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• NOTCH-mutations drive immune-escape mechanisms in B cell malignancies

  Here we provide access to MCL expression data that were used for interrogating the molecular functions of NOTCH1 and NOTCH2, which are two of the most commonly mutated genes in CLL and MCL and associated with a poor clinical outcome. The mechanisms underlying how NOTCH1 contributes to disease progression, resistance to treatment and Richter’s transformation remain largely unknown. The main goal of this study is to compare the gene expression profile of primary MCL cells transduced with the intracellular part of NOTCH1 or NOTCH2 lacking of the PEST domain vs cells transduced with an empty vector.

  Study EGAS00001005793

• Genome-wide search to find the genetic elements underlying visual contour perception

  Contour integration is a key function of the visual system to deal with occlusion and discontinuity in natural scenes. The current study is the first one to investigate the genetic basis of this visual function in humans. A total of 2619 normal participants were tested on their ability to detect continuous contours embedded in a cluttered background with a standard psychophysical protocol. Multi-level genomic analysis was performed, involving heritability estimation based on single nucleotide polymorphism (SNP) and association testing at SNP and gene levels.

  Study EGAS00001003639

• 'Targeted High Throughput Sequencing in Clinical Cancer Settings: Formaldehyde fixed-paraffin embedded (FFPE) tumor tissues, input amount and tumor heterogeneity'

  "Background: Massively parallel sequencing technologies have brought an enormous increase in sequencing throughput. However, these technologies need to be further improved with regard to reproducibility and applicability to clinical samples and settings. Methods: Using identification of genetic variations in prostate cancer as an example we address three crucial challenges in the field of targeted re-sequencing: Small nucleotide variation (SNV) detection in samples of formalin-fixed paraffin embedded (FFPE) tissue material, minimal amount of input sample and sampling in view of tissue heterogeneity.Results: We show that FFPE tissue material can supplement for fresh frozen tissues for the detection of SNVs and that solution-based enrichment experiments can be accomplished with small amounts of DNA with only minimal effects on enrichment uniformity and data variance. Finally, we address the question whether the heterogeneity of a tumor is reflected by different genetic alterations, e.g. different foci of a tumor display different genomic patterns. We show that the tumor heterogeneity plays an important role for the detection of copy number variations, but is of minor importance for the detection of somatic variations.Conclusions: The application of high throughput sequencing technologies in cancer genomics opens up a new dimension for the identification of disease mechanisms. In particular the ability to use small amounts of FFPE samples available from surgical tumor resections and histopathological examinations facilitates the collection of precious tissue materials. However, care needs to be taken in regard to the locations of the biopsies taken, which can have an influence on the prediction of copy number variations. Bearing these technological challenges in mind will significantly improve many large-scale sequencing studies and will - on a long-range - result in a more reliable prediction of individual cancer therapies."

  Study EGAS00001000136

• DAC_For_MPN

  This is the DAC for the MPN data set from Milena Kalmer.

  Dac EGAC50000000531

• Myocardial Infarction Genetics Exome Sequencing Consortium: BioImage Study

  The BioImage Study (BioImage Study: A Clinical Study of Burden of Atherosclerotic Disease in an At-Risk Population, NCT00738725), is a prospective, observational study aimed at characterizing subclinical atherosclerosis in U.S. adults (55 to 80 years old) at risk for clinical atherosclerotic cardiovascular disease (PMID: 25790876). All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Illumina's ICE Capture reagent and sequencing was performed on an Illumina HiSeq 2000 or 2500.

  Study phs001058

• Childhood Cancer Data Initiative (CCDI): CCDI Pediatric In Vivo Testing Program - Leukemia

  The goal of this study is to molecularly characterize a large panel of pediatric acute lymphoblastic leukemia (ALL) patient-derived xenografts (PDXs) previously established in immune-deficient mice. These PDXs are utilized as part of the NCI-funded Pediatric Preclinical In vivo Testing (PIVOT) program to identify novel agents and combinations. Biospecimen data include next-generation sequencing (RNAseq, whole exome sequencing, DNA copy number variation), whole-genome analysis of cytogenetic abnormalities, and DNA fingerprint for quality control.

