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• Ewings Sarcoma RNA-Seq

  Sarcomas are cancers of the bone and soft tissue often defined by their gene fusions. However, the timing, context, and processes by which these pathogenic fusions arise are unknown. We explored this in Ewing sarcoma, a cancer driven by EWSR1-ETS fusions, with very few cooperating mutations. Combining whole-genome sequencing with enhanced informatics, we found that the EWSR1-ETS fusion arose from striking rearrangement clusters in 42% of cases (52/124). Notably, these were organized in loops that universally contained the fusion at their center, while also weaving up to 18 genes together with it. We found the same pattern of rearrangements in three additional types of sarcoma. From these data, we define a new signature for sarcoma fusions that precedes other somatic changes, in the earliest replicating DNA of the genome. This dramatic, sudden process impinges on many genes – generating multiple coding changes that profoundly affect the transcriptome, with the disease-defining gene fusion at its core. These rearrangement loops emerge in an early ES clone from which both the primary tumor and the lethal relapse emerged, and then evolved in parallel until clinically detected.

  Study EGAS00001003062

• Next Generation Sequencing in an IBD Pedigree Whole Genome Data

  In 2009 we identified a four-generation family with over 700 members and 41 affected with Crohn's disease (CD). At the time we sequenced the exome of 6 affected individuals but did not identify any coding variants which appear to explain the high prevalence of disease. Since then we have collected DNA from a large number of additional family members, genotyped linkage arrays on the entire family to refine genomic regions shared by identity by descent and genotyped affected and unaffected members at known CD risk loci identified by Genome Wide Association Studies (GWAS). These analyses have confirmed that a significant unexplained excess of disease remains after accounting for all known genetic factors, and that several regions of the genome are shared by a large fraction of affected individuals. We therefore perform whole genomes sequencing from 8 individuals which will allow us to impute the complete sequence of nearly all the members of the two largest and most severely affected branches of the family.

  Dataset EGAD00001000399

• Breast Cancer Risk Pathways

  We sought to identify genomic variants that differed between individuals who developed familial breast cancer and individuals who had a family history of breast cancer but who had not developed breast cancer. We aggregated these data at the pathway level to identify pathways that play a role in familial breast cancer development. We profiled peripheral blood cells, extracted DNA, and sequenced the DNA using exome-capture sequencing to identify genomic variants in these samples. For 34 of the 35 samples, we also profiled peripheral blood using Affymetrix Human Exon 1.0 ST Array microarrays. Those data can be found in Gene Expression Omnibus under accession identifier GSE47862.

  Study phs001044

• Genome-Wide Association Study of Lung Cancer Susceptibility in Never-Smoking Women in Asia

  To learn about the etiology of lung cancer among never-smoking women in Asia, we formed the Female Lung Cancer Consortium in Asia (FLCCA), which includes studies of lung cancer in Eastern Asia and conducted a GWAS. We analyzed a total of 5510 lung cancer cases and 4544 controls and identified 3 novel loci (Lan et al., 2012). Of these study subjects, 4922 lung cancer cases and 3959 controls are available for posting. Lan et al.., Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat Genet. 2012 Dec;44(12):1330-5. doi: 10.1038/ng.2456. Epub 2012 Nov 11. PubMed PMID: 23143601.

  Study phs000716

• Single-cell RNA sequencing of human skin tumors (BCC, SCC and Melanoma)

  Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. Here, we elucidate the yet unresolved intra-tumoral CAF variety in three skin cancer types at molecular and spatial single-cell resolution in a large cohort. We show that two out of three CAF subtypes contribute to tumor immune surveillance with distinct mechanisms. Matrix CAFs (mCAFs) ensheath tumor nests and synthesize extracellular-matrix to prevent T cell invasion. Immunomodulatory CAFs (iCAFs), which express proinflammatory and immunomodulatory factors, are only detected in high abundance in aggressive tumors. Strikingly, iCAFs but not tumor cells are (apart from immune cells) the exclusive cell type producing chemokines and, thus, play a key role in immune cell recruitment and activation. Mechanistically, we show that cancer cells transform adjacent healthy fibroblasts into cytokine-expressing iCAFs, which subsequently recruit immune cells and modulate the immune response. In conclusion, targeting CAF variants holds promise for improved efficacy of immunotherapy.

