Search Results - EGA European Genome-Phenome Archive

BLUEPRINT September 2016, ATAC-seq for tonsil, on Genome GRCh38

ATAC-seq data for 7 sample(s) from tonsil, on Genome GRCh38. 7 run(s), 7 experiment(s), 7 alignment(s). Part of BLUEPRINT (September 2016).

Dataset EGAD00001002708

Chromatin Profiling in Twins (2019-08-21)

50 lymphoblastoid cell lines of adult female Twins which are part of the MuTHER study, subjected to Chromatin Immunoprecipitation using an antibody for H3K4me1. H3K4me1 peaks mark distal regulatory elements. . This dataset contains all the data available for this study on 2019-08-21.

Dataset EGAD00001005274

WGS files for Millighan BiTE WGS

WGS files for Mullighan BiTE WGS paper titled "Tumor intrinsic and extrinsic mechanisms of response and resistance to blinatumomab in relapsed/refractory acute lymphoblastic leukemia"

Dataset EGAD00001005729

WXS files for Mullighan BiTE WXS

WXS files for Mullighan BiTE WXS paper titled "Tumor intrinsic and extrinsic mechanisms of response and resistance to blinatumomab in relapsed/refractory acute lymphoblastic leukemia"

Dataset EGAD00001005730

RNAseq files for Mullighan BiTE RNASEQ1

RNAseq files for Mullighan BiTE RNASEQ1 paper titled "Tumor intrinsic and extrinsic mechanisms of response and resistance to blinatumomab in relapsed/refractory acute lymphoblastic leukemia"

Dataset EGAD00001005731

lowinput RNASEQ files for Mullighan BiTE RNASEQ2

lowinput RNASEQ files for Mullighan BiTE RNASEQ2 paper titled "Tumor intrinsic and extrinsic mechanisms of response and resistance to blinatumomab in relapsed/refractory acute lymphoblastic leukemia"

Dataset EGAD00001005732

Analysis File for 87 Argentinean individuals

VCF for 87 Argentinean samples. Only SNPs (no indels) that passed the Affymetrix QC. Data from Luisi et al. 2020. Plos One. Fine-Scale Genomic Analyses Of Admixed Individuals Reveal Unrecognized Genetic Ancestry Components In Argentina. Reference Allele column does NOT contain reference allele from genome assembly.

Dataset EGAD00001006227

RNASeq files for Mullighan TXVI dataset

RNASeq files for paper titled "Prognostic and therapeutic significance of leukemia subtypes and minimal residual disease measurements in pediatric acute lymphoblastic leukemia treated with contemporary risk-directed trial: a cohort study"

Dataset EGAD00001006609

High-throughput sequencing data for study of molecular drivers of resistance to castration in localised prostate cancer

Aligned whole-genome sequencing and RNA-seq of localised prostate cancer for study 'Loss of SNAI2 in prostate cancer correlates with clinical response to androgen deprivation therapy'.

Dataset EGAD00001006640

WGS and WES data for manuscript titled: ctDNA as a biomarker of progression in oesophageal adenocarcinoma

Dataset EGAD00001008554

COVID-19 scRNA-seq, TCR-seq and BCR-seq

COVID-19 scRNA-seq, TCR-seq and BCR-seq for 291 samples collected from 109 patients. Among 291 samples, 249 of them have two libraries (sequencing runs) for each assay, while 42 have only one library.

Dataset EGAD00001007995

CBD-RAW-REPERTOIRE-T: T cell bulk repertoire sequence files

fastq and filtered fasta files for T-cell receptor sequencing. For further information regarding this dataset, please contact Rachael Bashford-Rogers at contact@combat.ox.ac.uk.

Dataset EGAD00001007961

WGS files for Klco-NUP98 data

WGS files for paper titled "Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia" PMID: 39974131, PMCID: PMC11838931, DOI: 10.1101/2025.01.21.25320683

Dataset EGAD00001015443

WXS files for Klco-NUP98 data

WXS files for paper titled "Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia" PMID: 39974131, PMCID: PMC11838931, DOI: 10.1101/2025.01.21.25320683

Dataset EGAD00001015444

RNASeq files for Klco-NUP98 data

RNASeq files for paper titled "Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia" PMID: 39974131, PMCID: PMC11838931, DOI: 10.1101/2025.01.21.25320683

Dataset EGAD00001015445

scRNASeq files for Klco-NUP98 data

scRNASeq files for paper titled "Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia" PMID: 39974131, PMCID: PMC11838931, DOI: 10.1101/2025.01.21.25320683

Dataset EGAD00001015479

DNA WGS Short Read Sequence (Illumina NovaSeq) for manuscript titled: "Performance of Somatic Structural Variant Calling in Lung Cancer using Oxford Nanopore Sequencing Technology"

Dataset EGAD00001015399

Dataset for EGAS00001007937

WGS, RNAseq, Methylation, variant calling analysis for a Novel paediatric case of a spinal high-grade astrocytoma with piloid features in a patient with Noonan Syndrome

