The rest have other nested deletions, that include a deletion in the vicinity of TBX1 (between LCR22 A and B). A subset of the data was used to identify copy number variations serving as modifiers. Some data were previously published by Dr. Emanuel's team at Children's Hospital of Philadelphia in PA, USA (PMID:26742502; PMID:4896312; PMID:25892112; PMID:4570279). The de-identified DNA data from unrelated subjects come from multiple research sites in the US and Europe as part of the International 22q11.2 Consortium and the International 22q11.2 Brain and Behavior Consortium.

  Study phs001339

• Kids First: The Genomic Architecture of Hirschsprung Disease (HSCR)

  Hirschsprung disease (HSCR) is a male biased developmental disorder associated with a lack of innervation of the gastrointestinal tract. Genetic studies have been instrumental in understanding its multifactorial inheritance, high heritability, syndromic associations, and genetic heterogeneity with variable penetrance and expressivity. At least 24 genes and 9 loci with pathogenic alleles (PAs) are known to underlie HSCR pathogenesis and explain 62% of its population attributable risk (PAR). Despite this heterogeneity, there is functional unity in HSCR: ~53% of HSCR PAs disrupt RET and EDNRB signaling in the developing enteric nervous system (ENS) in which 11 genes comprising a gene regulatory network control RET and EDNRB gene expression. We propose to identify the remaining 30% PAR by studying 857 unrelated HSCR cases, their 125 affected and 1,446 unaffected firstdegree relatives by whole genome sequencing to increase statistical power of gene discovery through improved detection of all types of coding and regulatory PAs. HSCR arises from cell autonomous defects in enteric neural crest cell precursors (ENCCs) affecting their proliferation, differentiation and migration in the ENS, functional studies that will guide our detection of novel genes.

  Study phs003662

• Pan-neuroblastoma analysis reveals age- and signature-associated driver alterations

  Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes depending on age and other factors. To better understand neuroblastoma pathogenesis, here we analyze whole-genome, whole-exome and/or transcriptome sequencing data from 702 neuroblastoma samples, half of which are new data. Over 95% of samples harbor at least one recurrent driver alteration and most aberrations, including MYCN, ATRX, and TERT alterations, differ in frequency by age. MYCN alterations occur at median 2.3 years of age, TERT at 3.8 years, and ATRX at 5.6 years, suggesting age-specific susceptibility to genetic alterations. Mutational signature analysis shows that reactive oxygen-species (ROS)-induced mutations are the most common cause of single nucleotide variant (SNV) drivers in neuroblastoma, including most ALK and Ras pathway SNVs. ROS-induced mutagenesis is both an early event, as it causes truncal variants, and continuous as it also induces relapse-specific mutations. ROS-induced mutations are more abundant in neuroblastomas with MYCN amplification, 17q gains, and increased expression of mitochondrial ribosome genes. We observe recurrent FGFR1 N546K or internal tandem duplication variants in 6 patients and ALK N-terminal structural alterations in 5 samples, identifying additional patients amenable to precision therapy.

  Study EGAS00001003931

• Genomic and transcriptomic analysis of thymic epithelial tumors

  Thymic epithelial tumors (TETs), comprising various histologic types of thymomas and thymic carcinomas, originate from thymic epithelial cells. Each histologic type is typically associated with a distinct immune cell composition and clinical manifestation. A better understanding of the cellular origins and molecular pathways underlying this heterogeneity is needed to improve patient stratification and treatment. Here, we conducted an integrated genomic and transcriptomic analysis of 124 thymomas and 13 thymic carcinomas, including 20 newly sequenced cases combined with 117 cases from publicly available datasets. This approach stratified TETs into three subgroups with different possible origins: GTF2I-mutant (GTF2I-type) thymomas, copy number-altered (CN-type) thymomas, and thymic carcinomas.

  Study EGAS00001004227

• Genetic Basis of Cryptorchidism

  Non-syndromic cryptorchidism is a common malformation, but the genetic loci that increase susceptibility to cryptorchidism remain unknown. A genome-wide association study (GWAS) was completed to determine whether common allelic variants are associated with susceptibility to cryptorchidism. Two sets of discovery groups were genotyped. Group 1 (559 cases and 1772 controls) was genotyped with HumanHap550v1.0, HumanHap550v3.0 or Human610-quad v1.0. Group 2 (353 cases and 1149 controls) was genotyped with HumanOmniExpress-12v1 or HumanOmniExpress-12v1-1. The sample and marker QCs were performed separately using PLINK (v1.07; http://pngu.mgh.harvard.edu/purcell/plink/) and logistic regression analyses were performed with first and second multidimensional scaling (MDS) components as covariates.

  Study phs000986

• BIRC5 Upregulation Enhances DNMT3A-Mutant T-ALL Cell Survival and Pathogenesis

  The goal of this study was to determine how patients with T-ALL who have DNA methyltransferase 3 alpha (DNMT3A) mutations develop resistance to therapy. Since DNMT3A is a methyltransferase, we examined the effect of those mutations on epigenetic regulation using whole genome bisulfite sequencing (WGBS). We also assessed any changes in gene expression using RNA-sequencing. We found that T-ALL patients with DNMT3A mutations are resistant to apoptosis and some chemotherapies. WGBS showed that DNMT3A mutated patients clustered together by their epigenetic profile, which was associated with hypomethylation at TERT and HOX genes. RNA sequencing identified differences in JAK/STAT signaling.

  Study phs003623

• Chordoma_Sequencing_Project_RNAseq

  This is a continuation of the Chordoma Sequencing Project. All cancers arise due to somatically acquired abnormalities in DNA sequence. Systematic sequencing of cancer genomes allows acquisition of complete catalogues of all classes of somatic mutation present in cancer. These mutation catalogues will allow identification of the somatically mutated cancer genes that are operative and characterise patterns of somatic mutation that may reflect previous exogenous and endogenous mutagenic exposures. In this application, we aim to perform whole genome sequencing on 10 chordoma matched genome pairs. RNA Sequencing/Methylation and SNP6 and an additional sequencing of three cancer cell lines will be added to this work.