  Study EGAS50000000365

• Single-cell RNA sequencing of blood immune cells before and after interleukin-2 immunotherapy

  Single-cell RNA sequencing of flow cytometry sorted human CD45+ immune cells from 3 systemic lupus erythematosus patients (SLE_002, SLE_004, and SLE_006) collected at baseline (day 0, before interleukin-2 immunotherpay) and day 5 (after 1 treatment cycle of interleukin-2 immunotherapy). Sorted immune cells were hash tagged and then stained with TotalSeq Human Universal Cocktail (Biolegend) before further processing for single-cell RNA sequencing using the 10X-Genomics platform. Samples from all 3 patients were pooled and loaded on 3 lanes of the chromium controller, resulting in 1 raw sequncing file for each lane.

  Dataset EGAD50000000662

• Renal_habitat_WXS

  This project aims at correlating genetic diversity (as well as transcriptomic, metabolic and immune diversity) observed in multiple targeted tumour biopsies and circulating tumour DNA with heterogeneity on multiparametric MRI. To this end, 20 patients with RCC (15 patients with localised/locally advanced disease and 5 with mRCC) will undergo multiparametric MRI including metabolic assessment by 13C-MRSI as well as measurements of tumour perfusion, oxygenation and water diffusion. Based on unique combinations of these imaging parameters, tumour habitats will be defined through cluster mapping. Intra-operative biopsy and immediate freezing of tumour cores from different imaging habitats will be performed. Multiregional ex-vivo tumour biopsies will be spatially registered to the MR data by using 3D printed tumour moulds generated from high-resolution volumetric sequences. These moulds allow slicing tumour specimens in identical planes to the MR acquisition and increase the accuracy of tissue sampling. The biopsies will then undergo molecular profiling such as metabolomic and RNA sequencing (including mRNA immune profiling), as well as DNA sequencing to assess driver and clonal mutations in different tumour habitats and guide design of appropriate cfDNA probes. The targeted cfDNA capture panel will be employed to determine the ability of cfDNA to capture the full genetic diversity observed in the primary tumour and to relate cfDNA to various imaging habitats in both renal and pancreatic cancer. Data integration will be undertaken between imaging habitats and molecular profiles for each region.

  Study EGAS00001003703

• BarcUVa-Seq (Biology of Colorectal Cancer Risk Enhancers)

  This study was designed to generate a cohort of normal colon mucosal biopsies from the "average risk" population. Its primary aims included the development of an RNA-seq dataset of normal colon mucosal biopsies across three colon regions (ascending, transverse and descending). Further, we aimed to provide plausible prioritization to genetic components of colorectal cancer risk by employing methods such as expression quantitative trait loci analysis. In doing so, we provide a novel reference dataset for the study of colon cancer risk in the healthy colon epithelium. RNA-seq was performed in batches on an Illumina HiSeq 2500 (batch 1-7) or NovaSeq 6000 (batch 8) on a total of 463 samples. Matched genotyping data was generated on the Illumina OncoArray BeadChip. Phasing was carried out using Minimac 3 and imputation was performed using The Haplotype Reference Consortium panel on the Michigan Imputation Server.Genotype and RNA-seq data will be made available in dbGaP.

  Study phs003338

• Molecular Evolution of Cancer

  Recently developed methods that utilize partitioning of long genomic DNA fragments, and barcoding of shorter fragments derived from them, have succeeded in retaining long-range information in short sequencing reads. These so-called read cloud approaches represent a powerful, accurate, and cost-effective alternative to single-molecule long-read sequencing. We developed software, GROC-SVs, that takes advantage of read clouds for structural variant detection and assembly. We apply the method to two 10x Genomics data sets, one chromothriptic sarcoma with several spatially separated samples, and one breast cancer cell line, all Illumina-sequenced to high coverage. Comparison to short-fragment data from the same samples, and validation by mate-pair data from a subset of the sarcoma samples, demonstrate substantial improvement in specificity of breakpoint detection compared to short-fragment sequencing, at comparable sensitivity, and vice versa. The embedded long-range information also facilitates sequence assembly of a large fraction of the breakpoints; importantly, consecutive breakpoints that are closer than the average length of the input DNA molecules can be assembled together and their order and arrangement reconstructed, with some events exhibiting remarkable complexity. These features facilitated an analysis of the structural evolution of the sarcoma. In the chromothripsis, rearrangements occurred before copy number amplifications, and using the phylogenetic tree built from point mutation data, we show that single nucleotide variants and structural variants are not correlated. We predict significant future advances in structural variant science using 10x data analyzed with GROC-SVs and other read cloud-specific methods.

