15070 results for "cancer studies using rna-seq"

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• NCI's Collection of Studies for General Cancer Research

  This collection contains all of NCIs authorized individual-level genomic datasets currently in dbGaP that are approved for Cancer Research (DS-CA) use only and limitations outlined in the model Data Use Certification Agreement. Access to this study will include any additional authorized individual-level DS-CA datasets that become available. Renewal of this study is required annually. To request access to this study collection, select phs003967.v1.p1 in the dbGaP Authorized Access System.

  Study phs003967

• RNA-seq in LCLs derived from constitutional MLH1 epimutation carriers and non-carrier relatives

  Transcriptome profiling in human lymphoblastoid cell lines derived from constitutional MLH1 epimutation carriers and non-carrier relatives

  Study EGAS50000000498

• Characterization of a novel MEF2D-BCL9 fusion positive acute lymphoblastic leukemia cell line RNA-Seq

  A novel in-house-made pediatric MEF2D-BCL9 fusion positive acute lymphoblastic leukemia cell line was characterized

  Dataset EGAD00001009759

• Notch Signaling and Efficacy PD-1/PD-L1 Blockade in Relapsed Small Cell Lung Cancer

  Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine (NE) cancer that accounts for approximately 15% of all lung cancer, with an annual incidence of more than 34,000 in the United States alone. SCLC is characterized by loss of function of p53 and RB and high tumor mutational burden, which suggests that these tumors could be immunogenic and respond to immune checkpoint blockade (ICB). However, the benefit from ICB in an unselected SCLC population is modest. In this study, we evaluated the genomic features associated with clinical outcomes in relapsed SCLC to gain insight into the underlying mechanisms of ICB response. Exome, RNA and TCR sequencing data from a prospective clinical trial of relapsed SCLC treated with durvalumab and olaparib and RNA-sequencing data for second cohort of relapsed SCLC cohort treated with nivolumab are included.   

  Study phs002176

• Childhood Cancer Data Initiative (CCDI): OncoKids - NGS Panel for Pediatric Malignancies

  This study aimed to systematically collect clinical, registry and genomic data on pediatric cancer patients, and to contribute to the CCDI Pediatric Data Ecosystem. Clinical, treatment and outcome data on 1,039 pediatric cancer patients whose molecular profile was characterized on OncoKids gene panel at Children's Hospital Los Angeles was abstracted and harmonized for submission to the NCI’s Cancer Data Service. The OncoKids panel was designed to detect DNA mutations and amplification in almost 200 oncogenes and tumor suppressor genes, a limited number of pharmacogenomic targets and 1,700 disease-associated gene fusions at the RNA level. The panel encompasses the vast majority of FDA’s relevant pediatric molecular target list, as well as additional genes associated with ultra-rare pediatric tumors. The final data elements included DNA/RNA sequence data, OncoKids test results, clinical data on demographics, diagnosis, comorbidity and adverse events and treatment data.

  Study phs002518

• Ongoing_mutagenesis_RNAseq

  One of the key questions to be explored is whether the biological processes generating specific mutational signatures continue to operate in the human cancer cell lines or simply reflect past mutagenic activity which is no longer operative. To address this question, we have extracted mutational signatures from 1,000 cancer cell lines of diverse cancer types. Several cell lines with mutational signatures of interest were selected, subcloned over a defined period of time and their genomes sequenced. The increased load of the mutations representative of a specific mutational signature within the genome of a subclone when compared to its parental clone was informative of the on-going mutational processes. To further study the recent observation that some of the clones belonging to a same cell line acquired differencet numbers of mutations over a set period of time, their RNA will be subjected to RNA-sequencing to study their differences.

  Study EGAS00001002364

• Sequencing_component_for_the_whole_genome_methylation_analysis_in_PBMCs_and_cell_subsets__pilot_study_

  DNA methylation has been shown to play a major role in determining cellular phenotype by regulating gene expression. Moreover, dysregulation of differentially methylated genes has been implicated in disease pathogenesis of various conditions including cancer development as well as autoimmune diseases such as systemic Lupus erythematosus and rheumatoid arthritis. Evidence is rapidly accumulating for a role of DNA methylation in regulating immune responses in health and disease. However, the exact mechanisms remain unknown. The overall aim of the project is to investigate the role of epigenetic mechanisms in regulating immunity and their impact on autoimmune disease pathogenesis.The aim of this pilot study is to perform whole genome methylation analysis in peripheral blood mononuclear cells (PBMCs) and cell subsets (CD4, CD8, CD14, CD19, CD16 and whole PBMCs) obtained from 6 healthy volunteers. Whole genome methylation analysis will be performed using two methodological approaches, the Infinium Methylation Bead Array K450 (Illumina) and MeDIP-seq. mRNA expression arrays will also be performed in order to correlate DNA methylation with gene expression as well as genotyping on the Illumina OmniExpress chip