Dataset EGAD00001015412

Genome-Wide Predictors of Treatment-Related Toxicities in SWOG S0221 Trial

When undergoing treatment for breast cancer, many women experience severe side effects, some of which result in treatment-related death and some that can persist for years. Little is understood regarding factors that may predict drug toxicities. Pharmacogenetics, the investigation of variants in candidate genes in drug metabolism pathways, has been used to determine susceptibility to treatment-related toxicities, as well as to cancer recurrence. Although there have been some strong and important findings using this approach, such as identification of single nucleotide polymorphisms (SNPs) that predispose to side effects associated with thiopurines and irinotecan, there has been less progress in assessment of genetic variants that predispose to toxicities resulting from the multi-drug regimen commonly used to treat breast cancer, anthracyclines (A), cyclophosphamide (C), and taxanes (T). These difficulties in identification of key gene variants may be due to the complex metabolic pathways of these drugs, the lack of rate limiting enzymes in the processes, or the limitations of single SNP analysis, rather than capturing all of the variability across the genes. In addition to drug metabolism pathways, however, there may be a number of constitutional factors or other processes that affect damage to normal tissues in the course of chemotherapy, some known or hypothesized, such as DNA repair and oxidative stress pathways, and others not yet discovered. However, there have been no clear candidate genes that account for a large part of the variation in drug or treatment response, and there are likely important genes that influence sensitivity of cells to chemotherapy through unknown pathways which have not yet been identified or hypothesized. The present technological capabilities to screen the entire genome for variants that discriminate populations allows the opportunity to identify these as yet unknown pathways, and open the doors to exciting new avenues of research into mechanisms that had not been previously considered. We conducted a genome-wide scan (GWAS) in a clinical trial (S0221), in which women with high risk breast cancer were treated with different dosing schedules of C, A and T. Blood specimens were collected and banked, and DNA extracted for genotyping on the Illumina OMNI 1M platform. The GWAS data were used to examine genetic variants significantly associated with grades 3 and 4 toxicities, including peripheral neuropathy recorded during the T segment. In S0221, toxicities were graded according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE). The neurotoxicity is predominantly a distal sensory neuropathy, which is characterized by pain, numbness, tingling, and reduced functional capacity in the extremities. Other symptoms include parasthesias, ataxia, impaired vibration and joint position sense, and loss of tendon reflexes. By using a GWAS approach, it is likely that important pathways not previously considered can be revealed as important in susceptibility to treatment-related toxicities, identifying those at greatest risk for alternate drugs or dose reduction, and opening new areas of research for prevention of taxanes-related neuropathy among patients receiving chemotherapy for breast cancer.

Study phs001428

Whole Transcriptome Sequencing of Human Tumor Cells and Hematopoietic Stem and Progenitor Cells During Aging and Bone Marrow Disorders

Whole transcriptome sequencing analyses were performed on human hematopoietic stem and progenitor cells during aging and bone marrow disorders. For this purpose, normal and diseased bone marrow or peripheral blood-derived mononuclear cells were FACS-purified into hematopoietic stem (CD34+CD38-Lin-) or hematopoietic progenitor (CD34+CD38+Lin-) populations. Primary human samples from healthy individuals were used along with comparative analyses in some pre-malignant and malignant conditions, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and plasma cell dyscrasias (e.g., multiple myeloma). Studies were also performed on total mononuclear cell fractions from patients with newly-diagnosed or relapsed multiple myeloma, or plasma cell leukemia. Briefly, RNA was extracted from all samples and quality was assessed using a Bioanalyzer instrument. Only samples with RNA integrity (RIN) values >7 were subjected to library preparation for RNA-sequencing. The SMARTer v4 cDNA amplification kit was used along with library construction by the NEB Ultra DNA kit for Illumina. Paired-end sequencing was performed on Illumina NextSeq instruments (Scripps Next Generation Sequencing Core), with all samples run over two separate flow-cells (to generate additional sequencing reads); >95M reads were generated in total for each sample. The RNA-sequencing data are available as FASTQ files.

Study phs002291

The National Heart, Lung, and Blood Institute (NHLBI)-funded Next Generation Genetic Association Studies (NextGen) Consortium: Phenotyping Lipid traits in iPS derived hepatocytes Study (PhLiPS Study)

The goal of the PhLiPS study is to create a library of induced pluripotent stem cell (iPSC) lines and iPSC-derived hepatocytes of diverse genotypes for use in metabolic profiling and interrogating lipid phenotypes. These cell lines were created as a part of the Next Generation Genetic Association Studies (Next Gen) Program, which was a five-year, $80 million program to investigate functional genetic variation in humans by assessing cellular profiles that are surrogates for disease phenotypes. To achieve this, researchers from multiple institutions across the U.S. were awarded grants to derive iPSC lines from more than 1,500 individuals representing various conditions as well as healthy controls for use in functional genomic ("disease in a dish") research. This extensive panel includes a diverse set of age, gender, and ethnic backgrounds, and therefore will be an invaluable tool for evaluations across demographics. Further enhancing the utility of these cell lines are data sets such as phenotyping, GWAS, genome sequencing, gene expression and -omics analyses (e.g., lipidomic, proteomic, methylomic) that can be matched to the cell lines. The PhLiPS Study focuses on individuals free of cardiovascular disease or with lipoprotein metabolism disorders in the community served by the Hospital of the University of Pennsylvania.

