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• Characterization_of_individual_foci_of_multicentric_multifocal_breast_cancer_using_targeted_next_generation_sequencing

  Multifocality or multicentricity in breast cancer may be defined as the presence of two or more tumor foci within a single quadrant of the breast or within different quadrants of the same breast, respectively. This original classification of the breast cancer as multicentric or multifocal was based on the assumption that cancers arising in the same quadrant were more likely to arise from the same ductal structures than those occurring in separate areas of the breast. The problem with these definitions is that the “quadrants” of the breast are arbitrary external designations, as no internal boundaries do exist. This project will therefore focus both on synchronous multifocal and multicentric tumors. The incidence of multifocal and multicentric breast cancers was reported to be between 13 and 75% depending on the definition used, the extent of the pathologic sampling of the breast and whether in situ disease is considered evidence of multicentricity (1). Although this incidence is variable, those figures show that it is a frequent phenomenon. Multiple (multifocal/multicentric) breast carcinomas, especially when occurring in the same breast, represent a real challenge for both pathologists and clinicians in terms of identifying the cellular origin and the best therapeutic management of the cancer. Multifocality or multicentricity has been associated with a number of more aggressive features including an increased rate of regional lymph node metastases and adverse patient outcome when compared with unifocal tumors (2-3), and a possible increased risk of local recurrence following breast conserving surgery (4). For the moment, the literature is divided on whether there is a corresponding impact on survival outcomes. Today, the current convention to stage and to treat multifocal and multicentric tumors is the classical tumor-node-metastasis (TNM) staging guidelines with which tumor size is assessed by the largest tumor focus without taking other foci of disease into consideration. If some papers, as the recent one from Lynch and colleagues, support the current staging convention (3), others, however, as Boyages et al. suggested that aggregate size and not the size of the largest lesion should be considered in order to refine the prognostic assessment of those tumors (5). On the top of that, the question whether multifocal/multicentric carcinomas are due to the spread of a single carcinoma throughout the breast or is due to multiple carcinomas arising simultaneously has been a matter of debate. Some studies suggested that multifocal breast cancer may result from either intramammary spread from a single primary tumor or multiple synchronous primary tumors; whereas others suggest that multiple breast carcinomas always arise from the same clone (6-8). Recently, Pietri and colleagues analyzed the biological characterization of a series of 113 multifocal/multicentric breast cancers (8) which were diagnosed over a 5-year period. The expression of estrogen (ER) and progesterone (PgR) receptors, Ki-67 proliferative index, expression of HER2 and tumor grading were prospectively determined in each tumor focus, and mismatches among foci were recorded. Mismatches in ER status were present in 5 (4.4%) cases and PgR in 18 (15.9%) cases. Mismatches in tumor grading were present in 21 cases (18.6%), proliferative index (Ki-67) in 17 (15%) cases and HER2 status in 11 (9.7%) cases. Interestingly, this heterogeneity among foci has led to 14 (12.4%) patients receiving different adjuvant treatments compared with what would have been indicated if we had only taken into account the biologic status of the primary tumor. This study therefore showed that differences in biological characteristics of multifocal/multicentric lesions play a crucial role in the adjuvant treatment decision making process. In this study, we will concentrate on a larger series of patients with multifocal invasive ductal breast cancer lesions. We aim at: 1. Evaluating the incidence of multifocality according to the different breast cancer molecular subtypes (ER-/HER2-, HER2+, ER+/HER2-). 2. Evaluating the incidence of multifocality in patients with hereditary breast cancer disease (presence of germline BRCA1 or BRCA2 mutations). Moreover, we would like to investigate if multifocal lesions with BRCA1 or BRCA2 mutations exhibit a characteristic combination of substitution mutation signatures and a distinctive profile of deletions as demonstrated recently by Nik-Zainal and colleagues (9). 3. Correlating multifocality with clinical information in order to define its influence on patients’ survival (DFS and OS). 4. Carrying high coverage targeted gene sequencing of driver cancer genes and genes whose mutation is of therapeutic importance in order to compare clinically-relevant genetic differences between several multifocal breast cancer lesions. 5. Evaluating the impact of the distance between the different lesions on the clinical outcome but also on the genetic differences. 6. Comparing gene expression patterns between several multifocal breast cancer lesions and correlate them with the results of the targeted genes screen. 7. Characterizing the genomic and transcriptomic status of cancer related genes in metastatic lesions (local recurrence, positive lymph node or distant metastatic sites) from the same multifocal invasive ductal breast cancer patients in order to evaluate the consequence of genomic and transcriptomic heterogeneity of multifocal lesions on metastatic lesions. Multiple (multifocal/multicentric) breast carcinomas, especially when occurring in the same breast, represent a real challenge for both pathologists and clinicians in terms of identifying the cellular origin and the best therapeutic choice. This project has the potential to identify genetic/transcriptomic differences existing between several lesions constituting multifocal breast cancers, which in the routine clinical practice are usually considered to be homogeneous among them. We foresee validating significant results in a larger series of patients and this, in turn, could have a remarkable impact on the treatment and clinical management of multifocal breast cancers. Indeed, we hope to provide some evidence whether or not each focus matters in multifocal and multicentric breast cancer to define the adequate therapeutic approach, especially in the context of targeted therapies. The work to be done at Sanger will be target gene screen pooling of 1400 samples.

  Study EGAS00001000407

• HSC_population_dynamics___KX004_samples___WGS

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001003768

• HSC_population_dynamics___CB002_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001003743

• HSC_population_dynamics___KX007_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001004193

• HSC_population_dynamics___KX008_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001004490

• HSC_population_dynamics_CBD_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001003091

• HSC_population_dynamics___KX003_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001003550

• HSC_population_dynamics___TG001_2_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001003688

• The_GENCODE_exome___sequencing_the_complete_human_exome

  We report the design of an extended set of targets for capturing the complete human exome, based on annotation from the GENCODE consortium. The extended set covers an addition 5,594 genes and 10.3 Mb compared to current sets which mainly target the CCDS database. The additional regions include potential disease genes previously inaccessible to exome resequencing studies, such as 43 genes linked to ion channel activity and 70 genes linked to protein kinase activity. In total, the new GENCODE exome set developed covers 47.9Mb and performed well in sequence capture experiments with HapMap and clinical samples. Samples within this study are prepared with either the CCDS or GENCODE exome products.

  Study EGAS00001000016

• Comparison of the performance of two commercial genome-wide association study genotyping platforms in Han Chinese Samples

  Affymetrix 6.0, Illumina OMNIExpress, and llumina Immunochip genotype data for Han Chinese population including rheumatoid arthritis cases and controls. Data is in PLINK binary format. Illumina genotype clustering was performed using Illumina’s BeadStudio software. SNPs were reclustered using the study samples, low quality subjects were removed, and a subset of clustering results were manually inspected and verified. All SNPs with GenCall scores less than 0.15 were excluded. For Affymetrix chips, clustering was performed using the program Birdseed version 2, as implemented using Affymetrix Genotyper Console v4.0, using the default quality control (QC) thresholds.

  Study EGAS00000000131

• Primary Cytotoxic T Cell Lymphomas Harbor Recurrent Targetable Alterations in the JAK-STAT Pathway

  Cytotoxic cutaneous T cell lymphomas (CTCLs) are uncommon but highly aggressive cancers of skin-homing cytotoxic T cells. These include the established World Health Organization (WHO) entity primary cutaneous gamma delta T cell lymphomas (PCGDTLs), the provisional WHO entity primary cutaneous CD8+ aggressive epidermotropic T cell lymphoma (PCAETCL), and samples that do not currently fit into a WHO category, referred to as cytotoxic CTCL-NOS (not otherwise specified). In this study, 35 CTCL cases were examined, and 9 PCAETCL cases were confirmed by CD8 expression and full-thickness epidermotropism. Whole genome sequencing (WGS) and bulk RNA sequencing were performed on these samples.  

  Study phs002499

• PGRN/PAT: The genomic basis for susceptibility to drug-induced long QT syndrome (diLQTS)

  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 sequencing approximately 225 patients of European descent using next-generation targeted captured or whole exome sequencing. Data from cases and controls (1:2) were analyzed to identify both rare and common genetic variation.