  Study phs001255

• Complex genotype-phenotype relationships shape the response to treatment of Down Syndrome Childhood Acute Lymphoblastic Leukaemia

  Extensive genetic and epigenetic variegation has been demonstrated in many malignancies. Importantly, their interplay has the potential to contribute to disease progression and treatment resistance. To shed light on the complex relationships between these different sources of intra-tumour heterogeneity, we explored their relative contributions to the evolutionary dynamics of Acute Lymphoblastic Leukaemia (ALL) in children with Down syndrome, which has particularly poor prognosis. We quantified the tumour propagating potential of genetically distinct sub-clones using serial transplantation assays and SNP-arrays. While most leukaemias were characterized by a single dominant subclone, others were highly heterogeneous. Importantly, we provide clear and direct evidence that genotypes and phenotypes with functional relevance to leukemic progression and treatment resistance can co-segregate within the disease. Hence, individual genetic lesions can be restricted to well-defined cell immunophenotypes, corresponding to different stages of the leukemic differentiation hierarchy and varied proliferation potentials. As a result of this difference in fitness, which can be accurately quantified via competitive transplantation assays, matching diagnostic, post-treatment, and relapse leukaemias can be dominated by different genotypes, including pre-leukemic clones persisting throughout the disease progression and treatment. Intriguingly, plasticity also appears to be a temporally defined property that can segregate with genotype. These results suggest that Down Syndrome ALL should be viewed as a complex matrix of cells exhibiting genetic and epigenetic heterogeneity that foster extensive clonal evolution and competition. Therapeutic intervention reshapes this ‘eco-system’ and may provide the right conditions for the preferential expansion of selected compartments and subsequently relapse.

  Study EGAS50000001287

• Long-read whole genome sequencing as a tool for variant detection in inherited retinal dystrophies

  Advances in whole-genome sequencing (WGS) have significantly enhanced our ability to detect genomic variants underlying inherited diseases. In this study, we performed long-read WGS on 24 patients with inherited retinal dystrophies (IRDs) to validate the utility of nanopore sequencing in detecting genomic variations. We confirmed the presence of all previously detected variants and demonstrated that this approach allows for precise refinement of structural variants (SVs). Furthermore, we could perform genotype phasing by sequencing only the probands, confirming variants were inherited in trans. Moreover, nanopore sequencing enabled the detection of complex variants, such as transposon insertions and structural rearrangements. This comprehensive assessment illustrates the power of long-read sequencing in capturing diverse forms of genomic variation and in improving diagnostic accuracy in IRDs.

  Dataset EGAD50000001238

• cell-free methylated DNA immunoprecipitation and high-throughput sequencing data for samples from liver transplant recpients with graft pathologies

  Bam and indexed bam files after removal of duplicates and trimming of the unique molecular identifiers. Sequencing was performed on NovaSeq 6000 platform.

  Dataset EGAD50000001727

• Benchmark Dataset for Somatic Mutation Calling in Cell-Free DNA

  This study provides a comprehensive benchmarking resource for somatic variant detection in cell-free DNA (cfDNA) from cancer patients. Longitudinal plasma samples from colorectal and breast cancer cohorts were selected to create patient-matched dilution series spanning ultra-low to high circulating-tumour-DNA (ctDNA) fractions, while preserving each individual’s germline and clonal haematopoiesis background. Deep whole-genome sequencing (150×) and ultra-deep whole-exome sequencing (2,000×) generated a reference call set of ~37,000 single-nucleotide variants and ~58,000 insertions/deletions. These data enabled systematic evaluation of nine somatic variant callers across variable ctDNA levels and sequencing depths, and were further used to explore machine-learning–guided parameter tuning. The resulting dataset offers an openly accessible framework for developers and clinicians to assess and optimize somatic variant calling in liquid biopsy applications.

  Dataset EGAD50000001870

• RRBS of 25 pleural mesothelioma samples (Single-end)

  The dataset contains RRBS data (bam files) for 25 pleural mesothelioma samples.The samples were sequenced on NovaSeq6000 (Illumina, San Diego, CA) in single-end 150bp mode. RRBS raw reads were trimmed for adaptor sequences using trim galore (v. 0.6.5) (http://www.bioinformatics.babraham.ac.uk/projects/trim_galore/) and filtered for low-quality sequences using fastQC (v. 0.11.8) (https://www.bioinformatics.babraham.ac.uk/projects/fastqc/). High quality trimmed reads were mapped to the Human reference genome (UCSC genome assembly GRCh38/hg38) using Bismark (v. 0.22.3) with default parameters.

  Dataset EGAD50000002130

• Metastatic breast cancer targeted gene screen (2017-05-11)

  The samples will be sequenced for a targeted panel of cancer relevant genes (n ~ 370) and analysed for somatic mutations. This dataset contains all the data available for this study on 2017-05-11.