Study phs001341

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

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

Study phs003152

Longitudinal Study of Bone and Endocrine Disease in Children with MPS I, II, and VI: A Multicenter Study of the Lysosomal Disease Network

Mucopolysaccharidoses (MPS) I, II, and VI are a group of rare, lysosomal storage diseases in which certain enzymes are missing that are normally required for breaking down specific complex carbohydrates. Deficiencies in these enzymes result in the build-up of toxic substances in various tissues and cause damage to the body's organs. In the past, children diagnosed with MPS I, II, or VI frequently died in early to late childhood. Recent advances in treatments including hematopoietic cell transplantation (HCT) and enzyme replacement therapy (ERT) have been helping children with these disorders live into adulthood. The long term-course of the disease is now unknown. Unfortunately, severe skeletal disease persists for most individuals despite current therapies. This is a longitudinal study of 50 children and adults with MPS I, II, and VI. Study participants will be evaluated every year for up to 3 years. The purpose of this study is to document the progression of skeletal disease and identify biomarkers that either predict disease severity or could be used as therapeutic targets. This information is needed to: determine long-term benefits and limitations of current treatments including HCT or ERT direct development of further treatment options improve clinical care for children affected by the disorder

Study phs001576

Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA)

The OPPERA project has two sub-studies investigating effects of genetic, physiological, psychological and clinical factors on the risk of developing painful temporomandibular disorder (TMD). OPPERA I baseline case-control study of chronic TMJD (dbGaP study accession phs000762). This sub-study uses a case-control study design to investigate characteristics associated with chronic TMD. The parent OPPERA phenotype file contains an indicator variable (PHASE1CASECONTROL) identifying participants in this sub-study. Data users should use the relevant case-classification variable (CHRNONICTMDCASE) and apply statistical methods appropriate for case-control studies when analyzing TMJD in this sub-study. OPPERA I prospective cohort for first onset of TMJD (dbGaP study accession phs000850). This sub-study uses a prospective cohort study design to investigate characteristics that predict risk of developing first-onset TMD. The parent OPPERA phenotype file contains an indicator variable (PROSPECTIVECOHORT) identifying participants in this sub-study. Data users should use the relevant case-classification variable (INCIDENTCASE) and the relevant time-in-study variable (FOLLOWUPYEARS) when analyzing TMJD in this sub-study. It is recommended that data users apply statistical methods appropriate for cohort studies of a dynamic population (for example, Cox regression models, where INCIDENTCASE is the censoring variable and FOLLOWUPYEARS is time in study).

Study phs000761

PIEZO1 Loss of Function Compound Heterozygous Mutation in the Rare Congenital Human Disorder Prune Belly Syndrome

Prune Belly Syndrome (PBS) is a rare congenital myopathy that is incompletely understood genetically. In this IRB approved study, one white Non-Hispanic 35 year-old male PBS proband was prospectively enrolled and phenotyped. Blood lymphocyte DNA from the proband underwent paired-end Whole Exome Sequencing using the Illumina SureSelect kit and HiSeq2500 sequencer with data pipeline analysis. We aligned the subject's sequence against the GRCh38/hg19 assembly and variant calling was performed using data training sets from the 1000 Genomes Project, Omni 2.5 M SNP microarray, and HapMap phase 3.3. These variants were filtered for rare minor allele frequency ( 0.9, CADD score > 20, GERP > 4, MutationTaster = “DC”, Mutation Assessor = “M” or “NE”, and Vest > 3.00. Rare and novel candidate functional variants were screened in the ClinVar database for prior association with smooth muscle myopathy (SMM). Only variants that met these criteria were included for further analysis. Confirmed variants had inheritance analysis performed on available samples. Our WES analysis identified novel compound heterozygous variants in the PIEZO1 gene. We conducted an extensive functional analysis of the PIEZO1 PBS variants that revealed loss-of-function characteristics. Thus, PIEZO1 mutations may be causal for PBS. Our WES data will be available through dbGaP.

Study phs003475

Tumor detection by analysis of both symmetric- and hemi-methylation of plasma cell-free DNA

Aberrant DNA methylation plays a critical role in tumorigenesis. While DNA methylation has been used for cancer detection and classification, DNA hemi-methylation, a novel epigenetic mark has not been analyzed extensively in cancer epigenomes. Here we report a strand-specific (ss) sequencing method (MeDIP-Seq) for plasma cell free (cf) DNA (sscf-MeDIP-Seq), which can analyze both symmetrically methylated DNA regions (DMRs) as well as hemi-methylated regions (DHMRs). Using the sscf-MeDIP-Seq method, we analyzed plasma cfDNA methylomes of 271 samples from subjects with liver cancer and brain cancer and from individuals without cancer (controls). Among them, 215 samples were chosen as the discovery cohort for the identification of DMRs and DHMRs specific in each subject group and for the training of machine learning models of multi-cancer detection (MCD) using DMRs, DHMRs and DMRs+DHMRs as inputs. These models were then used to predict the 56 samples in the validation cohort. We found that models trained with DMRs+DHMRs as inputs in general outperformed models trained with DMRs or DHMRs alone, with AUROC being 0.971, 0.981, and 0.99 in predicting control, liver and brain cancer samples in the validation cohort, respectively, by the DMR+DHMR-trained models.