  Study phs000808

• ADHD Genomic Association Study

  Studies at Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands, has recruited participants with ADHD and participants without ADHD, which included matched healthy controls and family members of participants with ADHD. ADHD participants met DSM-IV-TR criteria for ADHD. DNAs of these participants, 1005 samples, were anonymously genotyped with Illumina PsychArray. These samples were not part of the PGC-ADHD group. After removing family members, 820 case/control independent samples, including 211 ADHD cases, went through genomic association analyses. Results of ADHD risk genetic markers were compared with genetic markers associated with brain structure alterations in ADHD in adults and adolescents.

  Study phs001869

• Whole Exome Sequences of Human Embryonic Stem Cell Lines

  Human embryonic stem cells (hESCs) are a powerful tool for the study of human development and can form the basis of cellular disease models or therapies. However, the genetic make-up and stability of hESCs has not been systematically studied at a genome-wide level with single nucleotide resolution. We therefore sequenced the whole exomes of widely available hESCs. The data generated has provided new insights about the nature of acquired variation and the genomic integrity of the cell lines. We anticipate that this online resource will enable investigators to access raw sequencing data in order to interrogate cell lines for different disease and trait-associated genetic variants.

  Study phs001343

• Impact of Mobile Element Insertions on Human Transcriptome Variation

  Mobile DNA elements are ubiquitous in nearly all species and mobile element insertions can affect nearby gene expression through many mechanisms, from disrupting coding regions to initiating DNA methylation to altering RNA splicing patterns. Thousands of mobile element insertions are still polymorphic in human populations, and these polymorphic mobile element insertions (pMEIs) can contribute to transcriptome and phenotypic variation in humans. We identified and genotyped pMEIs using the whole genome sequencing (WGS) data from the Genotype-Tissue Expression (GTEx) project. We then used the extensive multi-tissue transcriptome data from the GTEx project to systematically assess the effects of pMEIs on human transcriptome variation.

  Study phs002030

• NHLBI TOPMed - NHGRI CCDG: Massachusetts General Hospital (MGH) Atrial Fibrillation Study

  The Massachusetts General Hospital (MGH) Atrial Fibrillation Study was initiated in 2001. The study has enrolled serial probands, unaffected and affected family members with atrial fibrillation. At enrollment participants undergo a structured interview to systematically capture their past medical history, AF treatments, and family history. An electrocardiogram is performed; the results of an echocardiogram are obtained; and blood samples are obtained. For the TOPMed WGS project only early-onset atrial fibrillation cases were sequenced. Early-onset atrial fibrillation was defined as an age of onset prior to 66 years of age. Comprehensive phenotypic and pedigree data for study participants are available through dbGaP phs001001.

  Study phs001062

• Genetic Analysis of Limb Malformation Disorders: Miller Syndrome Sequencing Study (LMD-MS)

  The overall goal of this project is to investigate the etiology and pathogenesis of malformations (i.e., birth defects) of the limb, concentrating on abnormalities of limb patterning such as limb deficiency/duplications and multiple congenital contractures. The exome sequences of two siblings and two unrelated individuals were obtained by massively parallel DNA sequencing. The four individuals were affected with Miller syndrome (OMIM: 263750). Additionally, the whole-genome sequences of a family of four were obtained with the method of Complete Genomics Incorporated (CGI). The two offspring were both affected with Miller syndrome and is the same sibling pair mentioned previously from whom exome sequences were also obtained.

  Study phs000244

• Single Cell RNA-Sequencing in Adenoid Cystic Carcinoma

  This study of salivary adenoid cystic carcinoma aimed to profile individual malignant and stromal cells in treatment-naive head and neck adenoid cystic carcinoma, with or without metastatic cervical lymph nodes. Clinical and pathologic information was collected on all patients, in addition to a fresh biopsy sample from the primary tumor and/or metastatic lymph node at the time of initial surgery. A fresh biopsy sample from a matched local recurrence was also collected for a single unique patient. Biopsy specimens were processed for single cell RNA-seq. A total of ~1,700 single cells from seven participants were included in the final dataset.

  Study phs003070

• Linked Read Sequencing of Gastric Cancer Metastases for Complex SV Resolution

  In this study, linked read sequencing was performed on two ovarian metastases and matched normal tissue, from a patient with primary diffuse gastric cancer. Linked read sequencing is a DNA preparation technology whereby high molecular weight molecules of DNA are uniquely barcoded prior to fragmentation and sequencing, thus retaining information about genomic contiguity. This study performed an extended analysis of linked read sequencing data to resolve the complex structures of structural variants in the cancer genomes. Complex structural rearrangements were identified in the genomic region surrounding the known oncogene FGFR2, and the association between FGFR2 and gastric cancer metastasis was demonstrated in an organoid model.

  Study phs001362

• Somatic Copy Number Analysis of Endometrial Carcinomas

  Endometrial cancer (EC) is the most commonly diagnosed gynecologic malignancy in the United States and is the sixth leading cause of cancer death amongst American women. The purpose of this study was to identify somatic (tumor-specific) copy number alterations in 7 clear cell ECs, 31 serous ECs, 17 endometrioid ECs, and the clear cell components of 2 endometrioid/clear cell ECs. To this end, DNAs from de-identified primary endometrial tumors and matched non-tumor tissues or blood were hybridized to high-density Illumina Infinium HumanHap650Y Beadchips or to high-density Human660W-Quad Beadchips and the data analyzed to annotate somatic copy number alterations throughout the genome.

  Study phs001690

• A Multi-Omic Single-Cell Atlas of Human Gynecological Malignancies

  Matched single-cell transcriptomic sequencing (scRNA-seq) and single-cell chromatin accessibility sequencing (scATAC-seq) were performed for 11 fresh human tumors collected from the endometrium or ovary. More detailed information for each patient tumor will be provided in selected phenotype/attributes data. Both scRNA-seq and scATAC-seq assays revealed the underlying cellular heterogeneity in transcriptional output and in chromatin accessibility for each patient tumor specimen. In this work, we identified potential non-coding regulatory elements that mediate cell type-specific gene expression patterns. These data will serve as an important reference for the single-cell genomics and gynecologic oncology research communities.

  Study phs002340

• Mechanisms of Chemotherapy Resistance in T-ALL

  The goals of this study are to unravel the molecular mechanisms underlying leukemic transformation and chemotherapy resistance in T-cell acute lymphoblastic leukemia (T-ALL). Towards this end, a cohort of T-ALL lymphoblast specimens was collected at the time of initial T-ALL diagnosis (prior to the start of therapy) from children enrolled on contemporary clinical trials, Children's Oncology Group study AALL0434 and Dana-Farber Cancer Institute 05-001. Samples were analyzed using targeted exon sequencing and RNA sequencing analysis. Results of these analyses form the basis of studies that have been submitted for publication, and will be linked to this entry once published.

  Study phs001513

• NHLBI TOPMed: Genetics of Asthma in Latino Americans (GALA)

  This is a case pharmacogenetic study of bronchodilator drug response (Albuterol) among racially admixed Latino children with asthma between the ages of 8-40. Lung function testing was performed using the KoKo PFT system and each participant was administered albuterol dependent on age. Participants under 16 years of age, were administered 2 puffs of albuterol from a standard metered dose inhaler and 4 puffs for participants over 16 years old. The overall goal is to identify genetic factors which are predictive of drug response in children with asthma. The principal tools include a questionnaire and biological specimen collection. Participants with asthma have physician-diagnosed asthma, symptoms and medications.

  Study phs001542

• STAMPEED: Myocardial Infarction Genetics Consortium (MIGen)

  Myocardial infarction (MI) is a common complex disease and the leading cause of death and disability worldwide. The genetic basis of this disease is largely unknown. It has been thought that early-onset MI events would have a substantially greater heritability, thus making DNA collections with younger individuals desirable. More recently, genome-wide association studies have become feasible through the development of whole genome arrays and a large catalogue of common variants reported in the International HapMap database. This study aims to use Affymetrix genotyping platform to do a whole genome scan in 3000 early-onset MI cases and 3000 matched controls from 6 study collection sites.