  Dataset EGAD00001003330

• Metastatic breast cancer targeted gene screen (2014-09-24)

  The samples will be sequenced for a targeted panel of cancer relevant genes (n ~ 370) and analysed for somatic mutations. This dataset contains all the data available for this study on 2014-09-24

  Dataset EGAD00001001018

• 10x dataset of an obese human subject

  Biopsies from visceral adipose tissue from the omental depot (OAT) were obtained from an obese individual with participant informed consent obtained after the nature and possible consequences of the studies were explained under protocols approved by the Institutional Review Boards of the Perelman School of Medicine at the University of Pennsylvania, the Children’s Hospital of Philadelphia, or the Tel Aviv Sourasky Medical Center. The obese donor underwent bariatric surgery, the lean donor underwent cholecystectomy. OAT samples were placed in 1 mL of DMEM, and finely minced under sterile conditions before digestion in 50 mL of DMEM with 3 mg/1 mL collagenase IV (Gibco). Samples were incubated at 37°C in a rotating oven for 20-60 min. Adipocyte and stromal vascular fractions (SVF) were separated by centrifugation, and red blood cells (RBCs) were removed from the SVF by histopaque gradient (Sigma). Single-cell RNA-sequencing libraries were prepared using the Chromium platform (10x genomics), and sequenced on the MiSeq 500 or HiSeq 2500 Sequencing System (Illumina).

  Dataset EGAD00001005101

• Targeted Next-Generation Sequencing Data of IDH1 Exon 4 in Intrahepatic Cholangiocarcinoma Samples

  This dataset contains targeted next-generation sequencing data from 76 FFPE tumor tissues focusing on IDH1 exon 4 and codon 132. Genomic DNA was isolated using the QIAamp DNA FFPE Tissue Kit and sequenced on the Illumina MiSeq platform with 200x minimum coverage. The results are provided as encrypted somatic variant call files (VCF) generated through the Nextera XT library preparation protocol. This collection represents the specific somatic mutation profiles of the intrahepatic cholangiocarcinoma cohort for controlled access.

  Dataset EGAD50000002345

• Resequencing (MIPS) of candidate genes for Keratoconus (2020)

  The dataset consists of the BAM-files of 745 patients and 810 controls (retained after quality control) of a set of 34 candidate genes obtained after targeted enrichment via Molecular Inversion Probes (MIPS) technology. The sequencing was performed on the NextSeq 500 (Illumina, CA, USA) using custom sequencing and index primers in three 2 x 76 bp, dual indexed runs using a 150 cycles High-Output Illumina kit (Illumina, CA, USA). Alignment of the fastq reads to the human genome was performed using BWA (v0.7.4).

  Dataset EGAD00001006825

• RNAseq: Acquired non-permissive bone marrow microenvironment impairs hematopoietic stem cell proliferation and maintenance and B-cell development post-HSCT

  Defects in B-cell reconstitution upon hematopoietic stem-cell (HSC) transplantation (HSCT) are a common observation, yet the mechanism remains unexplained. The bone marrow (BM) stroma, including mesenchymal stromal cells (MSCs), guides HSC maintenance and B-lymphopoiesis by secreting crucial cytokines. We report acquired, permanent, selective and complete B-cell deficiency in the context of full donor-chimerism in a patient with X-linked lymphoproliferative disease and aimed to identify the contribution of the BM-microenvironment in disrupted B-cell reconstitution post-HSCT. We studied longitudinal BM samples from the patient and his identical twin, both of whom underwent HSCT with the same donor with opposite outcomes in B-cell reconstitution. In the index patient BM, we observed progressive loss of proliferation of HSCs and a selective block at the pre-BI cell stage. In vitro modeling studies showed limited survival of patient-HSCs and a relative accumulation of pre-B cells. Patient-derived MSCs failed to support survival and proliferation of HSCs and B-cell development of healthy-HSCs which was correlated with reduced CXCL12 levels. Using bulk RNA-sequencing of MSCs and in vitro functional studies, we showed global changes in the patients’ MSCs and a progressive loss of CXCL12 expression. Indeed, survival of patients HSCs improved supplementing in vitro development culture with CXCL12, suggesting a contribution of defective CXCL12 signaling to the phenotype. In summary, our data show that an acquired defect in the BM-stromal microenvironment and exhaustion of HSCs and committed progenitors may cause a permanent non-permissive state for normal B-cell development.