  Study EGAS00001000490

• RNA-sequencing from duodenal bipsies of Celiac disease patients

  Samples, in a form of PAXgene fixed and paraffin-embedded biopsies, were collected from the multi-site, double-blind, randomized, placebo-controlled trial, aimed at dose-finding and assessing the efficacy and tolerability of a 6-week treatment with ZED1227 capsules vs. placebo in subjects with well-controlled celiac disease undergoing gluten challenge. Total RNA was extracted from the PaxFPE biopsy specimens (n = 116) using additional cuttings from the samples on which histomorphometry was previously assessed. For the extraction, an RNeasy Kit (Qiagen, Hilden, Germany) was used according to the manufacturer’s instructions. Library preparation and next-generation sequencing (NGS) were performed by the Qiagen NGS Service. A total of 10 ng of purified RNA was converted into cDNA NGS libraries. Library preparation was quality controlled using capillary electrophoresis. Based on the quality of the inserts and the concentration measurements, the libraries were pooled in equimolar ratios and then sequenced on a NextSeq (Illumina Inc., San Diego, USA) sequencing instrument according to the manufacturer’s instructions, with 100 bp read length for read 1 and 27bp for read 2. The raw data were de-multiplexed, and FASTQ files for each sample were generated using bcl2fastq2 software (Illumina Inc., San Diego, USA).

  Dataset EGAD50000000491

• Genome-Wide Association Study of Sporadic and Familial Testicular Germ Cell Tumors

  Case-Control Study:Testicular germ cell cancer has been increasing among men during most of the 20th century. Despite this increase, the etiology of testicular cancer is poorly understood. To better understand the molecular epidemiology of testicular cancer, the National Cancer Institute and the Department of Defense are conducting a case-control study of testicular cancer among military servicemen. The project includes obtaining biosamples and questionnaire data from all participants. Pre-diagnostic serum samples are available from the approximately 1,000 cases and 1,000 controls enrolled in the study. Multiple-Case Family Study:In a parallel project, we are also studying families in which 2 or more testicular cancers have occurred. Among those men diagnosed with testicular cancer, about 1-3 percent report a family history of the disease (FTGCT). Brothers of affected individuals are 8 to 10 times more likely to develop testicular cancer, and men whose fathers had testicular cancer are four times more likely to develop testicular cancer, when compared with the relatives of men who have never had testicular cancer. Large-scale genetic linkage studies have failed to identify one or more rare, highly-penetrant testicular susceptibility genes. Rather, it appears that these familial clusters are due to the combined effects of multiple more common genes with low penetrance (so-called "polygenic inheritance"). Our cohort of FTGCT families was assembled to characterize this syndrome's clinical phenotype, and to discover the full range of cancer susceptibility loci that influence TGCT pathogenesis.

  Study phs001303

• Whole genome sequence analysis in patients with primary central nervous system lymphomas

  We performed target amplicon sequencing analysis in 28 patients with primary central nervous system lymphomas using target capture technology (NGS) on Cancer Panel to explore molecular targets.

  Study JGAS000258

• A fast, affordable and minimally-invasive diagnostic test for Cancer of Unknown Primary (CUP) using DNA methylation profiling

  CUP diagnosis on FFPE tissue and liquid biopsies (blood, pleural and peritoneal effusions) using cfRRBS (cell-free reduced representation bisulfite sequencing), a technique that allows for identification of the methylation profile starting from minimal amounts of highly fragmented DNA.

  Study EGAS50000000257

• Whole Genome DNA Methylation

  Whole Genome Bisulfite Sequencing on normal primary human uveal melanocytes. WGBS libraries were prepared using the Accel-NGS Methyl-Seq DNA Library Kit (Swift Biosciences 30024), the EZ DNA Methylation-Gold Kit (Zymo D5005), and DNA Clean & Concentrator-5 (Zymo D4013), following the instruction manual Accel-NGS Methyl-Seq DNA Library (Revision 160510). Paired-end (2 x 150 bp) libraries were sequenced on a DNBSEQ-T7 instrument (MGI) after library conversion.

  Dataset EGAD50000000766

• Whole Genome DNA Methylation MPI

  Whole Genome Bisulfite Sequencing on normal primary human uveal melanocytes. WGBS libraries were prepared using the Accel-NGS Methyl-Seq DNA Library Kit (Swift Biosciences, Catalog No. 30024), the EZ DNA Methylation-Gold Kit (Zymo, D5005) and DNA Clean & Concentrator-5 (Zymo, D4013), following the instruction manual Accel-NGS® Methyl-Seq DNA Library (Revision 160510). Paired-end libraries (2 × 150 bp) were sequenced on a NovaSeq 6000 instrument.

  Dataset EGAD50000001139

• DNA-seq FASTQ files from 16 patients affected by acute intermittent porphyria

  Paired-end DNA-seq FASTQ files from 16 patients affected by acute intermittent porphyria. Whole genome sequencing of these samples was performed in an Illumina HiSeq 4000 instrument. Libraries were prepared using the Fisher PE Kit (Kapa Biosystems). Each sample was multiplexed across flowcells and lanes, leading to a total number of 83 pairs of FASTQ files.