Study phs003462

Single-Cell Genomic and Transcriptomic Analysis of the Aging Human Brain

We studied human brain aging using single-cell whole genome sequencing and single-nucleus RNA sequencing of the pre-frontal cortex from 19 donors ranging in age from 0.4 years to 104 years. All donors were free of neuropathology and none received a clinical neurological diagnosis prior to death. snRNA-seq libraries were prepared in batches that always included old and young donors to mitigate batch effects in the preparations. Neurons for single-cell WGS were collected from the same tissue region as the snRNA-seq for each donor but represent independent cells. Multiplexed error-robust fluorescent in-situ hybridization (MERFISH) data was also collected from pre-frontal cortex samples of a subset of the 19 donors. Transcriptomic results identified infant-specific cell clusters, and common-down regulation of cell-essential genes involved in ribosomes, transport, homeostasis and metabolism during aging, across all cell types. scWGS identified two-age associated mutational signatures, as well as gene-length and expression-level dependent somatic mutation rates in neurons. Raw sequencing data in fastq format for single-nucleus RNA-seq and single-cell DNA-seq, as well as cell and gene count matrix, transcript metadata, and cell metadata for MERFISH will be available in dbGaP.

Study phs003445

BHD-associated kidney cancer

Background Birt-Hogg-Dub? (BHD) syndrome is a hereditary kidney cancer syndrome, which predisposes patients to develop kidney cancer, cutaneous fibrofolliculomas and pulmonary cysts. The responsible gene, FLCN is a tumor suppressor for kidney cancer which plays an important role for energy homeostasis through the regulation of mitochondrial oxidative metabolism. However, how FLCN-deficiency leads to renal tumorigenesis is unclear. Results Whole-exome sequencing analysis of BHD-associated kidney cancer revealed that copy number variations (CNV) of BHD-associated kidney cancer are considerably different from those already reported in sporadic cases. Somatic mutation analysis revealed BHD-associated kidney cancer has quite few common mutations in specific genes; however, chromatin remodeling genes in total were frequently mutated in BHD-associated kidney cancer (17/29 tumors, 59%). Metabolite analysis revealed that glycolysis, pentose phosphate pathway and lipid metabolism were upregulated whereas the rate of beta oxydation and TCA cycle is decreased in BHD-associated kidney cancer compared to normal adjacent kidney. Conclusions BHD-associated kidney cancer displays a unique molecular characteristics which is totally different from that of sporadic kidney cancer, providing the mechanistic insight into tumorigenesis under FLCN deficiency as well as the foundation for the development of novel therapeutics for kidney cancer.

Study JGAS000115

Assessing gene expression profiling from FFPE Patient Samples: A Comparison of Two Library Preparation Approaches and Recommendations

Next-Generation Sequencing (NGS) has transformed cancer research and clinical practice, with Whole Exome Sequencing (WES) driving advances in mutational profiling and personalized oncology. Yet, transcriptomic signatures remain essential for understanding disease mechanisms, including therapy resistance pathways. RNA sequencing (RNA-seq), however, faces unique challenges when dealing with low-input or degraded RNA, as often found in archival formalin-fixed paraffin-embedded (FFPE) tissues. Although previous studies have compared library preparation protocols, rapidly evolving technologies call for updated evaluations. Here, we present a direct comparison of two FFPE-compatible stranded RNA-seq library preparation kits: TaKaRa™ SMARTer® Stranded Total RNA-Seq Kit v2 (Kit A) and Illumina Stranded Total RNA Prep Ligation with Ribo-Zero Plus (Kit B). Both kits generated high-quality RNA-seq data, yet important differences emerged. Notably, Kit A achieved comparable gene expression quantification to Kit B while requiring 20-fold less RNA input, a crucial advantage for limited samples, albeit with increased sequencing depth. We critically discuss these results in relation to RNA availability, technical performance, cost-effectiveness, processing time, and automation potential, offering practical guidance for selecting optimal RNA-seq strategies in clinical and translational research settings

Study EGAS50000001066

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

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

Study EGAS50000000624

Whole-Genome sequencing of hepatocellular carcinomas

The French ICGC project on liver tumors is coordinated by Pr Jessica Zucman-Rossi and funded by Inca (French Institute for Cancer). The aim of the present project is to identify the catalog of somatic and germline mutations in liver tumors using whole genome and whole exome sequencing together with CGH-SNP, methylome and transcriptomic profiling. For this purpose, a series of 500 liver tumors are collected through the French National Liver Collection and these samples will be analyzed using the different omics technologies. The data will be deposited in the ICGC and EGA database to be publically available for the scientific community. Hepatocellular carcinoma (HCC) accounts for more than 90% of liver cancers, and is a major health problem. It is the 3rd cause of cancer-related mortality. Advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. Thus, the development of next-generation sequencing technologies has made it possible to generate more comprehensive catalogues of somatic alteration events (single nucleotide substitutions, structural variations, and epigenetic changes) in liver cancer genome than ever before. The dataset will include 50 whole genome sequencing tumor/germline pairs, of which 6 are deposited in February 2014.