  Study phs000294

• Exploring the Genomic Dark Matter of Neurodevelopmental Disorders

  Neurodevelopmental Disorders (NDDs) are a group of disorders that typically manifest early in development and may give rise to impaired cognition, communication, adaptive behavior, and psychomotor skills. This study aims to take a more comprehensive view into the genomic landscape of structural variants implicated in NDDs with intellectual disability (ID). We have evaluated the genome of families with a genetically unsolved severe NDD via optical genome mapping. This study identified likely pathogenic or pathogenic structural variants in known NDD genes, including BCL11A, OPHN1, PHF8, SON, and NFIA. Data is available in VCF format, following the standard filtering settings in Bionano Access and available as "variants_combine_filters_inMoleRefine1.vcf" files.

  Study phs002937

• 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

• HSC_population_dynamics___PX001_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001004146

• HSC_population_dynamics___KX009_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001004580

• HSC_population_dynamics___KX010_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001004581

• Genetic Analysis of Epidermal Inclusion Cysts

  The goal of this study was to identify a potential driver of epidermal inclusion cysts, or epidermoid cysts, (EICs) in human skin. Individuals were recruited at EIC excision appointments made a priori, with no exclusion criteria. Fresh biopsies and saliva were taken from consented patients, and DNA harvested immediately. Whole exome sequencing was performed (150-bp paired end reads) to 200X in tissue and 80X in saliva via Illumina NovaSeq 6000 sequencer. Identification of somatic mutations was performed using GATK best practices. Somatic variants in the NEK9 gene were found in 12/14 cases sequenced, with clustering of variants within the RCC1 and kinase domains of the protein.

  Study phs003776

• Association of Oxidative Stress Pathway Alterations with Risk of Treatment Failure in RTOG9512: A Randomized Trial of Hyperfractionation Versus Conventional Fractionation in T2 Squamous Cell Carcinoma of the Vocal Cord

  Based on the growing body of retrospectively collected and heterogeneously treated clinical cohorts and preclinical models, we investigated the clinical importance of NRF2 pathway alteration in an independent set of patients treated uniformly in the large prospective phase III trial RTOG 9512. We tested the hypothesis that patients with T2 glottic squamous cell carcinoma (SCC) harboring NRF2 pathway mutations would show radioresistance and have more local failure (LF) and locoregional failure (LRF) compared to those who did not have these mutations, using patients who received radiotherapy alone, thus removing potentially confounding effects of other therapies, like surgery or chemotherapy.

  Study phs003274

• Single-cell spatiotranscriptomic dissection of ex vivo human heart right atrial appendage and pericardial fluid in ischemic heart disease and heart failure

  We use cardiac and pericardial fluid biopsies collected during open-heart surgery in control, ischemic heart disease, heart failure, and myocardial infarction context. For each sample, single-nuclei RNA sequencing experiment is performed. We also perform spatial transcriptomics on the heart samples. We annotate the cells in major cell types, in addition to subtypes annotation of vascular and immune cells. The disease annotation enables us to reveal substantial differences in gene expression at the cell subpopulation levels. Our results demonstrate the importance of high-resolution cellular type/state mapping in the elucidation of human cardiovascular disease pathogenesis.

  Study EGAS50000000653

• Single-Cell Genomic Analysis of Gastrointestinal Cancer

  Our study aimed to define the heterogeneity of gastrointestinal cancers at a single-cell resolution. We subjected single-cell suspensions derived from surgical resections of gastrointestinal cancer tissue, paired normal tissue, peripheral blood mononuclear cells (PBMCs) or their ex vivo cultures to high-throughput microfluidics based single-cell RNA and DNA sequencing. We analyzed the features of the tumor microenvironment including fibroblasts, endothelial cells, macrophages and lymphocytes to determine their contribution to tumor growth and progression. We also characterized the mechanisms of immunosuppression in these tumors. This analysis led to novel insights into the biology of the microenvironment and also enabled the identification of new treatment targets.

  Study phs001818

• Bulk RNAseq - Calprotectin in vitro effects on human early hematopoiesis

  To explore the effects of calprotectin (CAL) on early hematopoiesis, we incubated CD34+ cells from four healthy donors for 7 days in the presence of stem cell factor (SCF), FLT3-ligand and thrombopoietin (TPO) without and with CAL, interleukin-6 (IL6) and the IL6_CAL combination before collecting cells. We performed the same experiment with CD34+ cells collected from three patients with JAK2-V617F-mediated myelofibrosis (MF). A total of 135,545 cells from healthy donors and 111,725 cells from myelofibrosis patients were analyzed by single-cell RNA sequencing (scRNA-seq) using the 10X Chromium droplet-based platform. Bulk RNAseq 4 conditons : -Control - Calprotectin - IL-6 - Calprotectin+IL-6

  Study EGAS50000000454

• RNA Sequencing Analysis of Patient-Derived Xenograft Tissue PIM-084 Treated with L-NMMA+Alpelisib vs Vehicle Control

  This dataset contains RNA-seq analysis of vehicle control compared to L-NMMA+alpelisib treated metaplastic breast cancer PDX PIM084 tumors (RNA sequencing and analysis performed by Novogene). The submitted data contains the gene ID, gene name, normalized read counts from all samples from control group and combination treatment group, log2-fold change derived from DESeq2 R/EdgeR package, p-value, adjusted p-value, read counts from each group, and gene FPKM from the each sample in the group. Due to patient privacy, we are submitting only the processed and desensitized RNA sequencing analysis to this repository.

  Study phs003814

• NHLBI TOPMed: Chicago Initiative to Raise Asthma Health Equity (CHIRAH)

  The CHIRAH project was a community-based study of the factors associated with asthma morbidity in the African American population. CHIRAH evaluated the role of various variables (biologic/environmental, psychologic/behavioral, and socioeconomic) on asthma morbidity and the function of changes in these variables on asthma morbidity in a longitudinal fashion. This involved collection of a cohort-based on school screening which was sampled to include similar numbers of underprivileged and non-underprivileged subjects which roughly equally represented self-reported African Americans and self-reported non-African Americans. Subjects were followed up every 3 months of this cohort over the course of 2 years.

  Study phs001605

• Targeting EGFR in NF1 Mutant Melanoma

  Our study focused on melanoma patients with driver mutations in the neurofibromin 1 (NF1) tumor suppressor gene, a subset of melanoma patients that have not benefitted from recent treatment advances. We have leveraged patient-derived short-term cultures (STCs) and multiomics approaches to identify molecular features that could be developed into therapies for NF1 mutant melanoma patients. Our studies revealed that the epidermal growth factor receptor (EGFR) is highly expressed and active in NF1 mutant melanoma cells, and that genetic or pharmacological EGFR inhibition impaired tumor cell proliferation, survival, and cell growth in patient-derived NF1 mutant but not NF1 wild-type melanoma models.

  Study phs003906

• HSC_population_dynamics_KSP_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001002762

• DNTR sequencing data of paediatric acute lymphoblastic leukemia

  This study used the DNTR-seq method in leukaemia samples to profile the whole-genome and mRNA jointly in single cells. Direct tagmentation is used in a collection of single-cell whole genome sequencing (scWGS) methods, including DNTR-seq, which provide high quality data at ultra-low to low coverage. The overall goal was to characterize the genetic and transcriptional heterogeneity of cancer samples. To infer clonal structure and evolutionary history, copy number analysis based workflows were implemented. Bone marrow mononuclear cells from pediatric acute lymphoblastic leukemia samples were FACS sorted into 384 plates to generate the DNA and RNA profiles.

  Study EGAS50000001247

• Whole genome sequencing data of paediatric T cell acute lymphoblastic leukemia (T-ALL)

  T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy accounting for approximately 15–25% of pediatric and adult ALL cases. Despite significant therapeutic improvements over the last decade, the prognosis of T-ALL remains less favorable than that of B-ALL, with 5-year EFS and OS of around 76–82% and 80–88%, respectively, depending on the treatment protocol used. T-ALL patients often suffer from failure of induction therapy or early relapse, which is associated with a dismal prognosis. Approximately 10–15% of T-ALL patients experience relapse, and survival after relapse is poor.

