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• ATAC-seq data for two BCL11B-a subtype leukemia cases

  ATAC-seq was performed in two BCL11B-a subtype leukemia specimens to identify putative regulatory elements and allow comparison of motif enrichment in open chromatin to experimental and normal cell datasets. Raw paired-end reads were quality trimmed and adapter trimmed using TrimGalore (v0.4.4) with a quality score cutoff of Q20. The first 15 bp of each read were clipped to reduce the GC bias introduced by the Tn5 enzyme. Quality trimmed reads were mapped to the GRCh38 reference genome with BWA (v0.7.12-r1039) and converted to bam format using samtools64 (v1.2). Duplicate reads were marked using biobambam2 (v2.0.87). Bam files were submitted

  Dataset EGAD50000002472

• 10X CD4 auto-antigens

  Ex vivo CD4 T-cells from 4 donors were stimulated with antigen-coupled beads to aCD3, ABD, EBNA1, ANO2 or CRYAB and the LiveCD3+CD4+CFSEdim cells were sorted by flow cytometry. Cells were labelled with barcoded antibodies to identify the original stimulus. All stimulations from each donor were pooled into four reactions, i.e. one reaction per donor. Libraries were assembled with the 10X Chromium Next GEM Single Cell 5’ Kit for TCR and transcriptome with feature barcodes. Dataset contains raw fastq reads as well as supplementary information needed to link fastq files to modality, i.e. gene-expression, protein or VDJ, and includes supplementary information to de-multiplex the reactions by stimulation condition.

  Dataset EGAD50000002201

• High-powered complex trait association mapping through whole genome sequencing of a selected subpopulation of the INGI-Val Borbera genetic isolate

  The VBSEQ project aims to combine available extensive genetic and phenotypic data to the latest high-throughput genome sequencing technology and ad hoc statistical analysis to identify new rare genetic variants underlying complex traits. Up to 100 Val Borbera samples will be sequenced to a 6x depth.

  Dataset EGAD00001000730

• Identification of drug resistance genes in melanoma

  Our aim is to analyze the genome of human melanoma cell lines and short term culture from human melanoma samples in order to identify genes that confer drug resistance to clinically relevant targeted therapies. We will perform whole-exome sequencing, copy number variation analysis and methylome analysis in a collection of human melanoma cell lines and short term culture that will be then screened for drug sensitivity/resistance through a library of clinically relevant drugs and drug combinations. By the combined analysis of the genomic lesion and the drug sensitivity/resistance profile of different cell lines, we will look for genes whose mutation is associated to the sensitivity or resistance to a specific drug in different samples.

  Dataset EGAD00001001124

• Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo

  Oncogenic alterations in EGFR frequently co-occur with additional genetic alterations in EGFR-driven lung adenocarcinoma (LUAD), but how specific combinations of mutations affect tumor phenotypes and responses to targeted therapy is yet unknown. We leveraged a genetically engineered mouse model of EGFR mutant/Trp53-deficient LUAD to study the consequences of inactivating 10 different tumor suppressor genes on the fitness and tyorosine kinase inhibitor (TKI) sensitivity of these tumors. We found that loss of Keap1 is associated with a reduced response to therapy. In patients, we found that mutations in the KEAP1/NFE2L2/CUL3 pathway are associated with a significantly shorter time to treatment failure for EGFR TKI therapy compared to matched patients with wild-type KEAP1/NFE2L2/CUL3 tumors. We also analyzed whole exome sequencing data from tumor specimens before TKI treatment and at the time of treatment resistance for mutations in the KEAP1 pathway and these data are being submitted here.  

  Study phs002334

• Molecular Analysis of Short- Versus Long-Term Survivors of High-Grade Serous Ovarian Carcinoma

  The underlying determinants for long-term survival (LTS, ≥10 years) versus short-term survival (STS, <3 years) of patients diagnosed with high-grade serous ovarian carcinoma (HGSC) are largely unknown. The present study sought to identify molecular predictors of LTS for women with HGSC. A cohort of 24 frozen HGSC samples (12 LTS and 12 STS) were collected and analyzed at DNA and RNA levels. Copy number variation and mutation did not indicate large differences between LTS and STS. From RNA-Seq analysis, 11 genes were found to be differentially expressed between the STS and LTS groups (fold change >2; false discovery rate <0.01). In the validation cohort, transmembrane protein 62 (TMEM62) was found to be related to LTS. Our in vitro and in vivo studies demonstrate that restoring TMEM62 may be a novel approach for treatment of HGSC. These findings may have implications for biomarker and intervention strategies to help improve patient outcomes.