Study EGAS00001000706

WGS of 32 paired SRCC samples

Signet-ring cell carcinoma (SRCC) has specific epidemiology and oncogenesis in gastric cancer, however with no systematical investigation for prognostic genomic features. We systematically investigated the clinical characteristics of 1,868 Chinese gastric cancer patients, and found that signet-ring cell content was significantly related to multiple clinical characteristics and treatment outcomes. Next, we performed whole genome sequencing for 32 SRCC patients with > 80% signet-ring cells in tumor, and identified frequent5 CLDN18-ARHGAP26/6 fusion (25%). With additional 797 patients for validation, we notice that prevalence of CLDN18-ARHGAP26/6 fusion is positively associated with signet-ring cell content (P = 4.1 x 10 -9 ), younger age at diagnosis (P = 4.2 x 10 -10 ), female/male ratio (P = 1.7 x 10 -9 ), and advanced TNM stage (P = 1.7 x 10 -5 ). Importantly, patients with CLDN18-ARHGAP26/6 fusion had a worse survival outcomes (P = 0.03), and got no benefit0 from platinum/fluoropyrimidines based chemotherapy (P = 0.92) compared to fusion-free patients (P = 0.001), which is consistent with the fact of oxaliplatin/fluoropyrimidine resistance acquired in CLDN18-ARHGAP26 introduced gastric cancer cell lines. Overall, this study provides new insights into the clinical and genomic features of SRCC, and highlights the importance of frequent CLDN18-ARHGAP26/6 fusions in chemotherapy response for SRCC.

Study EGAS00001002668

Direct Detection of Early-stage Cancers Using Circulating Tumor DNA

Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with stage I or II disease. Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients. In patients with resectable colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival. These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer.

Study EGAS00001002577

Reconstituting the transcriptome and DNA methylome landscapes of human implantation at single-cell resolution

Implantation is a milestone event during mammalian embryogenesis. Due to the extreme difficulty of obtaining in vivo human early post-implantation embryos, the gene regulatory network and epigenetics controlling human embryo implantation remains elusive. Here, combining an in vitro culture system for human post-implantation development and single-cell omics sequencing technologies, over 10,000 single cells at five representative stages of pre/post-implantation development were systematically analyzed. Unsupervised dimensionality reduction and clustering algorithm of the transcriptome data show stepwise implantation routes for the epiblast, primitive endoderm, and trophectoderm lineages, suggesting preparation for the establishment of a mother-to-offspring connection after implantation. Female embryos showed asynchronous progress of dosage loss of X chromosomes during implantation. Furthermore, using the single cell trio-Seq (scTrio-Seq) strategy, re-methylation of the genomes of all the three lineages was unambiguously revealed. Surprisingly, the genome re-methylation of PE lineage were much slower than both EPI and TE lineages during the implantation process, indicating distinct methylome features between EPI and PE although both of which were derived from ICM. Collectively, our work paves the way for understanding the complex molecular mechanisms that regulate human embryo implantation, informing new insights and future efforts in early embryonic development and reproductive medicine.

Study EGAS00001003443

RNA-seq study of human long-term and short-term hematopoietic stem cells from umblical cord blood with lentiviral overexpression of S1PR3

To investigate the molecular and biological pathways altered by S1PR3OE in human hematopoietic stem cells (HSC), we performed RNA-sequencing (RNA-seq) of LT- and ST-HSC 3 days after transduction with control or S1PR3 overexpression (OE) lentiviral vectors. LT-HSC and ST-HSC from 3 pool of CB lin- were FACS-purified, cells were prestimulated for 4 hours and transduced with lentiviral vectors. At day 3, 2000-5300 BFP+ cells were FACS-purified for RNA isolation with a PicoPure kit. We were able to isolate only 1600-1800 BFP+ cells from LT-HSC control samples as opposed to 4000-5400 BFP+ cells from S1PR3OE samples. Thus, we pooled all control BFP+ LT-HSC cells into one sample for RNA-seq analysis. BFP- LT-HSC from control vector transduction were purified from CB1 as an additional LT-HSC control. Nextera libraries generated from 10 ng RNA from 5 LT-HSC samples (2 controls, 3 S1PR3OE) and 6 ST-HSC samples (3 controls, 3 S1PR3OE) were subjected to 125 bp, paired-end RNA-sequencing on the Illumina HiSeq 2500 with an average of 50 million reads/sample at the Center for Applied Genomics, Sick Kids Hospital.