  Study EGAS00001000410

• National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III)

  The National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III) is a nationally representative cross-sectional survey of the U.S. general population, which was sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and conducted in 2012-2013. The NESARC-III's target population was the U.S. noninstitutionalized civilian population, 18 years and older, including residents of selected group quarters (e.g., group homes, workers' dormitories). Multistage probability sampling was used to randomly select respondents. Primary sampling units (PSUs) were individual counties or groups of contiguous counties, secondary sampling units (SSU) comprised groups of Census-defined blocks, and tertiary sampling units were households within SSUs. Finally, eligible adults within sampled households were randomly selected. Hispanics, Blacks, and Asians were oversampled and resulted in a total of 36,309 respondents. All respondents provided informed consent for survey participation. Data were adjusted for oversampling and screener - and person-level nonresponse, then weighted through post-stratification to represent the US civilian population based on the 2012 American Community Survey. These weighting adjustments were found to compensate adequately for nonresponse. Interviewer field methods involved initial structured home study, in-person training, ongoing supervision, and random respondent callbacks to verify data. The NESARC-III collected information on alcohol and drug consumption, alcohol use disorder, other substance use disorders (e.g., nicotine, cannabis and opioid), and associated physical and psychiatric adverse consequences. In addition to a full array of sociodemographic characteristics such as race/ethnicity, gender, age, risk and environmental factors including adverse childhood experiences (e.g., sexual, physical abuse and neglect) and family history for alcohol, drug use disorders and other psychiatric disorders (e.g., mood, anxiety, personality disorders and PTSD) were included (phenotypic variables=4,320). As part of the NESARC-III, 22,848 informative samples were genotyped on Affymetrix Axiom Exome Array consisting of 319,283 SNPs and 103,404 custom-selected SNPs Array (refer to the SNP annotation file). The latter array was selected based on the addiction associated genes, the results of 5 GWAS of alcohol and other psychiatric disorders, and animal models with addiction phenotypes. After filtering out poor quality SNPs using the standard Affymetrix pipeline there are 295,218 SNPs in the NESARC-III genetic data. The 22,848 subjects in this study were all deeply and consistently phenotyped via structured diagnostic interview. Controls group can be selected for specific disorders from a pool of all samples. Here are numbers of cases for major DSM-5 mental disorders in NESARC-III genetic data: Alcohol use disorder (7,075); Nicotine use disorder (6,641); Drug use disorder (2,570); Major depressive disorder (5,214); Persistent depression(1,429); Bipolar I (543); Anxiety disorders (4,226); PTSD (1,674); Personality disorders (4,014); Eating Disorders (457).

  Study phs001590

• Capturing disease severity in LIS1-lissencephaly reveals proteostasis dysregulation in patient-derived forebrain organoids

  Lissencephaly is a developmental cortical malformation characterized by reduced to absent gyri and a disorganized cortex, often leading to severe impairments in affected individuals and a reduced life expectancy. Heterozygous mutations in the LIS1 gene, encoding a regulator of the microtubule motor dynein, cause lissencephaly with different clinical severities. While the clinical disease spectrum correlates with the degree of lissencephaly, location and type of mutation may not. We leveraged forebrain-type organoids from LIS1-lissencephaly patients, diagnosed with mild, moderate or severe lissencephaly to investigate, in a cytoarchitecture and multi-omics approach, how the severity degree in patients might relate to specific mutations in the LIS1 gene. We questioned which processes during cortical development might be differentially affected by severity grade, and whether they could be pharmacologically targeted. We found alterations in neurodevelopment often with a severity-dependent gradient. Specifically, we identified alterations of the cytoarchitecture, progenitor cell homeostasis and neurogenesis. Particularly important disease-linked molecular mechanisms were microtubule destabilization, WNT-signaling, and perturbed cadherin- and unfolded protein-binding. Some mechanisms exhibited a severity-dependent gradient, or were specific to a severe grade. We present strategies to reverse phenotypic changes in LIS1-patient organoids, and an in silico approach with therapeutic potential. Thus, we show that different LIS1-severity grades can be recapitulated in vitro, that there is a direct link between the phenotype and genotype, that organoid-based disease modeling can identify molecular underpinnings of malformations of cortical development and that organoids provide a valid platform to develop and test therapeutic strategies.

  Study EGAS00001008227

• The mutational landscape and its longitudinal dynamics in relapsed and refractory Hodgkin lymphoma

  In classical Hodgkin-lymphoma (cHL), only a few cases recur, and only a limited fraction of patients is primary-refractory to standard-polychemotherapy. Underlying genomic features of unfavorable clinical courses remain sparsely characterized. Here, we investigated the genomic characteristics of primary-refractory/relapsed cHL in contrast with long-term-responders (LTR). In total, data from 84 samples were submitted.

  Study EGAS50000000149

• Myocardial Infarction Genetics Exome Sequencing Consortium: Precocious Coronary Artery Disease Study

  The Precocious Coronary Artery Disease (PROCARDIS) study is an international, multicenter case-control study aimed at discovering the genetic contributors to premature coronary artery disease. All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Agilent SureSelect Human All Exon Kit v2 and sequencing was performed on an Illumina HiSeq 2000 or 2500.

  Study phs000883

• Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE)

  The STRRIDE study is the combination of three interventional trials to evaluate dose and intensity of physical activity on cardiometabolic health. The three component studies are Peripheral Effects of Exercise on Cardiovascular Health (STRRIDE I, ClinicalTrials.gov Identifier: NCT00200993), Effects of Resistence and Aerobic Exercise on Cardiovascular Health (STRRIDE II, ClinicalTrials.gov Identifier: NCT00275145) and Exercise Dose-Response Effects in Prediabetes (STRRIDE-PD, ClinicalTrials.gov Identifier: NCT00962962).

  Study phs001855

• Genetic Analysis of Limb Malformation Disorders: Freeman Sheldon Syndrome Exome Sequencing Study (LMD-FSS)

  The overall goal of this project is to investigate the etiology and pathogenesis of malformations (i.e., birth defects) of the limb, concentrating on abnormalities of limb patterning such as limb deficiency/duplications and multiple congenital contractures. The exome sequences of four unrelated individuals were obtained by massively parallel DNA sequencing. The three individuals were affected with Freeman Sheldon syndrome (OMIM: 193700).

  Study phs000204

• FluOMICS

  The FluOMICS project is to generate predictive models of influenza virus pathogenesis, leveraging previous collaborations that generated global datasets and models that predict the severity of disease caused by three influenza virus strains with different levels of virulence. This case-control study of patients diagnosed with severe and mild influenza virus disease evaluates associations between potential molecular regulators of the host response and determinants of disease outcome.