  Study phs003020

• Simultaneous Trimodal Single Cell Measurement of Transcripts, Epitopes, and Chromatin Accessibility Using TEA-Seq

  Single-cell measurements of cellular characteristics have been instrumental in understanding the heterogeneous pathways that drive differentiation, cellular responses to signals, and human disease. Recent advances have allowed paired capture of protein abundance and transcriptomic state, but a lack of epigenetic information in these assays has left a missing link to gene regulation. Using the heterogeneous mixture of cells in human peripheral blood as a test case, we developed a novel scATAC-seq workflow that increases signal-to-noise and allows paired measurement of cell surface markers and chromatin accessibility: Integrated Cellular Indexing of Chromatin Landscape and Epitopes (ICICLE-seq). We extended this approach using a droplet-based multiomics platform to develop a trimodal assay that simultaneously measures Transcriptomics (scRNA-seq), Epitopes, and chromatin Accessibility (scATAC-seq) from thousands of single cells, which we term TEA-seq. Together, these multimodal single-cell assays provide a novel toolkit to identify type-specific gene regulation and expression grounded in phenotypically defined cell types.

  Study phs002316

• Sequencing of Coding and Non-coding Regions in Primary Breast Cancers and Patient-matched Controls

  Genomic analysis of tumor samples has led to the identification of hundreds of cancer genes based on the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here, we performed deep sequencing in 360 primary breast cancers and developed computational methods to identify significantly mutated promoters. Clear signals were found in the promoters of four genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbors a mutational hotspot in its promoter that leads to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that alter protein binding to the promoter and impact expression levels. Overall, our study shows that recurrent mutations in or near gene promoters in cancers have functional consequences. Power analyses indicate that more such genes remain to be discovered through deep sequencing of adequately sized patient cohorts.

  Study phs001250

• Kids First: Genomic Analysis of Esophageal Atresia and Tracheoesophageal Fistulas and Associated Congenital Anomalies

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a rare and complex aerodigestive congenital anomaly with an estimated incidence of 1 in 2500 to 1 in 4000 live births. We propose to elucidate the underlying genomic architecture of EA/TEF by performing whole genome sequencing to characterize new clinical syndromes associated with EA/TEF to provide more accurate clinical prognostic information.

  Study phs002161

• Characterizing Individual Cells Obtained from Bone Marrow Biopsies of MPN Patients

  We profiled the transcriptomes of individual cells obtained from bone marrow aspirates of 7 treatment-naïve newly diagnosed JAK2-mutant myeloproliferative neoplasm (MPN) patients (3 polycythemia vera and 4 essential thrombocythemia patients), and 2 healthy controls. The submitted data corresponds to sequencing reads mapped to the human reference genome GhRC38 build using CellRanger for a total of 9 samples (one per patient). In addition, to reconstruct the lineage histories of single cells in MPN patients, we performed whole-genome sequencing of single-cell-derived colonies of hematopoietic stem and progenitor cells from 2 essential thrombocythemia (ET) patients: 22 JAK2-mutant colonies and 20 WT colonies for patient ET 1; and 13 JAK2-mutant colonies and 21 WT colonies for patient ET 2. The submitted data consists of sequencing reads aligned to the human reference genome GhRC38 build using bwa-mem. Each file corresponds to the whole-genome sequencing data for one colony.

  Study phs002308

• Interpreting molecular role of DNA variants associated with Crohn's Disease through integrative analysis of open chromatin, epigenome and transcriptome data in diverse and relevant tissues and cells

  Crohn's disease (CD), one of the two major inflammatory bowel diseases (IBD), results from an inappropriately directed inflammatory response to the enteric microbiota in a genetically susceptible host. Genome wide association studies (GWAS) have linked >200 specific single nucleotide polymorphisms (SNPs) to CD disease pathogenesis. Within these regions, there are over 5600 additional SNPs that are in linkage disequilibrium (LD) with the tag SNPs, and it is not known which of these contribute to CD. Most of these SNPs map to non-coding regions of the genome, suggesting that causal variants contribute to CD by modifying gene regulatory element activity. In ths study, we have generated genotype, open chromatin (FAIRE-seq), and transcriptome (RNA-seq) data from macroscopically uninflamed regions of colon tissue for 21 CD patients and 11 non-IBD controls. All patients are adults (>18 years old).