Study EGAS00001004798

Nanopore_and_Illumina_sequencing_of_human_glioblastomas

Liquid biopsy analysis refers to methods designed to detect tumour-specific material (e.g., circulating tumour cells or tumour DNA) in body fluids, such as urine or blood samples. A widely-used liquid biopsy approach consists of genotyping the circulating tumour DNA (ctDNA) through sequencing of plasma/serum DNA. Although useful in the context of metastatic disease (where the concentration of ctDNA is high), current liquid biopsy technologies show limited sensitivity of detection for the early detection of cancer, and low specificity, as cancer-related mutations accumulate in healthy tissues as part of the ageing process, thus making it difficult to distinguish these from tumour mutations, and because sequencing errors and true mutations show overlapping profiles. Therefore, developing liquid biopsy protocols with increased sensitivity and specificity represents an urgent clinical need. Here we harness extrachromosomal circular DNA (eccDNA) elements, which are circular DNA structures physically separated from the chromosomes of up to several Mbp long pervasive in human cancers, for liquid biopsy analysis. In this pilot study we will focus on the analysis of glioblastomas, because there is strong evidence for the presence of eccDNA in these tumour types, and because developing liquid biopsy approaches for brain tumours to reduce the invasiveness of brain tumour biopsies remains an unmet clinical need.

Study EGAS00001005812

A panel of reference haplotypes for imputing complement component 4 (C4) gene structural variation

Neuropsychiatric and autoimmune disorders have substantial epidemiological correlations (Benros et al., JAMA Psychiatry 2013, PMID: 23760347) and broad, genome-wide patterns of shared genetic risk (Pouget et al., Hum Mol Genet, PMID: 31211845; Tylee et al., Am J Med Genet B Neuropsychiatr Genet 2018, PMID: 30325587). Some cases of psychosis involve autoantibodies against the NMDA receptor, AMPA receptor, or other synaptic proteins (reviewed in Dalmau et al, Lancet Neurol 2011, PMID: 21163445). The related autoimmune conditions lupus and Sjogren's Syndrome also involve the development of autoantibodies. The possibility that neuropsychiatric disorders can have molecular mechanisms in common with autoimmune disorders - for example, that psychosis involves an inflammatory or autoimmune component in some patients, or that immune molecules are re-used in the brain to underlie other important biological activities (Stevens et al., Cell 2007, PMID: 18083105) - could open novel therapeutic possibilities for neuropsychiatric disorders. At a genetic level, the strongest genetic associations of schizophrenia, lupus, and Sjogren's Syndrome to common genetic variation involve associations to genetic markers in the Major Histocompatibility Complex (MHC) locus. Bipolar disorder in some studies also associates with variation in or near the MHC locus, though less strongly than schizophrenia does. Intriguingly, the same specific SNPs appear to associate strongly with schizophrenia, lupus, and Sjogren's; these strongly associating SNPs span a genomic segment that includes the HLA class II genes (which have an important role in antibody production) and the complement component 4 (C4) genes. The specific genes and alleles responsible for these associations need to be completely defined, and the extent to which they represent shared or distinct genetic influences in neuropsychiatric and autoimmune illnesses needs to be clarified. The complement component 4 (C4A and C4B) genes are present in the MHC locus, between the class I and class II HLA genes. C4A and C4B commonly vary in genomic copy number and encode complement proteins with distinct affinities for molecular targets. The complex genetic variation at C4 - arising from many alleles with different numbers of C4A and C4B genes - has been challenging to analyze in large cohorts. We recently developed an approach to this problem based on imputation: people share long haplotypes with the same combinations of SNP and C4 alleles, such that C4A and C4B gene copy numbers can be imputed from SNP data (Sekar et al., Nature 2016, PMID: 26814963). In the current work, to analyze C4 in large cohorts, we developed a way to identify C4 alleles from whole-genome sequence (WGS) data, then analyzed WGS data from 1,234 individuals to create a large multi-ancestry panel of 2,530 reference haplotypes of MHC SNPs and C4 alleles that can then be imputed into still-larger cohorts for which SNP data are available. With this dbGaP submission, we make this reference panel available for other studies. Protocols and software for imputing C4 alleles into genome-wide SNP data, and for performing molecular analyses on the C4 genes (such as direct measurement of copy number from genomic DNA), can be found on the McCarroll Lab web site (http://mccarrolllab.org/resources). We are also working to create additional reference panels for imputation of C4 alleles that will be based on still-larger and more diverse population samples; links to these will also be available on the McCarroll Lab web site as we create and validate them.

Study phs001992

Evaluating potential drug candidates for the treament of Henamgiopericytoma on patient derived cell line models

Solitary fibrous tumor/Hemangiopericytoma (SFT/HPC) is a rare subtype of soft tissue sarcoma associated with NAB2-STAT6 gene fusions. This study established and characterized a novel SFT/HPC patient-derived cell line called SFT-S1. Potential drug candidates that could be repurposed for the treatment of SFT/HPC were screened.