  Study EGAS50000001387

• scRNAseq analysis of CD8 T cells infiltrating the bladder and tumor of 4 non-muscle-invasive bladder cancer patients, before and after BCG treatment.

  We performed scRNAseq analysis of CD8 T cells infiltrating the bladder and tumor of 4 non-muscle-invasive bladder cancer patients, before and after BCG treatment. In order to identify tumor-specific T cells, we selected CD8 T cells that were enriched in the tumor of the patient. We also selected CD8 T cells appearing in the bladder after BCG treatment, with the hypothesis that BCG treatment stimulates tumor-specific CD8 T cells. Next, we cloned the TCR of these T cells in a Jurkat cell line and tested these TCR for recognition of tumor-specific antigens.

  Study EGAS50000001384

• Extracellular vesicles from TGF-β-activated cancer-associated fibroblasts remodel the tumor microenvironment through EV surface-associated proteins.

  In this study, we explored the function of extracellular vesicles (EVs) derived from non-activated cancer-associated fibroblasts (CAFs) and TGF-β-activated CAFs. We tested these two types of EVs on other cell types in the tumor environment, including cancer cells, CD8+ T cells, and CAFs. We further explored the protein cargo in EVs altered by TGF-β treatment using quantitative proteomics, and selected several highly upregulated proteins for further analysis. We found that the majority of these proteins were presented on the EV surface, and they regulated the target cells in an EV-cell contact dependent manner.

  Study EGAS50000000922

• Chordoma_Sequencing_Project_RNAseq

  This is a continuation of the Chordoma Sequencing Project. All cancers arise due to somatically acquired abnormalities in DNA sequence. Systematic sequencing of cancer genomes allows acquisition of complete catalogues of all classes of somatic mutation present in cancer. These mutation catalogues will allow identification of the somatically mutated cancer genes that are operative and characterise patterns of somatic mutation that may reflect previous exogenous and endogenous mutagenic exposures. In this application, we aim to perform whole genome sequencing on 10 chordoma matched genome pairs. RNA Sequencing/Methylation and SNP6 and an additional sequencing of three cancer cell lines will be added to this work.

  Study EGAS00001000410

• ICGC Oesophageal adenocarcinoma - 100 tumour samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett’s oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data.

  Study EGAS00001000724

• Evolution and clinical impact of genetic epistasis within EGFR-mutant lung cancers: multi-timepoint exome sequencing of a single patient's disease

  This dataset is a time-series of EGFR-mutant NSCLC clinical specimens from an individual patient profiled using tumor-based whole exome sequencing and the data is in BAM format. DNA was extracted from FFPE for primary tumor and frozen tumor tissue samples and matched non-tumor tissue using the Qiagen Allprep DNA/RNA Mini Kit.  The library preparation protocol was based on the Agilent SureSelect Library Prep and Capture System. DNA was resuspended in a low TE buffer and sheared (Duty Cycle 5%; Intensity 175; Cycles/Burst: 200; Time: 300s, Corvaris S2 Utrasonicator).  Bar-coded exome libraries were prepared using the Agilent Sure Select V5 library kit per manfucaturer’s specifications. The libraries were run on the HiSeq2500. Raw paired end reads (100bp) in FastQ format generated by the Illumina pipeline were aligned to the full hg19 genomic assembly obtained from USCS, gencode 14, using bwa version 0.7.12. Picard tools version 1.117 was used to sort, remove duplicate reads and generate QC statistics. Tumor DNA was sequenced to median depth of 303X (range 114.39-383.41) and the matched germline DNA to average depth of 231.65.

  Dataset EGAD00001003769

• BLUEPRINT EpiVar ChIP-seq in lineage specifying transcription factors

  The BLUEPRINT project is a large-scale project investigating epigenetic mechanisms involved in blood formation, in health and disease. The human variation workpackage (WP10) of the project seeks to characterize the effect of common sequence variation on the epigenome status of a cell. To do this, the project will use highly purified blood cells to minimise "experimental noise" and therefore enhance the power to discover modest effects. Two peripheral blood cell types, the CD14+CD16- monocyte (an important central orchestrator of adaptive immunity and a bridge between innate and adaptive immunity) and the CD65+CD9- neutrophilic granulocyte (the frontline cell for innate immunity) have been selected for this purpose. The two types of cells will be obtained at high purity from adult blood (AB) of 200 healthy males and females, respectively. Cells will be purified by using already validated and fully operational protocols that are based on density gradient centrifugation of the buffy coat obtained from whole blood, followed by magnetic bead-based purification using monoclonal antibodies against Cluster of Differentiation (CD) lineage-specific cell surface markers. This data set contains functional genomics data for gene expression and chromatin state.

  Dataset EGAD00001004571

• Integrative genome profiling in AML

  AML emerges as a consequence of accumulating independent genetic aberrations that direct regulation and/or dysfunction of genes resulting in aberrant activation of signalling pathways, resistance to apoptosis and uncontrolled proliferation. Given the significant heterogeneity of AML genomes, AML patients demonstrate a highly variable response rate and poor median survival in response to current chemotherapy regimens. For the past 4 years we have conducted gene expression profiling on purified bone marrow populations equating to normal haematopoietic stem and progenitor cells from healthy subjects and patients with de novo AML in order to identify AML signatures of aberrantly expressed genes in cancer versus normal. We are now applying a series of bioinformatic methodologies combined with clinical and conventional diagnostic data to establish novel genomics strategies for improved prognostication of AML. Additionally, we use our AML signatures to unravel oncogenic signalling pathway activities in AML patients and test inhibitory drugs for these pathways inn preclinical therapeutic programmes. We consider that superimposing GEP and clinical data for our AML patient cohort with additional data on their mutational status will significantly improve the prognostic power of the study as well as unravel yet unknown mutations associated with aberrant signalling activities of oncogenic pathways.

  Dataset EGAD00001001873

• SNV and indel calls from 8921 individuals in the British Autozygosity Populations BioResource dataset

  This includes variant calls (single nucleotide variants and small insertions/deletions) from 8086 (mostly British Pakistani/British Bangladeshi) individuals from the following studies: 1. 5236 British Pakistani/British Bangladeshi adults from East London Genes and Health (ELGH) 2. 2624 British South Asian mothers from Born in Bradford (mostly Pakistani) (BiB) 3. 1061 British South Asian adults from Birmingham (mostly Pakistani) (Birm) All of the Birmingham and most of the Born in Bradford samples were previously sequenced as part of PMID: 26940866. In the sample list file, the columns of interest to most people will be: vcf.id - sample ID from the vcf cohort - which cohort they're in sex.assigned - sex inferred from coverage on the X and Y chromosomes. Individuals for whom this did not match their reported sex have been discarded total, chrX and chrY - coverage within bait regions across all chromosomes, chrX and chrY respectively Mapping was done with bwa-mem and variant calling was carried out with GATK HaplotypeCaller. We removed variant sites for which the following was true: SNPs: "QD < 2.0 || FS > 30 || MQ < 40.0 || MQRankSum < -12.5 || ReadPosRankSum < -8.0" Indels: "QD < 2.0 || FS > 30 || ReadPosRankSum < -20.0"

  Dataset EGAD00001005469

• Single Cell Sequencing of Sperm (scSperm)

  The aim of this project is to genotype and sequence single spermatozoa from two men, one in his twenties and the other in his seventies. The resulting data is used to quantify the mutations that have arisen in the gametes of both individuals in order to better understand the effect of aging on mutation rates and modes.Project Outline. In order to quantify mutations, semen from two individuals are sequenced. 48 single sperm cells are isolated from each individual, and their DNA is extracted. The resulting genomes are amplified using PicoPlex, GenomiPhi MDA, Repli-G MDA, and MALBAC. QC step is applied to check the quality of WGA DNA using standard Sequenom plex (26 SNPs). A subset of 32 amplification products which pass the intiall QC, are genotyped using Affymetrix SNP6 chips. 12 of the genotyped amplification products are also sequenced. In addition, one multi-cell sample per individual is sequenced as a reference and for validation purposes.Altogether, 12 single cell sperm genomes and two multi-cell genomes are sequenced, coming to a total of 14 genomes. Of the single cell sperm genomes, 2 are sequenced to 50x coverage, and the other 10 to 25x coverage. Both multi-cell genomes are sequenced to 25x coverage.