  Study phs001418

• Hi-C Profiling of Solid Tumor Samples

  Structural variants, such as translocations, inversions, duplications, and deletions, have long been recognized as mutations that can contribute to the initiation and progression of cancer. This can occur through a variety of mechanisms, including changes in gene dosage and the generation of fusion genes. In recent years, it is becoming increasingly clear that these events also can alter how genomes are organized in 3D space in the nucleus and contribute to changes in enhancer-promoter regulation. However, it remains poorly understand how often 3D genome structural changes occur in cancers, what genes are affected by these events, and in which tumor types. This study is part of ongoing work to better characterize 3D genome structural changes across a variety of tumor types to better understand where and when 3D genome structure changes as the result of structural variation in cancer genomes and to characterize the genes and tumor types affected.

  Study phs003227

• National Institute of Environmental Health (NIEHS) Sciences Study of Somatic Mutation Load in Clones of Single Human Cells

  Accumulation of genetic changes with time and proliferation of cells is inevitable. We report here the genome-wide magnitude and spectra of mutations accrued in skin fibroblasts over the lifetime of healthy humans. We found that every cell contains at least one somatic chromosomal rearrangement and 600 - 13,000 base substitutions, similar to the median mutation load in human cancers. The mutation spectra and correlation of changes with epigenomic features also resemble many human cancers. Interestingly, the magnitude of ultraviolet light-characteristic mutations, representative of environmental mutagenesis, in sun-exposed skin was comparable to the number of mutations attributed to endogenous DNA damage estimated in unexposed cells. Our methodology allows delineating the precise contributions of environmental and endogenous factors to the accrual of genetic changes in the human body. This is fundamental to understanding the etiology, and improving the prognosis and prevention of cancers and other genetic diseases.

  Study phs001182

• Genomic Profiling of Melanoma

  This study reports on genomic profiling [whole-exome sequencing (WXS), bulk RNA sequencing (RNA-seq), and/or single-cell RNA sequencing (scRNA-seq)] of patient-derived melanoma samples and matched normal samples. The goal is to elucidate the genetic and cellular basis of sun-exposed and sun-shielded melanomas and to relate these findings to survival and regional metastasis. Specimens were collected by the Tissue Resource Core of the Yale SPORE in Skin Cancer with participants' informed signed consent according to Health Insurance Portability and Accountability Act (HIPAA) regulations with a Human Investigative Committee protocol. The melanomas used for sequencing were from fresh or snap-frozen tumors, or from short-term cell cultures. The cell cultures were routinely checked for mycoplasma contamination and were discarded when found positive. Matching normal DNA was from circulating lymphocytes or normal skin. We also include 77 WES-sequenced samples from the Yale Spitzoid neoplasm repository, which collects specimen and data according to a protocol approved by the Yale Human Investigative Committee.

  Study phs000933

• NHLBI TOPMed: MWCCS: Sex Differences in the Role of Multi-Omics in HIV-Associated Carotid Artery Atherosclerosis

  The MACS-WIHS Combined Cohort Study (MWCCS) is a multicenter prospective cohort study of men and women in the U.S. that aims to understand and reduce the impact of chronic health conditions, including heart, lung, blood, and sleep (HLBS) disorders that affect people living with HIV. MWCCS, which currently has over 5000 active study participants, is designed to investigate a spectrum of questions relating to the basic science, clinical science, and epidemiology of HIV infection in the U.S., with a focus on comorbidities among men and women living with HIV. The current substudy, nested within the MWCCS, integrates detailed metabolomics and proteomics data, among other "omics" measures, to improve the understanding of the etiology of atherosclerosis and cardiovascular disease in women and men with HIV, guide mechanistic studies, and provide insights to more efficient intervention strategies. Data on 374 men are included in the current substudy.

  Study phs003651

• Multiplexing cortical brain organoids for the longitudinal dissection of developmental traits at single cell resolution

  Dissecting human neurobiology at high resolution and with mechanistic precision requires a major leap in scalability, given the need for experimental designs to multiple individuals and, prospectively, population cohorts. To lay the foundation for this, we have implemented and benchmarked complementary strategies to multiplex brain organoids by pooling cells from different pluripotent stem cell lines (PSC) either during organoid generation (mosaic models) or before single cell-RNAseq library preparation (downstream multiplexing). We have also developed a new computational method, SCanSNP, and a consensus call to deconvolve cell identities, overcoming current criticalities in doublets prediction and low quality cells identification. We validated both multiplexing methods for charting neurodevelopmental trajectories at high resolution, thus linking specificity to genetic variation. Finally, we modelled their scalability across different multiplexing combinations and showed that mosaic organoids represent an enabling method for high-throughput settings. Together, this multiplexing suite of experimental and computational methods provides a highly scalable resource for disease modelling.