  Study phs003164

• Integration of Clinical and Molecular Biomarkers for Melanoma Survival (Berwick)

  The long-term goal of the InterMEL Program Project: Integration of Clinical and Molecular Biomarkers for Melanoma Survival is to identify molecular and clinical factors that predict survival of melanoma patients. Our overarching hypothesis is that we can identify factors in the primary melanoma tumor that will lead to more aggressive disease. Melanoma patients diagnosed at American Joint Committee on Cancer (AJCC) tumor, lymph nodes, and metastases (TNM) stages IIA/IIB/IIC/IIIA/IIIB/IIIC/IIID display highly variable clinical outcomes and responses to therapy. We wish to identify robust and reproducible biomarkers or sets of classifiers that distinguish patients likely to have poor prognosis. These biomarkers will help establish targets for adjuvant therapies for this set of patients before the tumors metastasize. Aim 1. Classify actionable somatic mutations, and copy number variations (CNVs) in relationship to melanoma survival. In Project 1, Targeted Sequencing and Clinicopathology to Evaluate Primary Melanoma Molecular Subtypes and Outcomes, we will profile 468 genes using the MSKIMPACT ™ assay and identify somatic mutations and CNVs associated with melanoma-specific survival, as well as their co-occurrence with other mutations, in 1,000 tumors from patients at AJCC TNM stages IIA-IIID: approximately 500 from patients who died with melanoma within five years and approximately 500 from individuals who have lived at least five years. We will also evaluate the joint effects of somatic mutations, CNVs and pathologic characteristics associated with good and poor outcomes. Aim 2. Identify primary melanoma DNA methylation profiles to evaluate subtypes and survival. Although it has been established that melanomas frequently have aberrant DNA methylation, it is unknown if DNA methylation in primary melanomas predicts outcome. In Project 2, Primary Melanoma DNA Methylation Profiling for Evaluating Subtypes and Survival, we will profile the same primary melanomas as in Project 1 with Illumina Infinium 850K methylation arrays. We expect to: identify and characterize DNA methylation-based melanoma subclasses; train, test and validate a CpG signature prognostic for survival from melanoma; determine whether this profile adds information to outcome prediction beyond AJCC TNM staging. This project is based on the hypothesis that DNA methylation in primary melanoma will define subgroups (including a poor-prognosis CIMP – ‘CpG island methylator phenotype' subtype) and that a CpG signature will be prognostic for melanoma survival. Aim 3. Define microRNA expression changes in relation to melanoma survival. MicroRNAs have been associated with poor prognosis in melanoma, as well as in other cancers. In Project 3, Prognostic and Functional Role of a Gene Expression Signature in Melanoma Patients, we hypothesize that altered miRNA expression, captured at the time of diagnosis, may contribute to the aggressive behavior of a subset of early stage primary melanomas. We will profile the same primary melanomas as in Projects 1 and 2 with a Nanostring assay. This project will define and validate a tissue-based microRNA signature in conducted to determine whether the prognostic miRNA signature, as well as other candidate genes emerging from other projects, contribute to melanoma survival. Aim 4. Integrate data from multiple platforms to identify melanoma subtypes and survival. Despite substantial literature on gene tumor mutation-, methylation- and gene expression-based prognostic and predictive signatures for melanoma, few such signatures are used in clinical practice. Project 4, Multiplatform Analysis of Melanoma Molecular Subtypes and Patient Survival Outcome, will use novel integrative clustering methods to identify molecular subtypes of melanoma jointly defined across these platforms.

  Study phs003099

• Dana-Farber Cancer Institute (DFCI) Brown Lab CLL Sequencing Study

  Chronic Lymphocytic Leukemia (CLL) is a hematological malignancy characterized by accumulation of CD5+CD19+ B cells in peripheral lymphoid organs, bone marrow and blood. In this study we analyze matched whole genome sequencing and RNA-seq data from CLL patients to characterize the mutational processes operative throughout tumor evolution. Source of tumor and normal DNA used is patient PBMC or B cells and saliva respectively.

  Study phs000879

• The_British_Autozygosity_Populations_BioResource

  This data set contains whole exome sequences of individuals with self-stated parental relatedness from the East London Genes & Health cohort. Rare frequency functional variants in these healthy individuals will be studied with respect to the genetic health of the participants and loss-of-function analysis of human genes. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002742

• Cergentis FFPE-TLC

  In this study, formalin-fixed paraffin-embedded targeted locus capture (FFPE-TLC) sequencing is used as a novel technology for targeted detection of tumor-specific genomic structural variants (SVs) in the primary tumor of 29 colorectal cancer patients with metastatic disease. The tumor region was macrodissected and sequenced for 29 patients, and the "normal" region of the same slide was macrodissected and sequenced for 8 of these patients. SVs were found in the common fragile site (CFS)-associated genes MACROD2, PRKN, FHIT and WWOX as well as SVs caused by three LINE transposable elements. Tumor-specificity of selected SVs was independently verified by droplet digital PCR of tumor tissue DNA and their applicability as plasma circulating tumor DNA biomarkers was demonstrated.