  Study phs003407

• Constrained hypermutation and absence of TERT promoter mutations in Lynch syndrome-associated urothelial cancer

  Lynch syndrome is a hereditary condition characterized by defective DNA mismatch repair and high incidence of several cancers, including urothelial cancers (UC) of the upper urinary tract and bladder. We set out to study the somatic landscape of LS-associated urothelial cancer (LS-UC) by analyzing 41 surgical tumor samples and 3 urine DNA samples from 34 LS-UC patients.

  Study EGAS50000000831

• Differentiation-associated ISG expression of NK cells in chronic viral hepatitis

  Little is known about the effects of ISGs on NK cell responses in chronic viral hepatitis. Here, we determined the expression, regulation and function of ISGs in NK cells with respect to phenotype and function, we performed high-throughput single cell RNA sequencing of circulating CD3-CD56+ NK cells from healthy donors (HD) and patients with chronic HBV or HCV infections.

  Study EGAS00001007771

• Whole-exome sequencing of extranodal NK/T cell lymphoma

  Extranodal NK/T cell lymphoma (ENKTCL) is an aggressive Epstein-Barr virus-associated T/NK neoplasm that predominantly affects Asians. To explore the causative somatic events, we conducted a comprehensive genetic analysis of 19 ENKTCL patients including whole-exome sequencing (N = 16). Commonly deregulated gene pathways in ENKTCL included epigenetic modifiers followed by human leukocyte antigen (HLA) and related genes and JAK-STAT pathway.

  Study EGAS00001004357

• Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial

  ABACUS is a single arm phase 2 study that investigated 2 cycles of atezolizumab (1200mg Q3) prior to cystectomy in 95 patients with muscle invasive transitional cell cancer (T2-4N0M0). Pathological complete response (pCR) occurring in ≥20% of patients was the primary endpoint. Biomarker analysis on sequential tissue was a co-primary endpoint.

  Study EGAS00001004445

• Legal Notice EGA is a joint effort by the EBI and CRG. Please, check their terms of use and legal notice in order to follow them in the usage of the EGA website. EBI terms of use CRG terms of use

  Documentation legal-notice

• Paediatric glioma cell line WGS

  Whole genome sequencing of 5 paediatric glioma cells lines - KNS42, SF188, UW479, RES186 and RES259. Illumina paired end sequencing is provided as 5 BAM files aligned to hg19 with bwa.

  Dataset EGAD00001004123

• CHEWIE ctDNA in Rhabdomyosarcoma

  Targeted DNA based panel of multiple ctDNA samples from 10 patients througout clinical care to assess treatment response. The panel is custom-designed and property of UGS, IC.

  Dataset EGAD00001011127

• The Chromatin Landscape of Pathogenic Transcriptional Cell States in Rheumatoid Arthritis

  In this study, we characterized 24 rheumatoid arthritis (RA) synovial tissue chromatin classes (i.e., cell states defined by chromatin accessibility) across 5 cell types (T, B/plasma, myeloid, stromal, and endothelial). We also investigated the transcription factors that may regulate these chromatin classes, their connections to transcriptional cell states in a proposed superstate model, and their interplay with RA pathology through associations with histological parameters and risk variants.As part of the Accelerating Medicines Partnership (AMP) network, we obtained 18 synovial tissue samples from 14 RA and 4 osteoarthritis (OA) patients for this study. Samples were collected from 7 clinical sites. We performed a 10x single cell ATAC-seq experiment on each sample.We further collected synovial tissue samples from 11 RA patients and 1 OA patient from 2 clinical sites; each sample was used for a 10x single cell multimodal ATAC and Gene Expression experiment.For additional support of the proposed superstate model, we also collected peripheral blood mononuclear cells (PBMCs) from 4 RA patients, sorted for 4 populations (CD4+CD127-CD25hi Tregs, CD4+CD127-CD25int Tregs, CD4+CD25-PD1+CXCR5- TPH, CD4+CD25-PD1+CXCR5+ TFH), tagged each population with a hashing antibody, and pooled populations for one multimodal sequencing run.The FASTQ files are available for controlled access via dbGaP. Additional data can be found on Synapse.The presence of pooled subjects inflates the automatically-generated subject count; the actual consented subject count for this data is 34.

  Study phs003417

• Direct Comparative Analysis of 10X Genomics Chromium and Smart-seq2

  Single cell RNA sequencing (scRNA-seq) is widely used for profiling transcriptomes of individual cells. The droplet-based 10X Genomics Chromium (10X) approach and the plate-based Smart-seq2 full-length method are two frequently-used scRNA-seq platforms, yet there are only a few thorough and systematic comparisons of their advantages and limitations. Here, by directly comparing the scRNA-seq data by the two platforms from the same samples of CD45- cells, we systematically evaluated their features using a wide spectrum of analysis. Smart-seq2 detected more genes in a cell, especially low abundance transcripts as well as alternatively spliced transcripts, but captured higher proportion of mitochondrial genes. The composite of Smart-seq2 data also resembled bulk RNA-seq data better. For 10X-based data, we observed higher noise for mRNA in the low expression level. Despite the poly(A) enrichment, approximately 10-30% of all detected transcripts by both platforms were from non-coding genes, with lncRNA accounting for a higher proportion in 10X. 10X-based data displayed more severe dropout problem, especially for genes with lower expression levels. However, 10X-data can better detect rare cell types given its ability to cover a large number of cells. In addition, each platform detected different sets of differentially expressed genes between cell clusters, indicating the complementary nature of these technologies. Our comprehensive benchmark analysis offers the basis for selecting the optimal scRNA-seq strategy based on the objectives of each study.