  Dataset EGAD00001006950

• Methylation profiling by MCC-Seq of visceral fat (N=199) and whole-blood (N=206) derived from IUCPQ participants

  The study includes NGS-based methylC-capture sequencing (MCC-Seq) on 199 visceral adipose tissue and 206 whole-blood DNA samples derived from obese individuals (BMI >40 kg m-2) in the IUCPQ cohort. We generated 100bp paired-end reads using the Illumina HiSeq2000 or 2500 systems.

  Dataset EGAD00001004787

• Fecal microbiome predicts treatment response after the initiation of semaglutide or empagliflozin uptake

  To investigate the effect of semaglutide and empagliflozin initiation on the gut microbiome of type 2 diabetes patients. In addition, to analyze whether the pre-treatment gut microbiome can predict the treatment efficacy. Gut microbiome fecal samples donated at four timepoints (Baseline, Month 1, Month 3; Month 12) were studied using 16S ribosomal RNA gene sequencing and analysis.

  Study EGAS50000000531

• WES Profiles from the CheckMate-577 Clinical Trial

  The dataset contains WES profiles of 396 patients from the CheckMate-577 (CA209-577) clinical trial whose ICF allows data deposition into a public repository. The Allprep DNA/RNA FFPE kit was used to simultaneously purify genomic DNA and total RNA from formalin-fixed, paraffin embedded (FFPE) tissue sections. DNA was analyzed by Whole Exome Sequencing using Swift Biosciences Accel-NGS 2S Hyb DNA Library Kit for library preparation and hybridization using Agilent SureSelect All Exon v6, followed by sequencing on the Illumina NovaSeq platform with a 100bp paired-end strategy and a target read depth of 100M per tumor sample. Fastq files are included.

  Dataset EGAD50000002395

• Capture Hi-C on MM

  In situ promoter capture Hi-C on multiple myeloma cell line KMS11 in experimental triplicates. Hi-C libraries were prepared as previously described (Rao et al., 2014, http://dx.doi.org/10.1016/j.cell.2014.11.021). Promoter capture was based on 32,313 biotinylated 120-mer RNA baits (Agilent). Hi-C libraries were sequenced using Illumina HiSeq 2000 technology. The files are in FASTQ format.

  Study EGAS00001002614

• Adult B-precursor acute lymphoblastic leukemia transcriptomes

  Bone marrow or peripheral blood samples were collected of adult patients at first diagnosis of B-precursor acute lymphoblastic leukemia. RNA was isolated from mononuclear cells and subjected to mRNA library prep using Poly-A selection and sequencing on a NovaSeq 6000 system. Obtained gene expression profiles and gene fusion calls were used to allocate samples to molecular disease subtypes.

  Study EGAS00001006107

• MIBS MGS

  Metagenomic sequencing of the human gut in Maastricht IBS studies, cases and controls.

  Study EGAS00001001924

• Whole transcriptome profiling of liquid biopsies from tumour xenografted mouse models: validation cohort

  While cell-free DNA (cfDNA) in liquid biopsies is widely being used and investigated, free circulating RNA (extracellular RNA, exRNA) has the potential to improve therapy response monitoring and cancer detection due to its dynamic nature. A fundamental open question hampering the initiation of large-scale liquid biopsy collections for tumour exRNA analysis is that it remains unclear in which blood subcompartment tumour-derived exRNAs primarily reside. We set out to develop a host-xenograft deconvolution framework, exRNAxeno, with cDNA mapping strategies to either a combined human-mouse reference genome or both species genomes in parallel, that can be applied to exRNA sequencing data from liquid biopsies of human xenograft mouse models, enabling to distinguish (human) tumoural RNA from (murine) host RNA, and as such to specifically analyse tumour-derived exRNA. Subsequently, the preferred exRNAxeno combination pipeline was applied to total exRNA sequencing data from blood platelets and three plasma fractions from a breast cancer patient-derived and neuroblastoma cell line-derived xenograft mouse model. We show that tumoural exRNA concentrations are not determined by plasma platelet levels, while host exRNA concentrations increase with platelet content. Furthermore, a large variability in exRNA levels and gene content across individual mice is observed. In general, the tumoural gene detectability in plasma is correlated with the RNA expression levels in the tumour tissue or cancer cell line. Our results unravel new aspects of tumour-derived exRNA biology in xenograft mouse models.