  Study EGAS50000001437

• ATAC-seq: Acquired non-permissive bone marrow microenvironment impairs hematopoietic stem cell proliferation and maintenance and B-cell development post-HSCT

  Defects in B-cell reconstitution upon hematopoietic stem-cell (HSC) transplantation (HSCT) are a common observation, yet the mechanism remains unexplained. The bone marrow (BM) stroma, including mesenchymal stromal cells (MSCs), guides HSC maintenance and B-lymphopoiesis by secreting crucial cytokines. We report acquired, permanent, selective and complete B-cell deficiency in the context of full donor-chimerism in a patient with X-linked lymphoproliferative disease and aimed to identify the contribution of the BM-microenvironment in disrupted B-cell reconstitution post-HSCT. We studied longitudinal BM samples from the patient and his identical twin, both of whom underwent HSCT with the same donor with opposite outcomes in B-cell reconstitution. In the index patient BM, we observed progressive loss of proliferation of HSCs and a selective block at the pre-BI cell stage. In vitro modeling studies showed limited survival of patient-HSCs and a relative accumulation of pre-B cells. Patient-derived MSCs failed to support survival and proliferation of HSCs and B-cell development of healthy-HSCs which was correlated with reduced CXCL12 levels. Using bulk RNA-sequencing of MSCs and in vitro functional studies, we showed global changes in the patients’ MSCs and a progressive loss of CXCL12 expression. Indeed, survival of patients HSCs improved supplementing in vitro development culture with CXCL12, suggesting a contribution of defective CXCL12 signaling to the phenotype. In summary, our data show that an acquired defect in the BM-stromal microenvironment and exhaustion of HSCs and committed progenitors may cause a permanent non-permissive state for normal B-cell development.

  Study EGAS50000001438

• SNPArray_TW

  The compressed file contains plink format file for the Affymetrix Human Origins SNP array data of 55 individuals generated and analyzed in Liu et al 2023 study of Taiwanese groups.

  Dataset EGAD00010002424

• Single-Cell Transcriptomic Characterization of Microscopic Colitis

  Patients with microscopic colitis (MC), chronic diarrhea without histological signs of MC, or unaffected controls were profiled using single-cell RNA sequencing (scRNA-seq; inDrops and 10X Genomics were used). One profiled patient without clinical symptoms was found to have histological signs of MC (asymptomatic MC). Some of the subjects from dbGaP study phs003418 are controls in this study. T-Cell Receptor sequencing (TCR-Seq) was also performed on a subset of patients. Individual transcriptomes were analyzed to characterize the cellular profile associated with MC and search for mediators of disease pathology. Raw reads and processed count matrices will be available through dbGaP.

  Study phs003876

• Single-cell RNA sequencing of SI-NET

  Small intestinal neuroendocrine tumors (SI-NETs) arise from hormone-producing cells in the gut, yet the molecular changes driving malignant transformation remain poorly understood. Bulk tissue-based analyses make it challenging to distinguish signals derived from normal cells from those of normal hormone-producing cells. In this study, we analyzed SI-NETs at single-cell resolution and directly compared tumor cells with their corresponding normal hormone-producing counterparts using single-cell RNA sequencing. Tissue samples were obtained from two patients undergoing tumor resection surgery. Cells from corresponding normal intestinal mucosa and SI-NET tumors were isolated using specific markers and analyzed for direct comparison.

  Study EGAS50000001584

• Genomic Characterization of Duke Melanoma Brain Metastases

  Previous work has shown that melanoma brain metastases (MBM) have a unique molecular profile compared to extracranial metastases (ECM). Description of the biology of MBM and associations between biological features and clinical outcomes will facilitate the design of rational therapies for patients with MBM. To better characterize the molecular profile of MBM, we conducted whole exome sequencing (WES) and total RNA sequencing on MBM tissues obtained from an independent cohort of 14 patients from Duke University Medical Center. This cohort adds valuable patient samples to the field and enables strengthened investigation of somatic mutations and gene expression profiles within and between cohorts. The mutational landscape and gene expression of MBM from the Duke cohort resembled those previously reported in a previously published dataset of WES and RNA sequencing in MBM and matched ECM tissues from UT MD Anderson Cancer Center (Fischer et al., 2019 30787016). Duke MBM demonstrated similar rates of mutations in genes associated with melanoma, including BRAF, NRAS, and PTEN, as the MD Anderson cohort. Immune populations in MBM were similar between Duke and MD Anderson MBM, though Duke samples demonstrated more resting CD4+ memory T cells. The ratio of M2 to M1 macrophages in the Duke cohort was similar to that of the MD Anderson cohort. In MBM, a higher M2:M1 ratio may contribute to an immune-suppressive tumor microenvironment. Sequencing data and sample attributes from MBM tissues obtained from 14 patients from Duke University Medical Center will be available through dbGaP.

  Study phs003009