Study EGAS50000000027

10X single-cell Multiome (RNA+ATAC) and single-cell RNAseq of xenograft-derived HSPC, progenitors and myeloid progeny

10X genomics chromium single-cell ATAC+RNA (Multiome) was use to prepare single-nucleus RNA- and ATAC-seq libraries for human HSPC sorted from xenografts recovered from inflammatory challenge. 10X genomics 3' kits were used to prepare single-cell RNA-seq libraries for committed progenitors and myeloid cells from the same xenografts. These were sequenced on an Illumina NovaSea 6000 platform; BAM files are provided. Samples from 3 conditions were sequenced for each cell type; 3 chromatin accessibility runs and 9 gene expression runs are provided.

Dataset EGAD50000002328

Transcriptomics for LUNG-NSCLC2 cohort

The goal of IMMUcan is to understand how the immune system interacts with tumors and how therapeutic interventions influence this interaction. This cohort includes patients with non-small cell lung cancer who had surgical resection. This is a subcohort of the EORTC SPECTAlung study. This dataset contains transcriptomics data processed with the STAR pipeline. Two sequencing kits were employed: Roche KAPA for high-quality RNA samples and Takara SMART-Seq Stranded for samples with limited RNA quantities.

Dataset EGAD50000002236

HCC cfMeDIP-seq

This dataset comprises 406 raw fastq files derived from 203 plasma cfDNA samples from 90 patients diagnosed with hepatocellular carcinoma (HCC). The samples include 90 baseline HCC (b-HCC) samples, collected during liver transplant or resection surgeries, and 113 postoperative follow-up (f-HCC) samples. For each sample, 10ng of cfDNA was used for library preparation utilizing cfMeDIP-seq technology based on the 5mC antibody-immunoprecipitation strategy. Libraries were validated via Bioanalyzer trace analysis and sequenced on Illumina NovaSeq 6000 or HiSeq 2500 platform with paired-end 150-bp (NovaSeq) or 125-bp (HiSeq) model for ~100 million reads per sample.

Dataset EGAD50000000651

RNA sequencing of Notch inhibitor treated HCC PDX models across timepoints

To study the effect of Notch inhibition on the transcriptional profiles our PDX models, we generated bulk RNA-seq data for two Notch inhibition sensitive and three Notch inhibition insensitive models across multiple timepoints (8h, 24h, 48h, 7d, 17d) using anti-JAG1, anti-Notch2, anti-Notch1 or anti-gD antibodies. 3-5 samples were collected for each treatment condition, resulting in a total of 96 samples. Isolated RNA was used as input for library preparation using TruSeq RNA Sample Preparation Kit v2 (Illumina). The libraries were multiplexed and sequenced on Illumina HiSeq 2500 (Illumina) to produce FASTQ files.

Dataset EGAD50000000737

GenomeDenmark Phase 2 - MHC haplotypes

The MHC vcf call set was generated using a modified AsmVar and BayesTyper pipeline. In contrast to the original pipeline, where variant calling is performed using alignment of collapsed assemblies to a reference genome, the MHC call set was produced using alignment of phased MHC haplotypes. Two iterations of BayesTyper was run, a first iteration for each haplotype seperately and a second iteration performing joint variant calling on all haplotypes. The sample IDs for the fathers and mothers are TrioID-01 and TrioID-02, respectively, and the IDs for the children are TrioID-0x, where x is a number between 3 and 7.

Dataset EGAD00001003455

Longitudinal profiling of circulating tumour DNA for tracking tumour dynamics in pancreatic cancer

The utility of circulating tumour DNA (ctDNA) for longitudinal tumour monitoring in pancreatic ductal adenocarcinoma (PDAC) has not been explored beyond mutations in the KRAS proto-oncogene. We aim to characterise and track patient-specific somatic ctDNA variants, to assess longitudinal changes in disease burden and explore the landscape of actionable alterations.

Study EGAS00001005981

Long-read sequencing for cell-free DNA analysis (mouse)

In this study, we compared the two long-read sequencing platforms, namely the single-molecule real-time sequencing by Pacific Biosciences and nanopore sequencing by Oxford Nanopore Technologies, for the analysis of cell-free DNA from plasma. Artificial mixtures of sonicated human and mouse DNA at different sizes were sequenced with the two platforms.

Study EGAS00001006329

Cancer sequencing for somatic variant calling

This dataset includes WES and RNAseq for 11 patients with metastatic melanoma, lung, kidney, and stomach cancers, enrolled in phase I clinical trials of TIL ACT (NCT03475134 & NCT04643574). WES was performed on matched cancer and healthy tissues, whereas RNAseq was performed on cancer tissues, using Illumina HiSeq 2500/4000 and Illumina NextSeq 550 systems.