  Study EGAS00001006582

• 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

• Region-Specific Neural Stem Cell Lineages Revealed by Single-Cell RNA-Sequences from Human Embryonic Stem Cells

  During development of the human brain, multiple cell types with diverse regional identities are generated. Here we report a system to generate early human brain forebrain and mid/hindbrain cell types from human embryonic stem cells (hESCs), and infer and experimentally confirm a lineage tree for the generation of these types based on single-cell RNA-Seq analysis. We engineered SOX2Cit/+ and DCXCit/Y hESC lines to target progenitors and neurons throughout neural differentiation for single-cell transcriptomic profiling, then identified discrete cell types consisting of both rostral (cortical) and caudal (mid/hindbrain) identities. Direct comparison of the cell types were made to primary tissues using gene expression atlases and fetal human brain single-cell gene expression data, and this established that the cell types resembled early human brain cell types, including preplate cells. From the single-cell transcriptomic data a Bayesian algorithm generated a unified lineage tree, and predicted novel regulatory transcription factors. The lineage tree highlighted a prominent bifurcation between cortical and mid/hindbrain cell types, confirmed by clonal analysis experiments. We demonstrated that cell types from either branch could preferentially be generated by manipulation of the canonical Wnt/beta-catenin pathway. In summary, we present an experimentally validated lineage tree that encompasses multiple brain regions, and our work sheds light on the molecular regulation of region-specific neural lineages during human brain development.

  Study phs001205

• CMF_RNA_sequencing

  RNA sequencing will be undertaken to reconstruct rearrangements at level of transcription to determine pathogenomic genomic events in chondromyxoid fibroma

  Study EGAS00001000470

• Type I Interferon and Cycling Lymphocytes in Macrophage Activation Syndrome

  We performed immune profiling of peripheral blood mononuclear cells from patients with Still's disease and macrophage activation syndrome (MAS) using bulk RNA sequencing and single-cell RNA sequencing. Three groups were included in the study: healthy controls, patients with Still's disease without macrophage activation syndrome, and patients with Still's disease and macrophage activation syndrome. We found that macrophage activation syndrome is associated with transcriptomic signatures of interferon upregulation and cell cycling. We identified cycling lymphocytes within T cell and NK cell populations that are correlated with MAS disease activity. All sequencing data are available through dbGaP.

  Study phs003310

• Comparison of 3 protocols for deriving pancreatic progenitors from hPSC with RNA-seq and ATAC-seq

  Several distinct differentiation protocols for deriving pancreatic progenitors (PP) from human pluripotent stem cells have been described but it remains to be shown how similar the PP are across protocols, and how well they resemble their in vivo counterparts. Here we evaluated three differentiation protocols; performed RNA and ATAC-seq on isolated PP derived with these, and compared them to fetal human pancreas populations. This enabled us to define a shared transcriptional and epigenomic signature of the PP, including several genes not previously implicated in pancreas development. Furthermore, we identified a significant and previously unappreciated cross-protocol variation of the PP through multi-omics analysis and demonstrate how such information can be applied to refine differentiation protocols for derivation of insulin-producing beta-like cells. Together, our study highlights the importance of a detailed characterization of defined cell populations derived from distinct differentiation protocols, and provides a valuable resource for exploring human pancreatic development.

  Study EGAS00001003513

• Identification of the Global miR-130a Targetome Reveals a Novel Role for TBL1XR1 in Hematopoietic Stem Cell Self-Renewal and t(8;21) AML

  In this study, we identified miR-130a as a regulator of HSC self-renewal and differentiation. To characterize gene expression changes following enforced expression of miR-130a OE, we performed RNA-seq in CD34+ cord blood (CB) cells transduced with control and miR-130a OE lentiviruses. To capture miRNA targets in an unbiased, transcriptome-wide manner, we perfomed enhanced CLIPseq procol in 2 replicates of CD34+ CB cells and Kasumi-1 cell line, which represent a model system for t(8;21) AML. We chose this cell line, as we found miR-130a to be highly expressed in this AML subtype where it is critical for maintaining the oncogenic molecular program mediated by AML1-ETO. Chimeric Ago2 eCLIPseq in CD34+ CB cells combined with Mass Spectrometry data analysis identified TBL1XR1 as a principal target of miR-130a. To elucidate gene expression changes associated with TBL1XR1 loss of function, we performed RNA-seq in CD34+CD38- CB cells transduced with control and shRNA targeted against TBL1XR1. To determine the functional significance of high miR-130a expression levels in Kasumi-1 cells on the molecular network controlled by AML1-ETO, we performed CUT&RUN assay and RNA-seq in Kasumi-1 cells following miR-130a knock-down (KD). Collectively, our findings reveal a unique role of miR-130a in regulating normal hematopoietic stem cell self-renewal and how elevated levels of miR-130a in t(8;21) AML contribute to the leukemogenesis of this AML subtype.