  Study EGAS50000000698

• Deciphering craniopharyngioma subtypes: Single-cell analysis of tumor microenvironment and immune networks

  Craniopharyngiomas, including both adamantinomatous (ACP) and squamous papillary (PCP) types, present significant challenges in treatment due to their proximity to critical pituitary structures. In this study, we conducted a single-cell RNA analysis to examine the tumor microenvironments (TME) of ACP and PCP. Single-cell clustering revealed a wide range of cell types, which were further categorized based on gene expression patterns. For ACP, these categories included developing epithelia, calcification, and immune response, while PCP showed developing epithelia, cell cycle, and immune response as prominent categories. Subclustering analysis unveiled different types of immune cells in both ACP and PCP TMEs, with specific patterns of immune responses. Interestingly, smaller tumors were associated with particular immune cell ratios. Furthermore, we identified specific cell-to-cell interactions within the tumor cells. In conclusion, our study has led to the development of a comprehensive cell atlas, shedding light on the molecular characteristics and intricate interplay of immune cells within the TMEs of ACP and PCP.

  Study JGAS000722

• WFS1 mutation screening in a large series of Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis

  A heterozygous mutation in the Wolfram syndrome type 1 gene (WFS1) causes autosomal dominant nonsyndromic hereditary hearing loss, DFNA6/14/38, or Wolfram-like syndrome. To date, more than 40 different mutations have been reported to be responsible for DFNA6/14/38. In the present study, WFS1 variants were screened in a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA6/14/38 and Wolfram-like syndrome. Massively parallel DNA sequencing of 68 target genes was performed in 2,549 unrelated Japanese HL patients to identify genomic variations responsible for HL. The detailed clinical features in patients with WFS1 variants were collected from medical charts and analyzed. We successfully identified 13 WFS1 variants in 19 probands: eight of the 13 variants were previously reported mutations, including three mutations (p.A684V, p.K836N, and p.E864K) known to cause Wolfram-like syndrome, and five were novel mutations.

  Study JGAS000123

• Comprehensive assay for the molecular profiling of cancer by target enrichment from formalin-fixed paraffin-embedded specimens

  Tumor molecular profiling is becoming a standard of care for patients with cancer, but the optimal platform for cancer sequencing remains undetermined. We established a comprehensive assay, the Todai OncoPanel (TOP), which consists of DNA and RNA hybridization capture-based next-generation sequencing panels. A novel method for target enrichment, named the junction capture method, was developed for the RNA panel to accurately and cost-effectively detect 365 fusion genes as well as aberrantly spliced transcripts. The TOP RNA panel can also measure the expression profiles of an additional 109 genes. The TOP DNA panel was developed to detect single nucleotide variants and insertions/deletions for 464 genes, to calculate tumor mutation burden and microsatellite instability status, and to infer chromosomal copy number. Clinically relevant somatic mutations were identified in 32.2% (59/183) of patients by prospective TOP testing, signifying the clinical utility of TOP for providing personalized medicine to cancer patients.

  Study JGAS000164

• Patient-Derived Lung Cancer Organoid

  Lung cancer shows substantial genetic and phenotypic heterogeneity across individuals, driving a need for personalized medicine. Here we report lung cancer organoids and normal bronchial organoids established from patients tissues comprising five histological subtypes of lung cancer and non-neoplastic bronchial mucosa as in vitro models representing individual patient. The lung cancer organoids recapitulate the tissue architecture of the primary lung tumours and maintain the genomic alterations of the original tumours during long-term expansion in vitro. The normal bronchial organoids maintain cellular components of normal bronchial mucosa. Lung cancer organoids respond to drugs based on their genomic alterations: a BRCA2 mutant organoid to olaparib, an EGFR mutant organoid to erlotinib, and an EGFR mutant/MET amplified organoid to crizotinib. Considering the short length of time from organoid establishment to drug testing, our newly developed model may prove useful for predicting patient-specific drug responses through in vitro patient-specific drug trials.