  Study EGAS00001003973

• Genetics and therapeutic responses to TIL therapy of pancreatic cancer PDX models

  Pancreatic cancer is the 7th leading cause of cancer-related deaths worldwide. Checkpoint immunotherapy has not yet showed encouraging results in pancreatic cancer possibly owing to a poor immunogenicity and/or an immune suppressive microenvironment. The aim of this study was to develop patient-derived xenografts (PDX) models and to assess if autologous tumor-infiltrating lymphocytes (TILs) would have anti-tumoral activity in pancreatic cancer. Tumor biopsies from 29 patients were subcutaneously transplanted into NOG mice. Tumor growths were confirmed in 11 out of 29 transplantations. The PDX tumors histologically resembled their original biopsies, but since stromal cells in the PDX model tumors were from mouse, their gene expression differed from the original biopsies. Immune checkpoint ligands other than PD-L1 were expressed in pancreatic cancers but PD-L1 was rarely expressed. One of the three tumors that did express PD-L1 was an adenosquamous cancer and another had a mismatch repair deficiency. TILs were expanded from six tumors and were injected into NOG or human interleukin-2 transgenic-NOG (hIL2-NOG) mice carrying PDX tumors. Regression of tumors could be verified in hIL2-NOG mice in 3 of the 6 PDX models treated with autologous TILs, including the adenosquamous PDX model. In conclusion, PDX models of pancreatic cancer can be used to learn more about tumor characteristics and biomarkers, and to evaluate responses to ACT and combination therapies. The major benefit of the model is that modifications of T cells can be tested in an autologous humanized mouse model to gain preclinical data to support the initiation of a clinical trial.

  Study EGAS00001005596

• Resistance to anti-EGFR therapy in colorectal cancer

  Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR), such as cetuximab and panitumumab, have evolved to important therapeutic options in metastatic colorectal cancer (CRC). However, almost all patients with clinical response to anti-EGFR therapies show disease progression within a few months and little is known about mechanism and timing of resistance evolution. Here we performed whole genome sequencing of plasma DNA (plasma-Seq) from patients treated with anti-EGFR therapy. We demonstrate that development of resistance to anti-EGFR therapies is frequently associated with focal amplifications of KRAS, MET, and ERBB2. However, we also show that focal KRAS amplifications can be acquired in tumor genomes of patients under cytotoxic chemotherapy. Furthermore, we provide evidence that specific chromosomal polysomies, such as overrepresentations of 12p and 7p, harboring KRAS and EGFR, respectively, determine responsiveness to anti-EGFR therapy. In contrast, employing ultra-sensitive deep sequencing of genes associated with anti-EGFR resistance, such as KRAS, BRAF, PIK3CA, and EGFR, we did not observe the occurrence of novel, acquired mutations. Overall, whole-genome plasma DNA sequencing represents a non-invasive blood-based surrogate measure of changes in tumors. As such, plasma-Seq enables the identification of novel mutant clones and may therefore facilitate early adjustments of therapies that may delay or prevent disease progression.

  Study EGAS00001000582

• IHEC DEEP Release August 2016

  Additional sequencing data for the German IHEC contribution (DEEP, http://deep.dkfz.de/, http://www.deutsches-epigenom-programm.de/). This is the additional data released in August 2016. Contains datatypes: - Whole Genome Bisulfite sequencing - ChipSeq (H3K27ac, H3K27me3, H3K36me3, H3K4me1, H3K4me3, H3K9me3, Input) - tRNA – not unmapped - mRNA - snRNA - Dnase Hypersensitive sites - RRBS - NOMe

  Study EGAS00001001937

• Cerebrospinal fluid circulating tumour DNA allows the characterisation and monitoring of medulloblastoma

  The molecular characterisation of medulloblastoma, the most common paediatric brain tumour, is crucial for the correct management and treatment of this heterogenous disease. In this study we show that CSF ctDNA allows the molecular characterisation and monitoring of medulloblastoma. This can ultimately facilitate the clinical management of medulloblastoma patients.

  Study EGAS00001004651

• Melanoma_post_mortem_analysis

  This is a targeted pulldown validation in support of the existing whole-genome sequencing study of melanoma metastases (Canapps ID:1888). We are studying the genomic evolution of cutaneous melanoma metastases. In this pulldown analysis we are specifically sequencing the subclonal variants that we believe account for the variability between the metastases.

  Study EGAS00001003531

• Hereditary Cancer Diagnostics with I2HCP gene panel

  Germline blood DNA sequencing data generated in routine diagnostics of hereditary cancer using the I2HCP gene panel (~135 genes). There are 130 samples sequenced in a MiSeq machine and 108 sequenced in a HiSeq machine. There is a partial overlap between those two sets, meaning that some samples were sequenced in both machines. There is a strong enrichment in samples with copy-number variants (CNV), both single- and multi-exon, since this dataset was compiled for a benchmarking effort of CNV calling tools for genetic diagnostics.

  Dataset EGAD00001006171

• Melanoma-Til Study RNAseq

  In this study, mutations present in a series of human melanomas (stage IV disease) will be determined, using autologous blood cells to obtain a reference genome. From each of the samples that are analyzed, tumour-infiltrating T lymphocytes have also been isolated. This offers a unique opportunity to determine which (fraction of) mutations in human cancer leads to epitopes that are recognized by T cells. The resulting information is likely to be of value to understand how T cell activating drugs exert their action.

  Dataset EGAD00001000325

• High response rate to anti PD-1 therapy in desmoplastic melanoma

  Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, but is highly associated with ultraviolet light DNA damage. We analysed 60 patients with advanced DM treated with programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1) blocking antibody therapy. Objective tumor responses were observed in 42 of the 60 patients (70%, 95% confidence interval 57-81%), including 19 patients (32% overall) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF-1 mutations (14 out of 17 cases). Immunohistochemistry (IHC) analysis from 19 DM and 13 non-DM revealed a higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with increased CD8 density and PD-L1 expression in the tumor invasive margin. Therefore, patients with advanced DM derive significant clinical benefit from PD-1/PD-L1 immune checkpoint blockade therapy despite being a cancer defined by its dense desmoplastic fibrous stroma. The benefit is likely derived from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.

  Study phs001469

• USZ Dermatology and UZH DQBM DAC

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

  Dac EGAC50000000853

• Proteomic Analysis of Non-Muscle Invasive and Muscle Invasive Bladder Cancer Highlights Distinct Subgroups With Metabolic, Matrisomal, and Immune Hallmarks