  Dataset EGAD00001008412

• Correlative Studies for Protocol #14-C-0059: T Cells Expressing an Anti-GD2 Chimeric Antigen Receptor in Patients with GD2+ Solid Tumors, a Collaboration with CIMAC-CIDC

  This study is a retrospective correlative analysis of immune cell phenotypes in samples from a Phase I clinical trial (NCT02107963) of GD2 CAR-T cells (GD2-CAR.OX40.28.z.iC9) in children and young adults with osteosarcoma and neuroblastoma. The study was a 3+3 dose-escalation study with four dose levels (1 x 10(5) transduced T cells/kg; 1 x 106 transduced T cells/kg; 3 x 106 transduced T cells/kg; and 1 x 107 transduced T cells/kg). Apheresis and final manufactured GD2 CAR-T product samples were analyzed by bulk RNA sequencing and ATAC sequencing. The patients were stratified into good CAR-T expanders (peak CAR-T expansion >1000 GD2 CAR copies/100ng DNA) and poor CAR-T expansion (peak CAR-T expansion Increased naïve T cell subsets in baseline apheresis are associated with patients who experienced good CAR T cell expansion A T cell exhaustion signature was observed in the manufactured GD2 CAR-T product and may have contributed to lack of efficacy observed in this trial Increased myeloid-derived suppressor cell (MDSC) signatures were observed in patients with poor CAR-T expansion CAR-T product in good expanders displayed increased AP-1 factor transcription factor motifs, such as BATF, JUN, and FOS Data provided in dbGaP for this study include: Bulk RNA-Seq data for 11 pre-treatment peripheral blood and 11 GD2 CAR-T product from 14 patients. ATAC sequencing of 22 peripheral blood samples and 5 GD2 CAR-T products from 14 patients.

  Study phs003455

• Characterization of Neoantigen-reactive T cells by Single-Cell Analysis

  Through CITE-seq and TCR-seq analysis of non-small cell lung cancer (NSCLC) tumor-infiltrating lymphocytes (TIL), we developed a neoantigen-reactive T-cell signature based on clonotype frequency and CD39 protein and CXCL13 mRNA expression. There are four datasets from four NSCLC cases. Each dataset includes (1) Transcriptome of tumor infiltrating lymphocytes (TIL), (2) Cell surface protein expression on TIL by Feature barcoding, (3) T-cell receptor analysis of TIL, and (4) Reference file for feature-barcoding antibodies.

  Study phs002792

• Combination_Immune_Checkpoint_Inhibition_in_Australian_Rare_Cancers_WES

  Combination immune checkpoint inhibition (ICI) with anti-CTLA-4 and anti-PD-1 blockade has demonstrated significant clinical activity across tumour types. Rare cancer patients have limited treatment options due to the scarcity of studies of novel treatment options, so they are often offered chemotherapies untested in their disease. ONJ2016-001/CA209-538 is a prospective, multicentre clinical trial of combination ICI (ipilimumab and nivolumab) in patients with advanced rare cancers, including biliary tract, adrenocortical, rare gynaecological and neuroendocrine cancers (https://clinicaltrials.gov/ct2/show/NCT02923934). The primary endpoint is clinical benefit rate (complete response + partial response + stable disease >3 months) by RECIST 1.1. This study involves generation and analysis of pre-treatment formalin fixed paraffin embedded (FFPE) tumour DNA sequencing data, paired with germline DNA sequencing data, to potentially identify genomic biomarkers that may associate with clinical benefit or other clinical efficacy / toxicity metrics.

  Study EGAS00001005709

• Atezolizumab monotherapy following dCRT indicated a promising cCR rate in patients with unresectable locally advanced esophageal squamous cell carcinoma (EPOC1802)

  The objective is to analyze tumor and normal cell exome sequencing of esophageal cancer patients participating in the Tenergy trial before treatment and RNA sequencing specimens of tumor biopsy specimens at three points before treatment, after radiation chemotherapy, and after atezolizumab administration, in order to search for biomarkers to predict treatment response. Exome sequencing of pretreatment tumor tissue (27 specimens) and normal tissue (27 specimens) from esophageal cancer patients participating in the Tenergy trial, and RNA sequencing of tumor biopsy specimens at three time points before treatment (28 specimens), after radiation chemotherapy (25 specimens) and after atezolizumab administration (25 specimens).

  Study JGAS000708

• mUM patient biopsies bulk RNAseq

  Tumour biopsies were obtained from uveal melanoma patients (n = 35) pre and 16 days post treatment with tebentafusp. Biopsies, which were either snap frozen or put in RNA later, were analysed by bulk RNA sequencing (50 million reads per sample) using the Illumina NovaSeq system

  Dataset EGAD50000001225

• NCI-Maryland Prostate Cancer Case-Control Study

  The study seeks to examine the genetic and ancestral basis of prostate cancer-associated inflammation using a genome-wide association approach. The study population are the participants of the NCI Maryland Prostate Cancer Case-Control study. This study recruited both African American and European American men, and investigated the causes for the excessive burden of prostate cancer among African American men in more general terms. We measured 82 blood-based immune-oncology markers, and genotyped the participants using the HumanOmni5-Quad BeadChip, which provides a significant genome coverage for genetically-admixed and diverse populations, to evaluate the genetic basis and evidence for causality of any immune-inflammation marker that is associated with prostate cancer risk. We want to assess how germline genetics influence the abundance levels of these 82 markers in African American and European American men, which may contribute to differences between them.