  Study EGAS00001003786

• A Comprehensive Genetic Study of Classical Hodgkin Lymphoma Using Circulating Tumour DNA

  This study on classical Hodgkin lymphoma (cHL) used advanced methods to analyse circulating tumour DNA (ctDNA) in 297 cases, offering insights into its genetic landscape and linking it to disease pathophysiology and clinical progression. Key findings include the identification of whole genome duplication as a predictor of poor chemotherapy response. Additionally, a highly recurrent somatic expression quantitative trait locus of the BCL6 gene was discovered, implicating regulatory mutations in cHL pathophysiology and highlighting BCL6 as both a vulnerability and therapeutic target. Consensus clustering identified two cHL subtypes distinguished by the underlying mechanisms of genetic instability, rather than by specific genetic mutations or EBV infection. The study also linked the number and clonality of neoantigens with tumour microenvironment and response to checkpoint blockade. Finally, our results suggested ctDNA analysis as a tool to distinguish ambiguous PET/CT-positive lesions persisting after treatment, aiming to reduce unnecessary medical interventions.

  Study EGAS50000000873

• Maturation of Human Intestinal Epithelial Cell Layers Fortifies the Apical Surface against Salmonella Attack

  Pathogen invasion of intestinal epithelial cells (IECs) is a key gut infection event. The dynamics of this process in intact epithelia and the factors governing IEC susceptibility remain underexplored. We present a resource for live-cell infection imaging in human enteroid-/colonoid-derived IEC layers, across maturation states and in the presence or absence of soluble mucus production. Utilization of this resource shows how human IEC maturation fortifies the apical surface against invasion by Salmonella Typhimurium (S.Tm). Immature IEC layers appear permissive to S.Tm invasion, but maturation towards an enterocyte/colonocyte phenotype reduces the susceptibility by up to tenfold. This shift couples to downregulated expression of actin regulatory proteins exploited by the pathogen, an increased dependence on the S.Tm effector SipA, and the build-up of the apical IEC glycocalyx linked to surface-attached mucins like MUC13 and nullifiable by StcE-enzyme treatment. This underscores how the maturation state of human IECs governs susceptibility to bacterial invasion.

  Study EGAS50000001241

• High-grade B-cell lymphoma, not otherwise specified: an LLMPP study

  Molecular characterization of high-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS), is hindered by its rarity, evolving definition, and poor diagnostic reproducibility. To address this challenge, we analyzed 92 HGBCL-NOS tumors collected across Lymphoma/Leukemia Molecular Profiling Project sites. These tumors were profiled using whole-genome sequencing (WGS) or whole-exome sequencing (WES) to identify somatic mutations, WGS or low-pass WGS to detect copy number alterations, targeted capture sequencing to assess MYC and BCL2 structural variants, and RNA sequencing. The genetic features of HGBCL-NOS were compared to those of diffuse large B-cell lymphoma (DLBCL-NOS) and EBV-negative adult Burkitt lymphoma (BL). DLBCL-NOS tumors underwent targeted capture sequencing using a panel of 125 genes recurrently mutated in aggressive B-cell lymphomas. BL biopsies were drawn from the Burkitt Lymphoma Genome Sequencing Project and had available WGS (dbGaP Study Accession: phs000527.v18.p6).

  Study EGAS50000000932

• A single-chain derivative of the integrin β1-activating TS2/16 antibody potentiates organoid growth in Matrigel and Collagen hydrogels.

  Culturing epithelial organoids from Adult Stem Cells (ASCs) requires interaction of their β1-integrins with extracellular matrix (ECM) components such as laminin or collagen. Matrigel and BME® (extracts from Engelbreth-Holm-Swarm tumor cells grown in the mouse abdomen) are a popular source of ECM proteins. Yet, these preparations are costly and subject to batch-to-batch variation due to animal-derived contaminations. Here, we describe a single chain version (scFv) of antibody TS2/16, allosterically activating integrin β1 function in organoids. Addition of 5 nM of monomeric scFv to organoid medium results in up to 5-fold higher yields of organoids in Matrigel/BME®. In addition, scTS2/16 generates 6-7-fold higher yields of intestinal organoids in collagen-I hydrogel, when grown both in 3D and in 2D. Collagen is well-defined, available at clinical grade, and in combination with scTS2/16, will enable the clinical use of gastrointestinal organoids.

  Study EGAS50000001113

• Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma

  A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames. To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a step-wise approach to employ multiple CRISPR-Cas9 screens to elucidate functional non-canonical ORFs implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream open reading frames (uORFs) exhibited selective functionality independent of the main coding sequence. One of these, ASNSD1-uORF or ASDURF, was upregulated, associated with the MYC family oncogenes, and was required for medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future cancer genomics studies seeking to define new cancer targets.

  Study EGAS00001007426