  We present the proteome biology of bladder cancer based on a cohort comprising treatment-naïve non-muscle invasive (NMIBC, N=17) and treatment-naïve muscle-invasive bladder cancer (MIBC, N=51), as well as neoadjuvant-treated MIBC (N=11); using formalin-fixed, paraffin-embedded samples and data-independent acquisition yielding >8,000 protein identifications. The NMIBC proteome reveals two subgroups that represent cell adhesion or lipid metabolism biology. MIBC, compared to NMIBC, shows an altered metabolic proteome together with enrichment of extracellular matrix (ECM), immune response, and complement proteins; in line with three proteomic MIBC subgroups that represent ECM, metabolic, or immune signatures. The ECM and immune subgroups are enriched for markers of M2-like tumor-associated macrophages and dendritic cells, while markers for natural killer cells are exclusive for the ECM subgroup, and markers for cytotoxic T-cells are a hallmark of the immune subgroup. Infiltration of CD8+ PD1+ positive cytotoxic T cells correlated with PD-L1 expression of MIBC, as demonstrated by multiplex immunofluorescence analysis. The metabolic subgroup presents a comparably immune-depleted microenvironment. YAP1 signaling is particularly prominent in the ECM subgroup. The protein BSCL2 emerges as a prognostic marker for MIBC. We highlight increased endogenous proteolysis in MIBC alongside the upregulation of matrix metalloproteases exceeding the upregulation of their endogenous inhibitors. Genomic panel sequencing underlines prevalent FGFR3 mutations in NMIBC and prevalent TP53 mutations in MIBC, but a genomic underpinning of the MIBC subgroups remains elusive. Proteogenomic analysis yields protein-level evidence for more than 1,300 single amino acid variants. The proteomes of neoadjuvant-treated MIBC resembled treatment-naïve MIBC. Tumor-stroma interaction of MIBC was further investigated by proteomic analysis of patient-derived xenografts of MIBC. Our study adds to the proteome-level understanding of bladder cancer.

  Study EGAS00001007290

• Capmatinib shows superior efficacy for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy

  Pediatric high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGGs, and are associated with devastating morbidity and mortality. To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion iHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy (RT).

  Study EGAS50000000137

• National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) Consortium Glaucoma Genome-Wide Association Study

  This is a case-control study of primary open angle glaucoma (POAG). POAG is an intraocular pressure (IOP) related progressive optic neuropathy that ultimately leads to blindness. For this study we have formed a collaborative consortium contributing 2170 POAG cases and 2347 controls with a unified definition of POAG (the NEIGHBOR consortium: NEI Glaucoma Human genetic collaBORation). The case definition has also been harmonized with an additional 976 cases and 1140 controls from the NHGRI supported GENEVA (gene-environment) study of glaucoma (GLAUGEN) (NIH/NHGRI U01HG004728, Pasquale PI). Cases and controls were recruited from ophthalmology clinics and were examined by ophthalmologists. For cases, the clinical exam included intraocular pressure measurements, optic nerve assessment and visual field evaluation. Controls had no family history of glaucoma, normal intraocular pressure and normal optic nerves. Cases and controls were also drawn from two clinical trial populations: Advanced Glaucoma Intervention Study (AGIS, NEI U10EY006827, D. Gaasterland PI) and Collaborative Initial Glaucoma Treatment Study (CIGTS, NEI U10 EY009149, P. Lichter PI). The NEIGHBOR consortium has two Co-Principal Investigators: J. Wiggs (Harvard, MEEI), and M. Hauser (Duke). The consortium includes eleven different centers where data collection and analysis take place. The eleven sites and investigators are: Harvard Medical School (Massachusetts Eye and Ear Infirmary) (J. Wiggs, L. Pasquale); Duke University Medical Center (M. Hauser, E. Hauser, R. Allingham, S. Schmidt); University of Michigan (J. Richards, S. Moroi, P. Lichter); University of Miami (M. Pericak-Vance, R. Lee, D. Budenz); Vanderbilt University (J. Haines); University of California San Diego (K. Zhang, R. Weinreb; T. Gaasterland); University of Pittsburgh (J. Schuman, G. Wollstein); University of West Virginia (A. Realini, J. Charlton, S. Zareparsi); Johns Hopkins University (D. Friedman, D. Zack); Stanford University (D. Vollrath, K. Singh), Eye Doctors of Washington (D. Gaasterland). Hemin Chin serves as the NEI Staff Collaborator. This national collaborative study is supported by multiple NIH grants: NEI R01 EY015543 (Allingham); NEI U10 EY006827 (D. Gaasterland); NHLBI R01 HL073389 (E. Hauser); NEI R01 EY13315 (M. Hauser); NEI U10 EY009149 (Lichter); NEI R01 EY015473 (Pasquale); NEI U10 EY012118 (Pericak-Vance); NEI R03 EY015682 (Realini); NEI R01 EY011671 (Richards); NEI R01 EY09580 (Richards); NEI R01 EY013178 (Schuman); NEI R01 EY015872 (Wiggs); NEI R01 EY009847 (Wiggs); NEI R01 EY010886 (Wiggs); NEI R01 EY144428 (Zhang); NEI R01 EY144448 (Zhang); NEI R01 EY18660 (Zhang). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the National Eye Institute (X01HG005259).

  Study phs000238

• Genetic Analysis of Desmoplastic Melanoma

  Desmoplastic melanoma is an infrequent variant of melanoma with sarcomatous histology, distinct clinical behavior, and unknown pathogenesis. We performed low-coverage genome and high-coverage exome sequencing of 20 desmoplastic melanomas, followed by targeted sequencing of 293 genes to validate candidate genes. A high mutation burden (median 62 mutations/Mb) ranked desmoplastic melanoma among the most highly mutated cancers. Mutation patterns strongly implicate UV-radiation as the dominant mutagen, indicating a superficially located cell of origin. Novel alterations included recurrent promoter mutations of NF-kappa B inhibitor epsilon, NFKBIE (IkBε) in 14.5% of samples. Commonly mutated oncogenes in melanomas, in particular BRAF(V600E) and NRAS(Q61K/R), were absent. Instead, other genetic alterations known to activate the MAPK and PI3K signaling cascades were identified in 73% of samples, affecting NF1, CBL, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, PTPN11, MET, RAC1, SOS2, NRAS, and PIK3CA, some of which being candidates for targeted therapies. Reprinted from: Shain, A. H. et al. Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway. Nat. Genet. With permission from Nature Genetics

  Study phs000977

• Khoe-San genomes reveal unique variation and confirm deepest population divergence in Homo sapiens

  The southern African indigenous Khoe-San populations harbor the most divergent lineages of all living peoples. Exploring their genomes is key to understanding deep human history. We sequenced 25 full genomes from five Khoe-San populations, revealing many novel variants, that 25% of variants are unique to the Khoe-San, and that the Khoe-San group harbors the greatest level of diversity across the globe. In line with previous studies, we found several gene-regions with extreme values in genome-wide distributions, potentially caused by natural selection early in the modern human lineage and more recent in time. These gene-regions included immunity-, sperm-, brain-, diet- and muscle-related genes. When accounting for recent admixture, all Khoe-San groups display genetic diversity approaching the levels in other African groups and a reduction in effective population size starting around 100,000 years ago. Hence, all human groups show a reduction in effective population size commencing around the time of the Out-of-Africa migrations, which coincides with changes in the paleoclimate records, changes that potentially impacted all humans at the time.