  Study phs002939

• APCIM_Nanostring_HD

  Expression of immune related genes in 12 healthy donors. Expression assessed by analyzing whole blood-derived RNA samples using a Nanostring nCounter Immunology V2 panel (579 genes)

  Dataset EGAD00010002554

• Tumor inflammation and mutational burden are differentially associated with response to nivolumab or nivolumab plus ipilimumab in metastatic colorectal cancer

  Nivolumab alone and in combination with ipilimumab demonstrated durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer in the phase 2 CheckMate 142 study. Exploratory biomarker analyses of tumor and microbiome samples from CheckMate 142 were performed to evaluate associations between various biomarkers and the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab combination in these patients. Higher expression of inflammation-related gene expression signatures was associated with improved response per investigator assessment and survival benefit with nivolumab monotherapy. In contrast, higher tumor mutational burden, tumor indel burden and degrees of microsatellite instability were associated with improved response per investigator assessment and survival benefit with nivolumab plus ipilimumab. While interpretation is limited by the exploratory nature of these analyses, they suggest that tumor antigenicity rather than baseline tumor inflammation might be important for the combinatorial efficacy. Validation of these findings in larger, randomized studies is necessary.

  Study EGAS50000000416

• Origins and functional consequence of somatic mitochondrial DNA mutations

  Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mitochondrial DNA (mtDNA) are unclear. Here, we analysed somatic alterations in mtDNA from 1,675 tumors across 31 histologies. We identified 1,907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C>T and A>G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. Numbers of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria, and is fundamentally linked to mtDNA replication.

  Study EGAS00001000968

• Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation

  Presurgical studies allow study of the relationship between mutations and response of estrogen receptor positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in Phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 Controls). In poor responders (based on Ki67 change) we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores   occur in approximately 30% of tumours. In Phase II we combine targeted sequencing on another 28 treated patients with Phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy.

  Study EGAS00001001940

• A biobank of patient-derived pediatric brain tumor models

  Brain tumors are the leading cause of cancer-related death in children. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors that may lead to novel therapeutic strategies. To evaluate new treatments, better preclinical models adequately reflecting the biological heterogeneity are needed. Through the Children’s Oncology Group ACNS02B3 study, we have generated and comprehensively characterized 30 patient-derived orthotopic xenograft models and 7 cell lines representing 14 molecular subgroups of pediatric brain tumors. Patient-derived orthotopic xenograft models were found to be representative of the human tumors they were derived from in terms of histology, immunohistochemistry, gene expression, DNA methylation, copy number, and mutational profiles. In vivo drug sensitivity of targeted therapeutics was associated with distinct molecular tumor subgroups and specific genetic alterations. These models and their molecular characterization provide an unprecedented resource for the cancer community to study key oncogenic drivers and to evaluate novel treatment strategies.

  Study EGAS00001002536

• SDR-seq_06_BCL

  Multiomic targeted scDNA-scRNA-seq (SDR-seq) of primary B-cell non-Hodgkin lymphomas. Aim is to link genomci variants to gene expression in single cells. Profiled two follicular lymphoma (FL) primary patient samples and one germinal center subtype diffuse large B-cell lymphoma (GCB) primary patient sample.

  Study EGAS50000000374

• Peripheral clonal expansion of T cells (scTCR-seq)

  Single-cell TCR-seq of tumor-infiltrating lymphocytes from 14 cancer patients before treatment, taken from tumor, normal adjacent tissue, and peripheral blood. Dataset consists of paired-end FASTQ files, including replicate libraries and runs.

  Dataset EGAD00001005465

• Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia

  Fibromuscular dysplasia (FMD) is a poorly understood vascular disease that can lead to hypertension, stroke, myocardial infarction and even death. In 2013 we initiated the DEFINE study (ClinicalTrials.gov Identifier: NCT01967511), which has now recruited > 440 subjects and which aims to unravel the pathobiological mechanisms of this disease. Here, by integrating DNA genotype and RNA sequence data from primary fibroblasts of 83 FMD patients and 71 matched healthy controls from the DEFINE study, and its precursor the CAUSE study, we inferred 18 gene regulatory co-expression networks, four of which were found to act together as an FMD-associated super network in the arterial wall. Molecular studies indicated that this super network, termed SN-A and with the top key driver gene UBR4, governs multiple aspects of vascular cell physiology and functionality, including collagen/matrix production. The effects of UBR4 knockdown were also investigated in commercially available aortic smooth muscle and fibroblast cell lines by RNA sequencing, and these results are included in these datasets.Note, that of the 154 subjects in this analysis, 62 did not provide consent to have their genomic data made publicly available. Therefore the human subject data available here is from the 92 study participants who provided written informed consent to share their deidentified genomic data publicly.