  Study EGAS50000000427

• Comprehensive miRNA Sequence Analysis Reveals Survival Differences in Diffuse Large B-cell Lymphoma Patients

  Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease, with 30-40% of patients failing to achieve complete responses to standard therapy. miRNAs are RNA molecules that attenuate expression of their mRNA targets. To characterize the DLBCL miRNome, we sequenced miRNAs from 92 DLBCL and 15 benign centroblast fresh frozen samples and from 140 DLBCL formalin-fixed, paraffin-embedded tissue (FFPET) samples for validation.

  Study EGAS00001001025

• Mutated H3 Histones Drive Human Pre-Leukemic Hematopoietic Stem Cell Expansion And Promote Leukemic Aggressiveness

  Leukemogenesis is a stepwise progression from mutated, pre-neoplastic hematopoietic stem cells (HSCs) to full-blown leukemia. Our ability to prevent or treat acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption that is central to this process, including improper histone methylation. Comprehensive analysis of 16 histone H3 genes in 434 primary AML samples identified Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), and a higher incidence in secondary AML (s-AML) (9%). We establish that these mutations are important early events in leukemogenesis. They occur in pre-leukemic HSCs, increase the frequency of functional human HSCs, and alter differentiation. The mutations are present in the major leukemic clones in primary samples, and the mutant histones amplify leukemic aggressiveness with increased proliferation, expansion of leukemic progenitor and blast cells, and superior competitiveness in vivo. These effects are dependent on the specific mutation. Genome-wide analysis of K27 mutants revealed increased expression of genes involved in erythrocyte and myeloid differentiation with a corresponding decrease in histone H3 K27 tri-methylation and increase in K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutations, although they can co-occur. These data establish the involvement of H3 mutations as initial drivers of pre-cancerous stem cell expansion and leukemogenesis.

  Study EGAS00001003288

• MutWPX__CRUK_Grand_Challenge_Mutographs_of_Cancer__Effects_of_Chemotherapy_on_the_Somatic_Mutational_Landscape_in_Normal_Human_Tissue___Matched_Normals

  This study is investigating the effects of chemotherapy drugs used in cancer treatment on the somatic mutational landscape in normal human tissues. The samples used in this study have been taken from rapid autopsies of patients who have undergone chemotherapy using drugs thought to cause mutations in the DNA. Structures from a variety of tissues will be dissected using LCM and whole genome sequences will be produced in order to assess mutational burdens and signatures. This study contains the samples used as matched normals for each patient to remove germline mutations.

  Study EGAS00001004957

• Prediction of Resistance and Sensitivity to HER2 Targeted Therapy in the Neoadjuvant Setting

  Women with breast cancers that overexpress HER2 are at greater risk for disease progression and death than women whose tumors do not overexpress HER2. Trastuzumab, a recombinant humanized monoclonal antibody against the extracellular domain of the HER2 protein blocks downstream signaling of HER2 and substantially improves the efficacy of chemotherapy in women with metastatic and early-stage HER2-positive breast cancers. Because resistance to trastuzumab eventually results in progressive disease in the metastatic setting and contributes to recurrence following adjuvant trastuzumab-based therapy, it is important to develop agents other than trastuzumab that target HER2 signaling through different mechanisms of action. Lapatinib is an oral, small molecule, dual tyrosine kinase inhibitor of HER2 and EGFR. Lapatinib has shown a lack of cross-resistance with trastuzumab in preclinical studies and activity in women with HER2-positive, metastatic breast cancer that has progressed during trastuzumab treatment. Trastuzumab blocks the downstream signaling of HER2 by binding to the extracellular domain of the receptor. Lapatinib binds to the intracellular domains of HER2 and EGFR and prevents activation of downstream signaling pathways. Because of this different mechanism of action, lapatinib may be effective in trastuzumab-resistant disease. The study will also provide important safety information on trastuzumab and lapatinib combinations immediately following anthracycline exposure, and also provide an initial direct comparison of cardiac effects of trastuzumab and lapatinib when incorporated into a standard sequential adriamycin and cyclophosphamide (AC) followed by weekly paclitaxel neoadjuvant regimen. Availability of a second agent that can interrupt HER2-signaling pathways through completely different mechanisms than those of trastuzumab offers the potential for further improvement in the management of patients with HER2-overexpressing breast cancer in both the adjuvant and metastatic setting. Co-administration of both trastuzumab and lapatinib with chemotherapy may be important in improving outcomes in subsets of HER2-positive breast cancers. However, use of two inhibitors of the HER2 pathway will increase costs and may increase toxicity, so it will be important to identify the subsets of patients who would benefit from the dual therapy. Inhibition of HER2 with a single agent clearly is sufficient for many patients as evidenced by the results of the trastuzumab trials. Therefore, co-administration to unselected populations of women with HER2-positive breast cancers would not represent an optimal approach. Given the activity of lapatinib, it is likely that it will also be sufficiently active in inhibiting HER2-pathway activation in some patients to allow for its use as the sole inhibitor of the HER2 pathway. Different populations may also derive greater benefit from one of the HER2-blocking agents relative to the other. Identification of potential predictive factors for pathologic complete response to the combination or to either agent administered alone in neoadjuvant trials would provide important information for adjuvant trials designed to definitively address these important issues. This study will compare 3 combined chemotherapy regimens: AC followed by paclitaxel plus trastuzumab and lapatinib, AC followed by paclitaxel plus lapatinib, and AC followed by paclitaxel plus trastuzumab given before surgery to patients with HER2-positive breast cancer.Tumor samples were collected prior to and post-treatment, and RNA sequencing was performed with this version.