  Study EGAS00001004459

• Patient-derived neuroblastoma model system OHC-NB1

  Accurate disease modeling presents a bottleneck against effective translation of novel neuroblastoma therapies into the clinic. Recently, considerable intra-tumor genetic heterogeneity has been observed in neuroblastoma, which calls for preclinical models that reflect this feature. Flexibility in a testing platform is also desirable to support assessment of different endpoints and tumor cell characteristics. We present the novel neuroblastoma model OHC-NB1, propagated from a bone marrow metastasis from a patient with INRG stage M, MYCN-amplified neuroblastoma at first diagnosis. To model different aspects of the disease, several preclinical models were developed from the bone marrow aspirate: a tissue plastic-adherent cell line, a 3-dimensional (3D) spheroid culture, and cell line-derived xenografts that were subcutaneously passaged in mice. Typical aspects of MYCN-amplified neuroblastoma, such as MYCN amplification in double minutes, 1p deletion, 17q gain, and a diploid karyotype, are present in OHC-NB1 and persist in all culture types. Whole exome sequencing revealed intra-tumor heterogeneity in the bone marrow metastasis reflected in the culture models. The set of OHC-NB1 cultures with a genetically heterogeneous MYCN-amplified neuroblastoma background provide a flexible preclinical testing system that recapitulates important features of metastatic neuroblastoma.

  Study EGAS00001003031

• Precision Interception of Gastric Cancer Precursors Through Molecular and Cellular Risk Stratification

  The GAstric Precancerous conditions Study (GAPS, NCT04191551) is a cross-sectional study of patients undergoing endoscopy who are at increased risk of gastric cancer. Enrolled patients are administered a standardized questionnaire, undergo clinical biopsy collection using the Sydney system, and consent for the collection of saliva, blood, and additional gastric tissue. All patients are scored for intestinal metaplasia using the operative link on gastric intestinal metaplasia (OLGIM) scoring system.

  Study phs003648

• BCR_repertoire_sequencing

  Isotype-specific B-cell receptor repertoire sequencing in six immune-mediated diseases at diagnosis and during therapy reveals an unexpectedly complex B-cell architecture, which may provide a platform for a better understanding of pathological mechanisms and treatment responses. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003185

• An isogenic human iPSC model unravels neurodevelopmental abnormalities in SMA

  Whether neurodevelopmental defects underlie the selective neuronal death that characterizes neurodegenerative diseases is becoming an intriguing question. To address it, we focused on the motor neuron (MN) disease Spinal Muscular Atrophy (SMA), caused by reduced levels of the ubiquitous protein SMN. Taking advantage of the first isogenic human induced pluripotent stem cell-derived SMA model that we have generated and a spinal cord organoid system, here we report that the relative and temporal expression of early neural progenitor and MN markers is altered in SMA. Furthermore, the corrected isogenic controls only partially reverse these abnormalities. These findings raise the relevant clinical implication that SMN-increasing treatments might not fully amend SMA pathological phenotypes. The approach we have taken demonstrates that the discovery of new disease mechanisms is greatly improved by using human isogenic models. Moreover, our study implies that SMA has a developmental component that might trigger the MN degeneration.

  Study EGAS00001007259

• Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

  Mutation accumulation over time in normal somatic cells contributes to cancer development and is proposed as a cause of ageing. DNA polymerases POLE and POLD1 replicate DNA with high fidelity during normal cell divisions. However, in some cancers defective proofreading due to acquired mutations in the exonuclease domains of POLE or POLD1 causes markedly elevated somatic mutation burdens with distinctive mutational signatures. POLE and POLD1 exonuclease domain mutations also cause familial cancer predisposition when inherited through the germline. Here, we sequenced normal tissue DNA from individuals with germline POLE or POLD1 exonuclease domain mutations. Increased mutation burdens with characteristic mutational signatures were found to varying extents in all normal adult somatic cell types examined, during early embryogenesis and in sperm. Mutation burdens were further markedly elevated in neoplasms from these individuals. Thus human physiology is able to tolerate ubiquitously elevated mutation burdens. Indeed, with the exception of early onset cancer, individuals with germline POLE and POLD1 exonuclease domain mutations are not reported to show abnormal phenotypic features, including those of premature ageing. The results, therefore, do not support a simple model in which all features of ageing are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.

  Dataset EGAD00001006212

• Perceptions, Prevalence, and Patterns of Cannabis Use among Cancer Patients in NCI-Designated Cancer Centers

  This study aimed to better understand the evolving landscape of cannabis use among patients undergoing cancer treatment across diverse geographic regions. It sought to characterize patterns of use, patient perceptions, and contextual influences such as legal status and provider engagement that affect cannabis use. Given the shifting legal environment, this study addresses a critical gap in the literature by providing data on how cancer patients integrate cannabis into their care. The available delivery methods of cannabis have also undergone dramatic changes and now include edibles, oils, tinctures, topicals, and inhaled forms. State-based policy changes are rapidly changing. Yet research on cannabis use by cancer patients across a variety of geographic settings remains limited. The extent of cannabis use, the perceived and real benefits and risks of use, potential interactions with cancer treatment and other medications, and impact on comorbid conditions are uncertain. Clinicians should be aware of the extent of use in order to assess potential drug-drug interactions, side effects, and contraindications; hence, an understanding of how cancer patients and clinicians engage in discussions about cannabis use is essential. Twelve NCI-designated cancer centers were awarded supplemental funding to conduct surveys assessing cannabis use among recently diagnosed cancer patients. Selected sites were in 8 states with varied legal status for medical and recreational cannabis use at the time of the survey. The 12 cancer centers independently received approval from their institutional review boards (IRB) and collected data from September 2021 to August 2023. Eligible participants were cancer patients or survivors who resided in their respective cancer center's catchment area. Cancer centers were responsible for sampling patients within their catchment area with the goal of 1,000 completed surveys. Ten out of 12 cancer centers drew probability samples of patients from patient lists defining their catchment area with some stratifying the sample in various ways including by cancer type, by sex, by race/ethnicity or by a combination of demographic variables.