  Study phs003674

• A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer

  Background Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. Methods We combined immunohistochemistry (IHC) with RNA-sequencing and whole genome sequencing across a diverse spectrum of high-risk paediatric cancers to develop an alternative, expression-based signature associated with CD8+ T-cell infiltration of the TIME. Further, we explored transcriptional features of immune archetypes, T-cell receptor sequencing diversity, assessed the relationship between CD8+ and CD4+ abundance by IHC and deconvolution predictions, and assessed common adult biomarkers such as neoantigen load and TMB. Results A novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), was identified. Using this signature, we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. In addition, we showed that PD-L1 protein expression is poorly correlated with PD-L1 RNA expression and TMB and neoantigen load are not predictive of T-cell infiltration in paediatrics. Furthermore, deconvolution algorithms are only weakly correlated with IHC measurements of T-cells. Conclusions Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME.

  Study EGAS00001007029

• RaScALL: Rapid (Ra) screening (Sc) of RNA-seq data for prognostically significant genomic alterations in acute lymphoblastic leukaemia (ALL)

  RNA-sequencing (RNA-seq) efforts in acute lymphoblastic leukaemia (ALL) have identified numerous prognostically significant genomic alterations which can guide diagnostic risk stratification and treatment choices when detected early. However, a full RNA-seq Bioinformatics workflow is time-consuming and costly in a clinical setting where rapid detection and accurate reporting of clinically relevant alterations are essential. To accelerate the identification of ALL-specific alterations (including gene fusions, single nucleotide variants and focal gene deletions), we developed the rapid screening tool RaScALL, capable of identifying more than 100 prognostically significant lesions directly from raw sequencing reads. RaScALL uses the k-mer based targeted detection tool km and known ALL variant information to achieve a high degree of accuracy for reporting subtype defining genomic alterations compared to standard alignment-based pipelines. Gene fusions, including difficult to detect fusions involving EPOR and DUX4, were accurately identified in 98% (164 samples) of reported cases in a 180-patient Australian study cohort and 95% (n=63) of samples in a North American validation cohort. Pathogenic sequence variants were correctly identified in 75% of tested samples, including all cases involving subtype defining variants PAX5 p.P80R (n=12) and IKZF1 p.N159Y (n=4). Accurate detection of intragenic IKZF1 deletions resulting in aberrant transcript isoforms was also detectable with 98% accuracy. Importantly, the median analysis time for detection of all targeted alterations averaged 22 minutes per sample, significantly shorter than standard alignment-based approaches, ensuring accelerated risk-stratification and therapeutic triage.

  Dataset EGAD00001009087

• Mapping Systemic Lupus Erythematosus Heterogeneity at the Single Cell Level

  Patients with Systemic Lupus Erythematosus (SLE) display a complex blood transcriptome whose cellular origin is poorly resolved. Using single-cell RNA-seq, we profiled ~276,000 PBMCs from 33 children with SLE (cSLE) with different degrees of disease activity (DA) and 11 matched controls. Increased expression of Interferon-stimulated genes (ISGs) distinguished cSLE from healthy control cells. The high-ISG expression signature (ISGhi) derived from a small number of transcriptionally defined subpopulations within major cell types, including monocytes, CD4+ and CD8+ T cells, NK cells, cDCs, pDCs, B cells and especially plasma cells. Expansion of unique subpopulations enriched in ISGs and/or in monogenic Lupus-associated genes classified patients with the highest DA. Profiling of ~82,000 single PBMCs from adult SLE patients confirmed the expansion of similar subpopulations in patients with the highest DA. This study lays the groundwork for resolving the origin of the SLE transcriptional signatures and the disease heterogeneity towards precision medicine applications. Patient demographics, clinical and laboratory data and treatment are summarized and available. The genomic data for participant aHD2 will not be included in the dataset The study description is reprinted from Nehar-Belaid et. al. Nature Immunology, 2020, with permission from Nature Immunology Group

  Study phs002048

• Uncovering Inversion Formation in the Human Genome and its Impact to Disease

  The relevance of inversions for disease causation, speciation and adaptation is broadly recognized, although the prevalence of inversions is unknown. In humans, de novo inversions are associated with congenital anomalies in approximately 9.6% of patients. Yet, despite the biological relevance of inversions, their molecular features, formation mechanism, impact to the genomic structure of carriers, as well as their contribution to clinical phenotypes, have not been further explored. Inversions are typically classified as balanced reciprocal events generated by ectopic recombination, although recent studies reveal a distinct picture whereby inversions originate from mechanisms that concomitantly generate copy number variants (CNVs). Surprisingly, those complex inversions underlie as much as 30% of neurodevelopmental-associated CNVs. The hypothesis of this project are: inversions are often generated de novo by mechanisms other than ectopic recombination a relevant fraction of inversions are associated with complex genomic rearrangements (CGRs), often overlooked in sporadic diseases, and inversions are a "hidden" type of structural variation for which contribution to a clinical phenotypes has been under assessed due to the lack of appropriate detection tools. A combined strategy using multiple genomic tools will be applied to characterize inversions and associated genomic alterations in individuals with neurodevelopmental disorders and controls: whole genome sequencing (WGS) with short-and long-reads; genome mapping; classical cytogenetics; and array CGH. This project will establish common ground to bridge studies of rare and common diseases, human evolution, and population genetics.