Study EGAS00001007101

H3K27ac/H3K27me3 landscape of medulloblastoma

We profiled 111 patient medulloblastoma primary tumor samples by bulk RNA-seq (19 samples), 27ac (98 samples) / 27me3 (61 samples) ChIP-Seq, WGS (4 samples) and 27ac hichip (8 samples). Submitted data consists of data generated from previously unpublished tumors as well as complementary data for data sets already published for identical medulloblastoma tumors (ex: 27me3 ChIP-Seq and RNA-Seq data submitted for a tumor with publicly available WGS data). The raw fastqs and hg19 aligned RNA-Seq bams are provided.

Dataset EGAD00001009709

IntEnd study

Formalin-fixed, paraffin-embedded samples from 643 colorectal adenomas collected in different hospitals in Norway, from which DNA was extracted, were analysed for DNA copy number alterations. Some adenomas had more than one block (n=42), thus 643 individuals, 685 blocks. Low-coverage whole genome sequencing was run in all samples. For 529 individuals all the clinical information was available. A subset was matched for follow-up time, age and sex in a nested case-control approach (n=366; cases - individuals who developed later on CRC; controls - individuals who did not develop CRC within the same follow-up time).

Dataset EGAD00001010119

CSER: Genomic Sequencing to Aid Diagnosis in Pediatric and Prenatal Practice: Examining Clinical Utility, Ethical Implications, Payer Coverage, and Data Integration in a Diverse Population

Congenital abnormalities and developmental disorders affect 3-5% of live born infants and children. Despite advances in both pre- and post-natal treatment, the utility of genetic testing in diagnosing the etiology underlying such conditions in order to guide management has been frustratingly limited. Traditional genetic testing with specific gene tests, or even gene panels, is diagnostic in only a small percentage of cases. Recent technological advances in next generation sequencing (NGS) have led to the ability to sequence and interpret the entire exome relatively quickly, allowing a diagnosis in 25-30% or more of cases of developmental disorders when other genetic tests have not yielded a result. Although whole exome sequencing (WES) holds great promise for improved diagnosis leading to better clinical outcomes, challenges remain in determining how best to apply and utilize sequence data. Fulfilling the promise of WES also requires investigation of ELSI (ethical, legal, social) concerns, given skepticism in some communities that research will benefit them; economic considerations that ultimately determine access to and equitable use of WES; and a need to share clinical genetic results with families and across health care systems to enable better prognostication and management of rare conditions in community settings. We propose a Program in Prenatal and Pediatric Genomic Sequencing (P3EGS) at UCSF to examine the diagnostic and clinical utility of WES. P3EGS will recruit and study affected individuals and their parents, including pregnancies in which the fetus has a confirmed structural anomaly and children with previously undiagnosed developmental disorders that are likely of genetic etiology. Following consent and collection of standardized phenotypic data, the families will undergo WES as part of clinical care. To achieve diversity, patient ascertainment and recruitment will occur at four UCSF sites that serve a broad range of underrepresented minorities (target of 75%) and span the full socio-economic spectrum, including the underserved. Our specific aims will: 1) examine the clinical utility of WES, including assessment of a variety of health-related and reproductive outcomes, in undiagnosed individuals; 2) address ethical, social and economic issues in the delivery of genomic sequencing results to ancestrally and economically diverse populations through (2.1) a mixed methods, longitudinal empirical study of clinical interactions and experiences, (2.2) an economic analysis of insurance coverage, price and reimbursement of multigene tests, and (2.3) creation of an Ethics Advisory Board to respond to emerging issues and establishment of authentic stakeholder engagement; and 3) pilot a user-friendly web-based patient/provider application integrating genomic and clinical data as a shared evidence base to support result communication, interpretation and clinical decision making; the application will be based on the “Bioscreen” model created and successfully implemented at UCSF.

Study phs002324

MP2PRT: Comprehensive Genomic Profiling to Identify Alterations Associated with Relapse for NCI Standard Risk (SR) B-Lineage ALL and NCI High Risk (HR) B-Lineage ALL with Favorable Genetic Features

The Molecular Profiling to Predict Response to Treatment (MP2PRT) program is part of the NCI's Cancer Moonshot Initiative. The aim of this program is the retrospective characterization and analysis of biospecimens collected from completed NCI-sponsored trials of the National Clinical Trials Network and the NCI Community Oncology Research Program. This study, titled "Comprehensive Genomic Profiling to Identify Alterations Associated with Relapse for NCI Standard Risk (SR) B-Lineage ALL and NCI High Risk (HR) B-Lineage ALL with Favorable Genetic Features," is one of the selected studies under this program. For this study, genomic characterization (WGS 30X, WXS, Total RNAseq) was performed on NCI Standard Risk B-lineage ALL patients who relapse and subsets of NCI High Risk B-lineage ALL patients who relapse as well as two non-relapse control cases for each relapse case. It was hypothesized that the comprehensive characterization of these sample sets will allow the identification of somatic genetic features that will facilitate early intervention to improve cure rates for those enrolled on future trials. Data were generated and genetic subtype was integrated with clinical variables, including age, presenting white blood cell count, sex, race, and levels of minimal residual disease at the end of induction. Additional secondary alterations were identified and included if they occurred in more than 10 patients. The study has been completed and a manuscript has been prepared.

Study phs002005

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