  Study phs004046

• Benchmarking dataset for ProSolo, a probabilistic single nucleotide caller for single cell DNA sequencing data

  This is the dataset used in the benchmarking of ProSolo, a new probabilistic single nucleotide variant caller for single cell DNA sequencing data that provides control over the false discovery rate of different single cell events at genomic sites (e.g. alternative allele presence or allele dropout). It provides the whole exome sequencing data used in assessing ProSolo's performance that is not available elsewhere, namely bulk whole exome sequencing data of a patient with a constitutional mismatch repair defect (MSH6-) and their parents and siblings, a bulk whole exome sample of granulocytes from that patient and 5 single granulocytes whole exome sequenced after whole genome amplification.

  Dataset EGAD00001005929

• Gut microbiome profiles according to sex, body mass index and dietary fiber intake

  Findings from recent studies suggest that the community of microbes residing in the human body is important in disease etiology; however, it remains unclear whether personal factors modulate human microbial composition. Studies based on animal models indicate that differences in composition might be attributed to sex-mediated effects. We analyzed the relationship of sex, adiposity, and dietary fiber intake with gut microbial composition using fecal samples from human subjects. We explored the associations of these factors with metrics of community composition and specific taxon abundances. We found that men and women had significantly different microbial community composition and that women had reduced abundance of a major phylum. Adiposity was associated with gut microbiome composition and specifically in women but not in men. Fiber from fruits and vegetables and fiber from beans were each associated with increased abundance of specific bacterial taxa. These findings provide initial indications that sex, adiposity, and dietary fiber might play important roles in influencing the human gut microbiome. Better understanding of these factors may have significant implications for gastrointestinal health and disease prevention.

  Study phs000884

• Clinical and ctDNA data for IMpassion031

  Clinical and ctDNA data for IMpassion031, including survival, response, and ctDNA data from baseline through post-surgery time points. 222 samples run on Signatera assay. File type is csv.

  Dataset EGAD50000001420

• A Case-Controlled Study for Genotype-Phenotype Associations in Multiple Sclerosis (MS)

  This is a multi-centre, case-controlled study to develop a dataset containing 1000 MS cases and 1000 matched controls and to associate DNA sequence (allelic) variations with MS phenotypes. Study subjects were enrolled through a prospective effort initiated in 2003. Three MS clinical centres were involved in subject recruitment and biological specimen collection using identical inclusion/exclusion criteria, two in Europe (Vrije Universiteit Medical Center, Amsterdam; and University Hospital Basel) and one in the US (University of California San Francisco). This study recruited subjects of northern-European ancestry with a diagnosis of MS (McDonald et al., 2001), with dissemination in time and space. Patients with Clinically Isolated Syndromes (CIS) were also included if they fulfilled 3 of the 4 Barkhof criteria for dissemination in space as per application of the McDonald criteria (McDonald et al., 2001). While recruitment predominantly included subjects with a relapsing onset of MS, individuals with all clinical subtypes of the disease participated, including clinically isolated syndrome (CIS), relapsing remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PRMS). The control group consisted of unrelated individuals, primarily spouses/partners, friends, and other volunteers. Control subjects were of northern-European ancestry and matched as a group, proportionally with cases according to age (±5 years) and gender. A familial history or current diagnosis of MS as well as a relation to another case or control subject were considered exclusionary for this group. Protocols were approved by the Committees on Human Research at all Institutions and informed consent was obtained from all participants prior to participation in the study. Primary Study Objective:To identify DNA sequence variations (genotype) and flanking sequences that are associated with clinical factors (phenotype) which differ between study subjects with and without MS. Secondary Study Objectives: To develop a clinical dataset including quantitative measures of 1000 well-characterized cases with MS, and 1000 ethnically matched controls. To identify other genotype-phenotype associations in MS study subjects such as magnetic resonance imaging (MRI) measures of disease burden and/or severity. To identify or confirm candidate surrogate markers of neurodegeneration using a variety of techniques including biochemical assays, blood transcriptome analysis, plasma proteomics and MRI*. GenotypingGenotyping of the complete dataset was performed at the Illumina facilities using the Sentrix® HumanHap550 BeadChip. *MRI results are not available on dbGaP.

  Study phs000171

• Genome-wide DNA methylation sequencing identifies epigenetic perturbations in the upper airways under long-term exposure to moderate levels of ambient air pollution

  While the link between exposure to high levels of ambient particulate matter (PM) and increased incidences of respiratory and cardiovascular diseases is widely recognized, recent epidemiological studies have shown that low PM concentrations are equally associated with adverse health effects. As DNA methylation is one of the main mechanisms by which cells regulate and stabilize gene expression, changes in the methylome could constitute early indicators of dysregulated signaling pathways. So far, little is known about PM-associated DNA methylation changes in the upper airways, the first point of contact between airborne pollutants and the human body. Here, we focused on cells of the upper respiratory tract and assessed their genome-wide DNA methylation pattern to explore exposure-associated early regulatory changes. Using a mobile epidemiological laboratory, nasal lavage samples were collected from a cohort of 60 adults that lived in districts with records of low (Simmerath) or moderate (Stuttgart) PM10 levels in Germany. PM10 concentrations were verified by particle measurements on the days of the sample collection and genome-wide DNA methylation was determined by enzymatic methyl sequencing at single-base resolution. We identified 231 differentially methylated regions (DMRs) between moderately and lowly PM10 exposed individuals. A high proportion of DMRs overlapped with regulatory elements, and DMR target genes were involved in pathways regulating cellular redox homeostasis and immune response. In addition, we found distinct changes in DNA methylation of the HOXA gene cluster whose methylation levels have previously been linked to air pollution exposure but also to carcinogenesis in several instances. The findings of this study suggest that regulatory changes in upper airway cells occur at PM10 levels below current European thresholds, some of which may be involved in the development of air pollution-related diseases.

  Study EGAS00001007374

• Atypical teratoid/rhabdoid tumors (ATRT) are comprised of three epigenetic subgroups with distinct enhancer landscapes

  Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants and young children. Although the prognosis of ATRT patients is poor, some patients respond very well to current treatments, suggesting inter-tumor molecular heterogeneity. To investigate this further, we genetically and epigenetically analyzed a large cohort of ATRTs (n = 170). Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location and type of SMARCB1 alterations, were identified using DNA-methylation or gene expression analyses. Whole genome DNA- and RNA-sequencing found no other recurrent mutations explaining the differences between subgroups. However, whole genome bisulfite-sequencing and H3K27Ac ChIP-sequencing of primary tumors revealed clear differences in methylation patterns and enhancer landscapes, leading to the identification of subgroup-specific regulatory networks.