  Study phs003275

• ENU-CCK-81 cetuximab pilot project

  Cetuximab is a targeted monoclonal antibody against the epidermal growth factor receptor (EGFR) which is used therapeutically for the treatment of KRAS wild-type colorectal cancer (CRC). The Cetuximab sensitive KRAS wild-type CRC cell line NCI-H508 has been treated with a fixed concentration of ENU for 24 hours and then selected with Cetuximab until drug resistant clones were ready to be picked and grown up as sub-clones of the parental cell line. These will have genes causally implicated in cancer sequenced to identify common point mutations in multiple independently derived drug resistant clones as a forward genetic screen for mechanisms of resistance to Cetuximab in CRC.

  Dataset EGAD00001001947

• ENU-NCI-H508 cetuximab fixed concentration project

  Cetuximab is a targeted monoclonal antibody against the epidermal growth factor receptor (EGFR) which is used therapeutically for the treatment of KRAS wild-type colorectal cancer (CRC). The Cetuximab sensitive KRAS wild-type CRC cell line NCI-H508 has been treated with a fixed concentration of ENU for 24 hours and then selected with Cetuximab until drug resistant clones were ready to be picked and grown up as sub-clones of the parental cell line. These will have genes causally implicated in cancer sequenced to identify common point mutations in multiple independently derived drug resistant clones as a forward genetic screen for mechanisms of resistance to Cetuximab in CRC

  Dataset EGAD00001001948

• Illumina short-reads and 10X Genomics linked-reads sequencing data for MCF7 and a primary breast tumor sample

  This dataset contains whole genome sequencing data from Illumina short-reads sequencing (2X150bp) and 10X Genomics linked-reads sequencing. Both the sequencing technologies were used to sequence MCF7 cell line and a primary breast triple-negative cancer sample. The fastq of paired-end reads for both the samples sequenced with both the technologies is available.

  Dataset EGAD00001005724

• Exome sequencing of a cohort of Rett syndromelike patients (2017-08-16)

  The aim of the project is the definition of the molecular defect in a cohort of Rett-like patients negative for mutations in known disease genes. To this aim, a number of unrelated trios (patients plus parents) will be analysed by exome sequencing. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ This dataset contains all the data available for this study on 2017-08-16.

  Dataset EGAD00001003564

• Successful Clinical Response in Pneumonia Therapy (SCRIPT)