  Dataset EGAD00001001216

• HSC_population_dynamics___LEUK4_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001004247

• RNA sequencing of a glioblastoma PDX cohort

  Patient-derived xenograft (PDX) models represent an essential tool for the preclinical evaluation of novel targeted therapies and their combinations. In this project, we molecularly characterized a comprehensive panel of glioma PDX models with well conserved molecular and pathological features over multiple passages. PDX samples were subjected to next generation sequencing (NGS). Characterization of cancer-relevant features including driver mutations or cellular processes was performed using mutational and gene expression data in order to identify potential biomarker or treatment targets in glioblastoma. In summary, we reported a newly established and molecularly characterized panel of glioma PDX models with high relevance for translational preclinical research.

  Study EGAS00001007119

• RNA sequencing in primary inflammatory (TPP) macrophages treated with a MEK1/2 inhibitor

  By investigating an intergenic haplotype on chr21q22, independently linked to inflammatory bowel disease (IBD), ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis, we discover that the causal gene, ETS2, is a master regulator of inflammatory responses in human macrophages and delineate how the risk haplotype increases ETS2 expression. Using a database of cellular signatures, we identified drugs that could modulate this pathway. To validate the anti-inflammatory activity of one class of small molecules in vitro, we treated TPP macrophages with vehicle control or a selective, non-ATP competitive MEK inhibitor (PD-0325901) at 2 doses (100nM and 500nM) and performed RNA sequencing.

  Study EGAS00001007552

• WGS___Exploration_of__mutational_processes_in_human_cancer_cell_lines

  Approximately 25 cell lines representative of 11 mutation signatures have been selected and will be grown from a single cell, referred to as parental clone, for a period of 3 months to allow accumulation of mutations. Following that period, we will obtain 2 subclones from each of the parental clone for analysis by exome-sequencing . In total we will therefore be sequencing 2 parental clones and 4 subclones per cell line for approximately 25 cell lines. Once the data has been analysed and the potential ongoing mutation processes determined, we will perform whole-genome sequencing of the parental clones and subclones of the candidate cell lines.

  Study EGAS00001002680

• HSC_population_dynamics___CB001_samples

  My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

  Study EGAS00001003397

• Molecular Characterization of ETMRs

  ETMRs are poorly characterized embryonal brain tumors with a dismal outcome. We collected tumors from 184 ETMR patients and 23 matched recurrences to investigate the genomic landscape of this distinct entity. Tumors without C19MC amplification, the proposed driver, harbor other miRNA related aberrations like DICER1 mutations and amplifications of the MIR17-92 miRNA cluster. All tumors behave molecularly similar and no subgrouping was observed. Whole-genome sequencing revealed an overall low recurrence of SNVs, but highly prevalent R-loop associated genomic instability. Finally, we show that targeting R-loops with TOP1 and PARP inhibitors might be an effective treatment strategy for this deadly disease.

  Study EGAS00001003256

• Mongolia Western HCC

  Mongolia has the world’s highest incidence of hepatocellular carcinoma (HCC), with ~100 cases/105 inhabitants. We molecularly characterize the Mongolian (n=192) compared to Western HCCs (n=187) by RNA-seq and WES. Mongolian patients were predominantly younger, female, with HBV-HDV non-cirrhotic livers. Mongolian HCCs had higher rates of protein-coding mutations (121 vs 70 mut /tumor in West), and mutations in known (i.e. APOB) and putative HCC drivers (TSC2). A novel mutational signature (SBS Mongolia) was identified in 25% of cases associated with the carcinogenic DMS genotoxic signature. Two unique molecular classes enriched in HBV-HDV infection, female gender and inflamed tumors are described.

  Study EGAS00001005364

• 'KOREAN' never-smoker female adenocarcinoma RNA-seq

  Multi-layered genomic studies such as the TCGA project have greatly advanced our understanding on molecular pathogenesis of lung cancer. For Asian nonsmoker patients, however, majority of studies have been limited to mutational analyses, emphasizing ethnic differences in driver mutations (e.g. more frequent EGFR mutations and ALK fusions). In essence, a comprehensive multi-layered characterization that could lead to molecular etiology and patient stratification scheme to be translated into clinical applications for this patient group is still missing. Here we report molecular profiling of tumor and matched normal tissues from 114 non-small-cell lung adenocarcinoma patients using whole exome sequencing, transcriptome sequencing, and array comparative genomic hybridization (CGH).

  Study EGAS00001003789

• Genomic landscape of malignant peripheral nerve sheath tumor (MPNST)

  Neurofibromatosis type 1 (NF1) is the most common tumor predisposition syndrome, and is associated with an aggressive soft-tissue sarcoma, malignant peripheral nerve sheath tumours (MPNSTs), the greatest cause of morbidity and mortality in people with NF1. The only potentially curative therapy involves surgery which is not always possible. Even therapy with curative intent is associated with poor overall survival for both sporadic and NF1-related MPNSTs. The development of novel therapies has been largely hindered by a lack of understanding of the molecular events underpinning MPNST pathogenesis. This is a comprehensive multi-omic study of MPNST evolution based on whole genome sequencing and transcriptomic data.

  Study EGAS00001006069

• Methylation-based classification of human mesenchymal chondrosarcoma

  We applied methylome and copy number profiling to a set of 45 well characterized MCS cases to evaluate their potential diagnostic value. Notably, the findings were reproducible also when analysing the round cell and cartilaginous component separately. Furthermore, four outliers were identified by methylome profiling for which the diagnosis had to be revised. Methylome profiling represents a sensitive, specific and reliable tool to support the diagnosis of MCS, particularly if only the round cell component is obtained in a biopsy and the diagnosis is not suspected. It can furthermore aid in confirming the diagnosis in case RNA sequencing for the HEY1::NCOA2 fusion transcript is not available.

  Study EGAS00001007042

• Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor infiltrating T cells.

  Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring underlying functional and dysfunctional states of human tumor infiltrating lymphocytes (TILs) is incompletely understood. Here, we identify tissue-specific and general gene-regulatory landscapes in the wide breadth of CD8+ TIL functional states covering four cancer entities using single-cell chromatin profiling. We map enhancer-promoter interactions in human TILs by integrating single-cell chromatin accessibility with single-cell RNA-seq data from tumor entity-matching samples and prioritize key elements by super enhancer analysis. Our analysis reveals a human core chromatin trajectory to TIL dysfunction and identifies key enhancers, transcriptional regulators, and deregulated target genes involved in this process. Finally, we validate enhancer regulation at loci encoding PD1, TCF1, and TIM3 by targeting non-coding regulatory elements with potent CRISPR activators and repressors. In summary, our study advances the understanding of molecular regulation of TIL (dys-)function and provides a framework for modulating immunotherapeutic relevant TIL genes via their enhancers.