  Dataset EGAD00001001444

• RNAseq data from the study - Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML

  This study assessed molecular determinants of response in a cohort of patients with AML that were treated with venetoclax in combination with either DNA methyltransferase inhibitors or low dose cytarabine. RNA sequencing was performed on 31 patients from three different response classes [10 Group A - Durable remission (n=10), Group B - Relapsed (n=10) and Group C - Refractory (n=11)]. Library preparation and sequencing was performed at the Australian Genome Research Facility, using the Truseq Stranded mRNA library kit. Technical and batch replicate samples are included. Gene count data are provided with the original publication. The use of the sequencing data is subject to a data transfer agreement and is restricted to ethically approved research into blood cell malignancies and cannot be used to assess germline variants.

  Dataset EGAD00001005949

• NIDDK IBD Genetics Consortium Repository Immunochip

  The Immunochip is a custom Illumina Infinium chip comprising 196,524 SNPs and small indels selected primarily based on GWAS analysis of 12 autoimmune and inflammatory diseases. The chip has two purposes: fine mapping of 289 established associations corresponding to 187 distinct loci, and deep replication of suggestive, but not yet proven, associations. Fine-mapping regions were defined as 0.2cM centered on GWAS hit SNPs, and all SNPs and short indels in these regions from the 1000 Genomes Project low coverage pilot CEU samples, as well as variants discovered in resequencing experiments conducted by groups collaborating in the chip design were selected for inclusion. Replication of autoimmune and inflammatory GWAS (including Crohn's disease and ulcerative colitis) contributed the bulk of the remaining SNP lists. Approximately 25,000 SNPs were included as replication of unrelated diseases as part of the WTCCC2 project, which serve as useful null SNPs for these analyses. In total, approximately 240,000 SNPs were selected for inclusion, with an assay design success rate of ~80%. Reprinted from Jostins et al. (2012), with permission from Springer Nature (see https://www.nature.com/reprints/permission-requests.html). Jostins, L., et al. (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491, 119-24. PMID: 23128233.

  Study phs001721

• Genetic Predictors of Ibrutinib-Related Cardiovascular Side Effects in Patients with Chronic Lymphocytic Leukemia

  The goal of this study was to identify genetic polymorphisms associated with ibrutinib-related cardiovascular side effects (CVSEs). This is an observational non-interventional pharmacogenomic study of 50 patients with newly diagnosed or relapsed refractory chronic lymphocytic leukemia (NDCLL or RRCLL) receiving ibrutinib 420 mg for at least six months. The ibrutinib-related CVSEs included atrial fibrillation and hypertension, which occurred in 20% of patients. DNA obtained from buccal swabs was genotyped for 40 single nucleotide polymorphisms (SNPs) in GATA4, SGK1, KCNQ1, KCNA5, NPPA, and SCN5A using a customized next generation sequencing panel. It was found that GATA4 rs804280 AA (P =.043), KCNQ1 rs163182 GG (P =.036) and KCNQ1 rs2237895 AA (P =.023) were associated with the ibrutinib-related CVSEs. Patients with a high-risk score had at least two of the three significant risk genotypes identified in univariate analysis for GATA4 rs804280 A>C, KCNQ1 rs162182 G>C and KCNQ1 rs2237895 A>C, and patients with a low-risk score had either one or none of these genotypes. In multivariate analysis, 18 patients with at least two of the three high-risk genotypes had an 11.5-fold higher odds of CVSEs (P =.019; 1.79-119.73 at 95% CI).

  Study phs003370

• Rapid detection of expanded short tandem repeats in personal genomics using hybrid sequencing.

  Long expansions of short tandem repeats (STRs); i.e., DNA repeats of 2-6 nucleotides, are associated with some genetic diseases. Cost-efficient high throughput sequencing can quickly produce billions of short reads that would be useful for uncovering disease-associated STRs. However, enumerating STRs in short reads remains largely unexplored because of the difficulty in elucidating STRs much longer than 100 bp, the typical length of short reads. We propose ab initio procedures for sensing and locating long STRs promptly by utilizing the frequency distribution of all STRs and paired-end read information. We validated the reproducibility of this method using biological replicates and used it to locate an STR associated with a brain disease (SCA31). Subsequently, we sequenced this STR site in eleven SCA31 samples using SMRT? sequencing (Pacific Biosciences), determined 2.3-3.1 kb sequences at nucleotide resolution, and revealed that (TGGAA)- and (TAAAATAGAA)-repeat expansions determined the instability of the repeat expansions associated with SCA31. Our method could also identify common STRs, (AAAG)- and (AAAAG)-repeat expansions, which are remarkably expanded at four positions in an SCA31 sample. This is the first proposed method for rapidly finding disease-associated long STRs in personal genomes using hybrid sequencing of short and long reads.

  Study JGAS000002

• Genentech Colon Cancer Screen

  Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.

  Study EGAS00001000288

• Single cell sequencing of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis

  The quantity of tumor infiltrating lymphocytes (TILs) in breast cancer (BC) is a robust prognostic factor for improved patient survival particularly in triple negative and HER2-overexpressing BC subtypes. Whilst T cells are the predominant TIL population, the relationship between quantitative and qualitative differences in T cell subpopulations and patient prognosis remains unknown. We performed single-cell RNA sequencing (scRNA-seq) of 6311 T cells isolated from human BCs, and show for the first time that significant heterogeneity exists in the infiltrating T cell population. We demonstrated that high TIL BCs contained significant numbers of CD8+ T cells with features of tissue-resident memory T (TRM) cell differentiation and that these CD8+ TRM cells expressed high levels of immune checkpoint molecules and effector proteins. A CD8+ TRM gene signature developed from the scRNA-seq data was significantly associated with improved patient survival in early-stage triple negative breast cancer (TNBC) and provided better prognostication compared with CD8 expression alone. Our data suggests that CD8+ TRM contribute to BC immunosurveillance and are the key targets of modulation through immune checkpoint inhibition. Further understanding of the development, maintenance and regulation of TRM cells will be crucial for successful immunotherapeutic development in BC.

  Study EGAS00001002845