  The goal of this study is to iteratively identify, validate and refine biomarkers to predict clinical failure, and identify novel targets for therapy, beyond traditional antibiotics, for patients with severe pneumonia requiring intubation, including severe community-acquired pneumonia (CAP), hospital-acquired pneumonia, and ventilator-associated pneumonia (HAP/VAP). We hypothesize that factors within the alveolar microenvironment in many patients with pneumonia prevent the active process of pneumonia resolution.The major emphasis will be on HAP. Mechanically ventilated CAP patients are a very high-risk group for subsequent VAP, and therefore CAP samples will be included to determine baseline bacteria, microbiome, and host defense patterns for those that do or do not develop HAP/VAP. Hospital-acquired pneumonia is the leading cause of death from nosocomial infections. Even in patients receiving pathogen-appropriate therapy, reported clinical failure rates are increasing, approaching 50% in recent clinical trials. Current approaches to improve outcomes in patients with pneumonia almost exclusively focus on the development of antibiotics to address the problem of resistance. However, the prevalence of antibiotic-resistant pathogens is insufficient to explain the high rates of clinical failure. Instead, we hypothesize that factors within the alveolar microenvironment in many patients with pneumonia prevent the active process of pneumonia resolution. These factors include pathogen-specific adaptations to the injured lung that modulate the innate and adaptive immune response, as well as changes to the alveolar microbiome, driven by selective pressure within our modern intensive care units. Understanding this complex adaptive system requires the integration of clinical information with unbiased measures of the host, pathogen, and microbiome changes within the alveolar microenvironment. These measures must be repeated over time to identify factors that distinguish successful from failed therapy for pneumonia sufficiently early during the clinical course to allow for effective interventions. To address this challenge, we have assembled a talented group of investigators in the Successful Clinical Response In Pneumonia Therapy (SCRIPT) Systems Biology Center. We will leverage our routine clinical practice of safe alveolar sampling in mechanically ventilated patients with pneumonia with repeated non-bronchoscopic bronchoalveolar lavage (NBBAL) sampling over the course of pneumonia. From this fluid, we will combine flow cytometry with multi-omic technologies (cell population-specific transcriptomics, epigenomics, shotgun microbiome sequencing, and pathogen-specific sequencing). Our systems scientists will integrate these genomic data with robust clinical -omics with the goal of identifying biomarkers that can be prospectively tested in patients and causally evaluated in humanized mouse models.The addition of a pooled sample artificially increases the number of automatically computed subjects by one.

  Study phs002300

• Reference exome data for Australian Aboriginal populations from Western Australia and the Northern Territory

  Here we provide a catalogue of variants called after sequencing the exomes of 50 Aboriginal individuals from the Northern Territory (NT) of Australia and compare these to 72 previously published exomes from a Western Australian (WA) population of Martu origin. Sequence data for both NT and WA samples were processed using an ‘intersect-then-combine’ (ITC) approach, using GATK and SAMtools to call variants. The data is provided as 2 VCF files, one for the WA population and one for the NT population.

  Dataset EGAD00001005189

• MethylBERT enables read-level DNA methylation pattern identification and tumour deconvolution using a Transformer-based model

  This is the DAC for the study "MethylBERT enables read-level DNA methylation pattern identification and tumour deconvolution using a Transformer-based model" of Pavlo Lutsik (DKFZ B370/KU Leuven, pavlo.lutsik@kuleuven.be) and Clarissa Gerhauser (DKFZ B370, c.gernauser@dkfz.de)

  Dac EGAC50000000497

• WGS dataset for malignant pleural and peritoneal mesothelioma

  This dataset contains Whole Genome sequencing data of pleural and peritoneal mesothelioma. The number of samples is 40. Sequencing was performed on Illumina NovaSeq 6000 and Illumina NovaSeqXPlus. The sequencing was always paired.

  Dataset EGAD50000001343

• PGRN-Leducq: Identification of the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes

  The goal of this study was to search for genetic variants that could be responsible for modifying the risk of drug-induced long QT syndrome (diLQTS). diLQTS is a relatively common adverse drug event and has been a leading cause for drug relabeling and withdrawal from the market. Our hypothesis, that variants in genes which regulate electrical properties in the heart modify the risk of diLQTS, was tested by genotyping patients of European descent at 1424 single nucleotide polymorphisms (SNPs) in 18 candidate genes. We found that the SNP KCNE1 D85N was highly predictive of diLQTS with an odds ratio of 9.0 (95% confidence interval: 3.5-22.9).

  Study phs000617

• COMPARE study: participants typed during UK Biobank version 2 array development phase

  The COMPARE study enrolled 29,066 British blood between donors between February 2016 and March 2017, the study aim is to find the optimum technology for haemoglobin screening (ISRCTN 90871183). All participants were at the time of recruitment active blood donors. The 4,796 participants in this dataset have consented to join the NIHR BioResource. Genotyping data was produced using the Thermo Fisher Scientific Axiom Genotyping platform. The UK Biobank version 2 array design was used, content on this array has been added to allow for accurate DNA based identification of human blood group antigens.

  Study EGAS00001003748

• Spatially Resolved Tumor Ecosystems and Cell States in Gastric Adenocarcinoma Progression and Evolution

  Gastric cancer (GC) is a major cause of global cancer mortality with high levels of heterogeneity, and intratumoral heterogeneity (ITH) represents a significant barrier to GC patient outcomes. In this study, we applied GeoMx DSP technology to identify ITH in GC. We found spatially colocalized RNA-based intratumor subgroups within samples, each correlated with distinct spatially oriented TME and immune profiles. The findings broadening our understanding of the spatial and molecular complexity of GC ITH and offering a valuable data resource for future exploration and discovery.

  Study EGAS50000000345