  Dataset EGAD00001008662

• Methylation biomarker study of magnesium deficiency and colorectal cancer

  Five US studies using the Mg tolerance test, the "gold standard" test of Mg status, indicated that >50% participants had Mg deficiency. In our ongoing US trial, we have found a similar result. In growing recognition of the importance of Mg in human health, very recently, Mg was selected by the US Federal Dietary Reference Intake (DRI) Committee to update the DRI. In US and other populations at high risk of Mg deficiency, high Mg intake has been linked to reduced risk of colorectal neoplasia, insulin resistance, metabolic syndrome, type 2 diabetes, and cardiovascular disease (CVD). Conversely, in populations not at high risk of Mg deficiency, high Mg intake has been related to increased risk of total mortality (e.g. total cancer, colorectal cancer, and CVD), particularly when calcium intake is low. These observations suggest that the associations between high Mg intake and disease risks may completely differ by the underlying Mg status. Due to major limitations, the Mg tolerance test is not used in conventional clinical practice and rarely used in research. Instead, serum Mg is used for clinical diagnosis. However, serum Mg performs very poorly at identifying those with Mg deficiency. There is a great need to develop implementable, sensitive, and specific biomarkers which can be easily used for identifying people with Mg deficiency. Without such a marker, it is impossible to develop effective strategies that minimize adverse effects by targeting those who, as a result of Mg deficiency, are at risk of common diseases. It is known that DNA methylation changes are inducible by environmental exposures, including nutrients, and reversible when the exposure disappears. There are two major types of cytosine modifications in DNA, 5-hydroxymethylcytosine (5-hmC) and 5-methylcytosine (5-mC). 5-mC is often associated with suppressed gene expression. 5-hmC, generated by the oxidation of 5-mC, is specifically enriched in expressed genes and plays a critical role in activating and/or maintaining gene expression. However, current epigenomic profiling platforms cannot distinguish 5-hmC from 5-mC. Just recently, our collaborator, Dr. Chuan He (HHMI Investigator), established a novel and state of the art technique, TAB-Seq and TAB-Array protocol, which can separate 5-hmC from 5-mC in the genome. Our pilot studies indicate that Mg intake or treatment significantly affects methylation capacity, 5-mC and 5-hmC biomarkers. Our findings suggest blood leukocyte 5-hmC/5-mC biomarkers may serve as more sensitive biomarkers to identify Mg deficiency than serum Mg. Thus, a comprehensive epigenome-wide association study (EWAS) may help to identify the most sensitive 5-hmC/ 5- mC biomarkers for Mg deficiency. We propose to identify 5-hmC/5-mC biomarkers for Mg deficiency by a 4- phase EWAS study in the "Personalized Prevention of Colorectal Cancer Trial [PPCCT, R01CA149633; PI, Dai and Yu]" with a total of 240 participants. Mg tolerance test will be used as the gold standard. Finally, using newly identified biomarkers, we will evaluate if 12-week Mg treatment reduces TRPM7 expression, essential in Mg homeostasis and colorectal carcinogenesis, in rectal tissues only among those with Mg deficiency.

  Study phs002037

• A genome-wide meta analysis on stroke and ischemic stroke within four populations

  In this analysis a genome-wide meta-analysis was performed on all stroke and ischemic stroke.

  Study EGAS00000000060

• GBM Up and Down Responder EZH2 ChIPseq

  ChIPseq using anti-EZH2 with a sheared input DNA control to assess EZH2 genomic biding in one longitudinal pair of samples (pre- and post-treatment) from one UP and one DOWN responder GBM patient

  Dataset EGAD50000000134

• COVID-19 Exome Sequencing DAC policy

  This is the DAC policy for exome sequencing data from COVID-19 patients from EASI genomics and NIMgentics and belonging to the study "Variability in immune response genes and prediction of severe SARS-CoV-2 infection(INMUNGEN-Cov2 project)"

  Dac EGAC50000000065

• Whole-genome sequencing for 61 early-onset diabetes patients and 174 controls

  This dataset contains 241 paired FASTQ files for 61 early-onset diabetes patient and 174 controls sequenced with MGI Tech DNBSEQ-T10 and DNBSEQ-T7.

  Dataset EGAD50000001450

• Whole genome and whole exome sequencing of mucosal melanomas

  NGS of 10 mucosal melanomas:Whole genome sequencing of 5 mucosal melanomas and matched normal DNAWhole exome sequencing of 5 mucosal melanomas and matched normal DNA

  Dataset EGAD00001000945

• Chip-exo and Chip-nexus for five TFs in three colorectal cancer cell lines

  Chip-exo and Chip-nexus for FOXA1, HNF4A, KLF5, MYC, and TCF7L2 in colorectal cancer cell lines LoVo, GP5D, COLO320DM

  Dataset EGAD00001004099

• B15PON dataset

  Organoid cultures derived from normal colon and/or colorectal adenomas and/or colorectal carcinomas. RNA and DNA was isolated from these cultures for genome wide profiling.

  Dataset EGAD00001008411

• Whole-exome sequencing data from head and neck cancer patients

  This dataset contains paired-end whole-exome sequencing data (2x50 bp) from the normal samples, the primary tumors and the recurrences/metastases of 8 head and neck cancer patients.

  Dataset EGAD00001011278

• Colon adenomas and adenocarcinomas and matched mucosae

  Whole exome sequencing of neoplastic colorectal lesions, matched normal mucosa and peripheral blood leucocytes from 7 individuals. Data is contained within FASTQ files.

  Dataset EGAD00001010875

• Analysis of somatic mutations in normal blood, AML and MDS samples

  Targeted pulldown of genes known to be recurrently mutated in AML & MDS from patient and normal samples using Agilent Sureselect and for some cases also using Illumina Truseq technology.

  Dataset EGAD00001002180

• Differential Mutations in Matched Primary and Metastatic Colorectal Cancers

  This study compares DNA mutations detected in matched primary and metastatic colorectal cancer samples from 18 individuals across 1,321 genes. We found many more mutations were shared between tumor pairs (avg. 33.3 mutations/tumor) than were discordant (avg. 2.3 mutations / tumor). Nearly all tumors showed at least one discordance, and these were observed in genes known to be involved in colorectal cancer progression. Therefore, although primary and metastatic colorectal tumors are highly genetically concordant, evidence exists for discordance, which has clinical implications especially in situations of chemotherapy resistance or insensitivity.

  Study phs001084

• Transcriptome and TCR Sequencing of T Cells from Metastectomies

  T cells were sorted from metastatic tumors (colon, rectal, breast, anal, melanoma primary histologies) following tumor dissociation and single-cell sequencing was performed (RNAseq and TCRseq). For samples from tumors that had been previously studied, cells were analyzed comparing known neoantigen-reactive TCR-expressing cells to other T cells. For samples without previously identified neoantigen reactivity, TCRs were predicted on the basis of T cell transcriptomic states. To determine candidate neoantigen screening, exome and RNA sequencing were performed on fragments of matched tumors from which T cells were sequenced   

  Study phs002748

• Patient Microbiome and Surgical Site Infection in Spine Surgery

  Single center, prospective cohort study on the contribution of the preoperative patient microbiome and resistome to surgical site infection (SSI) and resistance to surgical antibiotic prophylaxis in spine surgery. The samples in this entry comprise a subset of patients for whom paired preoperative microbiome samples and postoperative wound culture isolates were obtained. These samples were analyzed by Illumina-based sequencing of metagenomic libraries enriched for the SSI pathogen of interest using the GenCap-Seq methodology (PMID: 36121157) to identify instances of endogenous infection with strains present in the preoperative microbiome.

  Study phs003358

• Single-Cell Analysis of the Multiple Myeloma Microenvironment after Gamma-Secretase Inhibition and CAR T-Cell Therapy

  We examined the effects of gamma-secretase inhibition (GSI) on the bone marrow microenvironment in multiple myeloma patients before anti-B-cell maturation antigen (BCMA) CAR T-cell therapy. Single-nuclei RNA and ATAC sequencing revealed significant changes in gene expression and chromatin accessibility, especially in monocytes and tumor cells, following exposure to GSI. The findings suggest that GSI influences not only BCMA signaling but also broader cellular interactions within the tumor microenvironment. De-identified sequencing data from the study is available through dbGaP.

  Study phs003741

• Characterization of the molecular signature of human monocytes in aging and myelodysplastic syndrome

  Deep immunophenotypic profiling of peripheral blood immune cells from young and older control subjects as well as patients with MDS was initially performed, using mass cytometry to identify monocyte subpopulations. Abundance of monocyte subpopulations separated the samples from patients with MDS from elderly control subjects was identified. Therefore, targeted immunophenotyping of monocytes was also performed with flow cytometry and RNA sequencing from isolated CD14+ peripheral blood longitudinally in 26 subjects, six young healthy individuals, nine older healthy individuals and eleven patients with MDS.