  Study phs002999

• B cell receptor silencing reveals origin and dependencies of high-grade B cell lymphomas with MYC and BCL2 rearrangements

  High-grade B cell lymphomas with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) represent highly aggressive Germinal center (GC) derived B cell malignancies with dismal prognosis and limited therapeutic options. In the present study, we investigated the expression of BCR complex components, including immunoglobulin (IG) heavy (H) and light (L) chains, and CD79A and CD79B signaling subunits in HGBCL-DH-BCL2, scoring 65% of cases with undetectable IGH immunoreactivity (IGHUND). Transcriptomics (bulk RNA-seq) and genetic (whole exome/genome sequencing) analyses indicated that IGHUND and IGH+ HGBCL-DH-BCL2 lymphomas represent distinct biological entities. Specifically, IGHUND HGBCL-DH-BCL2 exhibit a GC DZ-like molecular program, and select subset-specific gene mutations pointing to distinct evolutionary trajectories respect to the IGH+ counterparts. IG profiling revealed that IGHUND HGBCL-DH-BCL2 preserved potentially productive, hypermutated IGH variable (V) gene rearrangements, indicating a selective advantage conferred to the malignant B cells by residual IGH molecules. Accordingly, disruption of the productively rearranged IGHG1 gene in BCRnull HGBCL-DH-BCL2 cell line model confirmed the dependency on IGH expression for optimal fitness. Using transcriptomics and in situ RNA-scope analysis, we reported that IGHUND HGBCL-DH-BCL2 originated from IG-class switched GC B cells, while IGH-expressing tumors were selected for continuous IGM expression. Moreover, while IGH+ HGBCL-DH-BCL2 favor IGM/IG-Kappa expression, IGHUND counterparts complete IG-Lambda light chain rearrangements. Notably, BCR silencing, caused by accelerated IGH turnover and reduced IGH expression, precedes HGBCL-DH-BCL2 onset, inducing RAG1/2-dependent IG light chain editing and eventually facilitating t(8;22)/IGL::MYC translocations. Finally, IGH silencing observed in HGBCL-DH-BCL2 cell models, which leads to intracellular retention/silencing of CD79B, results in reduced sensitivity to the CD79B-targeting antibody-drug conjugate Polatuzumab-vedotin. Collectively, HGBCL-DH-BCL2 originates from isotype-switched t(14;18)+ GC B cells that undergo IG light chain editing fuelling intra-clonal diversification, BCR silencing, and the acquisition of t(8;22) translocation, while preserving IGH dependency.

  Study EGAS50000001047

• DAC for Studies of "Genetics and Genomics of Cardiovascular Diseases" Group at MDC Berlin, Germany

  DAC for Studies of "Genetics and Genomics of Cardiovascular Diseases" Group at MDC Berlin This is an umbrella DAC.

  Dac EGAC50000000481

• RNA sequencing of Non-Small Cell Lung Cancer and adjacent normal tissue

  RNA sequencing was performed on 108 NSCLC tumor samples and their paired adjacent normal tissues (n=21) to identify associations with clinical and immune characteristics.

  Study EGAS50000000246

• Analytical study of protein function and RNA expression involved in predicting treatment efficacy and adverse event development in lung cancer radiotherapy.

  The purpose of this study is to elucidate the functions of DNA repair proteins and RNA expression that are involved in the therapeutic efficacy and adverse events of radiotherapy for lung cancer at our hospital. In particular, this is an exploratory study to identify proteins and RNAs involved in the expression of proteins that are likely to be involved in the prediction of radiotherapy response and adverse events.

  Study JGAS000545

• A Comprehensive Catalogue of Somatic Mutations from a Human Cancer Genome

  We previously reported the whole-genome sequencing of the well-studied human malignant melanoma cell line, COLO-829, and a lymphoblastoid cell line from the same individual, providing the first comprehensive catalogue of somatic mutations from an individual cancer (Pleasance et al. (2010) Nature 463, 191). This initial study was carried out using the Illumina Genome Analyzer II, largely using paired-end reads of 75 bases from standard Illumina paired-end libraries. Here we report the results of sequencing the genomes of COLO-829 and its matched lymphoblastoid sample using HiSeq2000 with v3 cluster-generation and sequencing chemistries. This has significantly improved the evenness and completeness of genomic coverage, particularly in areas of extreme sequence composition that were underrepresented in the initial study.

  Study EGAS00001000245