  Study EGAS00001007676

• Subclonal diversification of primary breast cancer

  Cancers are ecosystems of genetically related clones, competing across space and time for limited resources. To understand the clonal structure of primary breast cancer, we applied genome and targeted sequencing to 295 samples from 49 patients’ tumors. The extent of subclonal diversification varied considerably among patients and encompassed many spatial patterns, including local growth, intraductal dissemination and clonal intermixture. Landmarks of disease progression, such as acquiring invasive or metastatic potential, arose within detectable subclones of antecedent lesions, suggesting that subclonal mutations could be relevant if actionable. No defined temporal order of mutation was evident, with the commonest genes, including PIK3CA, TP53, BRCA2, PTEN and MYC, mutated early in some, late in others, often exhibiting parallel evolution across subclones. Signatures of homologous recombination deficiency correlated with response to neoadjuvant chemotherapy. Thus, the interplay of mutation, growth and competition drives clonal structures of breast cancer that are complex, variable across patients and clinically relevant.

  Dataset EGAD00001000898

• Single-cell targeted DNA-sequencing and protein sequencing

  We performed single-cell targeted DNA sequencing (MissionBio) on 13 high hyperdiploid B-ALL patients at diagnosis to study the genetic heterogeneity. For a number of patients single-cell surface protein antibody sequencing was added (DAB-seq) to better characterize the different cell types. Furthermore, additional samples during treatment were collected and analysed for some patients. In this way we want to study the clonal heterogeneity of these B-ALL samples, based both on mutations and CNVs, and identify resistant clones that could be targeted after relapse.

  Study EGAS50000000580

• Molecular correlates for HPV-negative head and neck cancer engraftment prognosticate patient outcomes

  Head and neck squamous cell carcinoma (HNSCC) tumors were sampled from 88 patients. Samples were implanted subcutaenously into the flank of NOD/SCID/IL2R-/- mice. Mice were then monitored weekly for tumor growth and the time of initial palpation was recorded. Mice were euthanized when tumors reached 15 mm in diameter or after 6 months. If no tumor formed by 6 months, the patient tumor was defined as Non-engrafter (N). RNA-seq was performed on all primary tumor samples and successfully engrafted patient-derived xenograft (PDX) samples.

  Study EGAS50000000714

• Gene Expression Signature in Normal Mammary Gland from 83 Breast Cancer Patients Indicates Pre-tumorous Changes and Adverse Outcomes

  This study assessed the transcriptomic profiles of 242 samples from 83 breast cancer patients with unfavorable outcomes, including paired uninvolved mammary gland samples collected at varying distances from primary lesions. As a reference, control samples from 53 mammoplasty individuals without cancer history were studied. A custom panel of 634 genes linked to breast cancer progression and metastasis was employed for expression profiling (targeted RNA sequencing), followed by whole-transcriptome (RNA sequencing) verification experiments and statistical analyses to discern molecular signatures and their clinical relevance.

  Study EGAS50000000011

• Sequencing of in vitro generated macrophages and T cells

  Monocyte derived macrophages were polarised into M1 or M2 using IFNg+ ILP or IL-4 respectively (n =4) . Pan T cells were cultured with or without IL-2 for 4 days (n=4 - 6). Pan T cells were co-cultured with THP1 tumour cells for 20 hours in the presence or absence of ImmTAC molecules and in the presence or absence of M2 macrophages. Sorted T cells and macrophage populations prior and post co-culture were analysed by bulk RNA sequencing (60 million reads per sample) using the Illumina NovaSeq system.

  Study EGAS50000000837

• Deciphering the complex clonal heterogeneity of polycythemia vera and the response to interferon alpha

  We integrated colony formation and differentiation assays with single-cell RNA sequencing and single-cell genotyping in PV patient-derived cells vs. healthy controls to dissect how IFNa targets diseased clones during erythroid differentiation. Our findings indicate that PV-derived clones either undergo apoptosis or pass through their typical differentiation cycle, contributing to the long-term exhaustion of mutant cells in the bone marrow. The pivotal roles of ribosomal genes and clonal prerequisites in the therapeutic mechanism of IFNa are underscored by our study.

  Study EGAS50000000904

• A Prospective Study of the Oral Microbiome and Pancreatic Cancer

  Two prospective cohort studies - the Black Women's Health Study and the Southern Community Cohort Study - were used to investigate the oral microbiome in relation to pancreatic cancer risk. Using a nested case-control study design, 148 cases and 510 matched controls were included (122 Black American pancreatic cancer cases and 409 matched controls). DNA was extracted from oral wash samples, using the PowerSoil Pro kit. Paired-end whole metagenomic shotgun sequencing was performed, using the Illumina HiSeq2000 platform with a read length of 100 bp (insert size 350 bp).

  Study phs002454

• Datasets of RNA-seq of tumor samples from clear cell renal cell carcinoma patients included in the Translational Program of the NIVOREN GETUG-AFU-26 trial

  RNA-seq analyses were performed on tumor tissue samples of 115 advanced clear cell renal cell carcinoma patients who participated in the NIVOREN GETUG-AFU-26 trial. The samples were obtained prior to treatment initiation. RNA-seq was performed to evaluate previously published gene expression signatures. These included: the IMmotion T effector (CD8A, EOMES, PRF1, IFNG and CD274) and the IMmotion Myeloid (IL-6, CXCL1, CXCL2, CXCL3, CXCL8, and PTGS2) gene signatures represent gene expression patterns associated with T effector cells and myeloid cells, respectively, while JAVELIN Renal 101 Immuno (T-cell receptor signaling: CD3G, CD3E, CD8B, THEMIS, TRAT1, GRAP2, CD247; T-cell activation, proliferation, and differentiation: CD2, CD96, PRF1, CD6, IL7R, ITK, GPR18, EOMES, SIT1, NLRC3; Natural killer cell mediated cytotoxicity: D2, CD96, PRF1, CD244, KLRD1, SH2D1A; Chemokine: CCL5, XCL2; and Other immune response genes: CST7, GFI1, KCNA3, PSTPIP1) represents gene expression patterns associated with both innate and adaptive immune response.

  Dataset EGAD50000001541

• An investigation into the effects of progestin on follicular development and oocyte maturation during controlled ovarian stimulation using the Progestin-Primed Ovarian Stimulation (PPOS).

  In recent years, the Progestin-Primed Ovarian Stimulation (PPOS) method, utilizing progestin as ovulation suppressants, has gained traction as a controlled ovarian stimulation (COS) strategy in assisted reproductive technology (ART). However, the impact of progestin agents on follicular fluid, granulosa cells, and cumulus cells at the levels of gene and protein expression has not been fully assessed. This study aims to evaluate the effects of progestin agents, used in the PPOS method, on follicular development and oocyte maturation.

  Study JGAS000770

• Estonian Microbiome Project second time point dataset

  Out of the 2,509 Estonian Microbiome Project participants, a sub-cohort of over 300 individuals provided an additional stool sample after a median follow-up period of 4.4 years. All participants of the EstMB cohort gave informed consent for the data and samples to be used for scientific purposes. In the second time point, the participants were instructed to send the samples by post immediately after taking the sample and time their sample collection to avoid shipping on the weekends. The median time between sampling and arrival at the freezer in the core facility for the second time point was 53 hours and 1 minute (mean: 59 hours and 22 minutes; minimum: 34 minutes; maximum: 168 hours and 7 minutes [note: additionally, one outlying measurement was 508 hours and 27 minutes. The shotgun metagenomics paired-end sequencing was performed by Novogene Bioinformatics Technology Co., Ltd., using Illumina NovaSeq6000 platform, resulting in 4.62 ± 0.44 Gb of data per sample (insert size 350 bp, read length 2 × 250 bp).

  Dataset EGAD50000001686

• Single-cell RNA sequencing of control and Notch inhibitor treated HCC PDX model

  We generated single-cell RNA-seq data for anti-Notch2 (n=3), anti-JAG1 (n=1) and anti-gD (n=4) treated LIV78 tumors. NCR nude mice bearing similarly sized LIV78 tumors (volumes between 300-900mm3) were injected intravenously with 30mg/kg body weight of either anti-Notch2, anti-Jag1 or anti-gD control antibody 72hrs prior to tumor harvest and tumor cell isolation. Following the depletion of CD45+ and Ter119+ cells, the samples were processed for single-cell RNA-seq (scRNAseq) as described previously (Long et al., 2019) using the Chromium Single Cell 3’ Library and Gel bead kit v2, following the manufacturer’s manual. cDNAs and libraries were prepared following the manufacturer’s manual (10X Genomics). Libraries were profiled by Bioanalyzer High Sensitivity DNA kit (Agilent Technologies) and quantified using Kapa Library Quantification Kit (Kapa Biosystems, Wilmington, MA). Each library was sequenced in one lane of HiSeq 2500 (Illumina) following the manufacturer’s sequencing specification (10X Genomics) to produce the resulting FASTQ files.

  Dataset EGAD50000000738

• Evaluation of Local Response of Prostate Cancer to Irradiation Using Multiparametric MRI and MR-Guided Biopsies

  The purpose of this study was to determine the rate of local recurrence in patients with intermediate and high risk prostate cancer treated with radiotherapy. In this study, multiparametric MRI was first performed, and biopsy tissue was acquired from cancerous regions detected on MRI. Blood samples were also taken. DNA and RNA were extracted from tissue taken at baseline. DNA was used for whole exome sequencing (WES). RNA was used for gene expression microarray. Each patient then received radiation therapy with androgen deprivation therapy.

  Study phs001821

• Exome Sequencing of familial and sporadic Meniere disease patients

  This study aims to characterize the genetic architecture of spanish patients diagnosed with Meniere disease (MD), focusing on both familial (FMD) and sporadic (SMD) forms, by analyzing coding variants. Whole-exome sequencing was performed on these patients, and variants were called and annotated using the nf-core/sarek bioinformatics pipeline, including alignment to the GRCh38 reference genome. The resulting data provide a curated resource for investigating the potential genetic contribution to the pathophysiology of MD. All data will be made available for reuse under controlled access.

  Study EGAS50000001178

• Establishment of an integrated database for clinical and genomic data in cancer

  In this study, to clarify the genomic varieties of MM in Asian population, we planned to investigate the genomic features in Japanese population, represented as an Asian cohort, and preformed the comprehensive genomic analysis of MM cells with newly diagnosed multiple myeloma (NDMM) by means of targeted capture sequencing (TCS) method. In our TCS assay, MM cells are subjected to the detection of following genomic abnormalities; IG rearrangements, IG associated translocations, CNAs, and somatic mutations from 340 genes related to the pathogenesis and therapeutic agent of MM.

  Study JGAS000206

• CUT&Tag sequencing of ZFHX4 and H3K27ac in midbrain dopaminergic neurons.

  CUT&Tag sequencing of the transcription factor ZFHX4 and the histone mark H3K27ac was performed in midbrain dopaminergic neurons (mDANs) derived from induced pluripotent stem cells. This epigenomic approach enabled the identification of ZFHX4 binding sites in this specific cellular context. Comparing the CUT&Tag profiles of ZFHX4 and H3K27ac provided insights into epigenetic landscapes in mDANs and revealed whether ZFHX4 exhibits patterns similar to the active transcription mark H3K27ac. Finally, enrichment analysis of the identified peaks highlighted potential primary targets of ZFHX4 in mDANs.

  Study EGAS50000001112

• 16S rRNA gene V4 region sequencing data, ASV profiles, and sample metadata of human faecal samples predominantly from the Estonian population

  This dataset comprises 16S rRNA gene V4 region amplicon sequencing data generated from 1,826 human faecal samples, predominantly from the Estonian population. The dataset includes raw sequencing reads and processed amplicon sequence variant (ASV) outputs, consisting of ASV abundance tables, representative ASV sequences, and taxonomic assignments. In addition, a sample metadata table is provided, containing sample and host information, including sample identifier, sequencing run identifier, date of sampling, sex, age, height, weight, nationality, disease status, and Bristol stool type. Sequencing was performed using the Illumina MiSeq and iSeq 100 platforms. The cohort includes individuals with no reported disease (n = 889), gastrointestinal diseases (n = 217), allergies and asthma (n = 194), thyroid gland disorders (n = 117), cardiovascular diseases (n = 103), various general health conditions (n = 139), cancer (n = 28), diabetes (n = 20), gynaecological issues (n = 7). Disease status was unavailable for 112 samples.

  Dataset EGAD50000002306

• Independent development of lymphoid and histiocytic malignancies from a shared early precursor

  Recent reports have described lineage flexibility in patients with recurrent hematologic malignancies. We encountered a boy with T-lineage acute lymphoblastic leukemia, non-Langerhans cell histiocytosis and histiocytic sarcoma. All tumors showed identical T-cell receptor rearrangements, but SNP arrays and whole exome sequencing revealed unique aberrations in each tumor. From the genetic data we conclude that the tumors were derived from a precursor cell with lineage plasticity for both lymphoid and myeloid development. From this precursor cell, the tumors evolved with independent genetic progression in a non-linear manner.

  Study EGAS00001001353

• Single-cell RNA sequencing on 5063 single T cells isolated from peripheral blood, tumour and adjacent normal tissues from six hepatocellular carcinoma patients.

  Single-cell RNA sequencing on 5063 single T cells isolated from peripheral blood, tumour and adjacent normal tissues from six hepatocellular carcinoma patients. The transcriptional properties of these individual cells, coupled with the assembled T cell receptor (TCR) sequences, were used to delineate the molecular subtypes, lineage, and functional properties of each T cell group. For five HCC patient, the exome-seq data of matched normal/tumor and bulk RNA-seq data of tumor are also available.

  Study EGAS00001002072

• A practical guide for mutational signature analysis in hematological malignancies

  Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, prognosis, and even treatment decisions. However, the field lacks a consensus on analysis and result interpretation. Using whole-genome sequencing of multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and acute myeloid leukemia, we compare the performance of public signature analysis tools. We describe caveats and pitfalls of de novo signature extraction and fitting approaches, reporting on common inaccuracies: erroneous signature assignment, identification of localized hyper-mutational processes, overcalling of signatures. We provide reproducible solutions to solve these issues and use orthogonal approaches to validate our results. We show how a comprehensive mutational signature analysis may provide relevant biological insights, reporting evidence of c-AID activity among unmutated CLL cases or the absence of BRCA1/BRCA2-mediated homologous recombination deficiency in a MM cohort. Finally, we propose a general analysis framework to ensure production of accurate and reproducible mutational signature data.

  Dataset EGAD00001005028

• MARS-seq dataset of five obese human subjects and a lean human subject

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

  Dataset EGAD00001005100

• Colorectal cancer cells possess an equipotent capacity to enter a developmental pausing-like state to survive chemotherapy

  Cancer cells enter a reversible drug tolerant persister (DTP) state to evade death from both chemotherapies and targeted agents. It is increasingly appreciated that the DTP state is an important driver of therapy failure and tumor relapse. We combined cellular barcoding and mathematical modeling in patient-derived colorectal cancer xenograft models to identify and characterize the cancer cells capable of generating DTPs in response to standard-of-care chemotherapy. Barcode analysis revealed no loss in clonal complexity of tumors that entered the DTP state and recurred following treatment cessation. Our data fits a mathematical model in which all cancer cells, and not a small subpopulation, possess an equipotent capacity to enter the DTP state. Mechanistically, we determined that DTPs display remarkable transcriptional and functional similarities to diapause, a reversible state of suspended embryonic development triggered by unfavorable environmental conditions. Our study provides new insights into how cancer cells use a developmentally conserved mechanism to drive the DTP state pointing to novel therapeutic opportunities to target diapause-like DTPs.

  Dataset EGAD00001006849

• The mutational landscape of normal human endometrial epithelium

  All normal somatic cells are thought to acquire mutations. However, characterisation of the patterns and consequences of somatic mutation in normal tissues is limited. Uterine endometrium is a dynamic tissue undergoing cyclical shedding and reconstitution lined by a gland-forming epithelium. Whole genome sequencing of normal endometrial glands showed that most are clonal cell populations derived from a recent common ancestor, with mutation burdens differing from other normal cell types and many fold lower than endometrial cancers. Mutational signatures found ubiquitously account for most mutations. Many, in some women all, endometrial glands are colonised by cell clones carrying driver mutations in cancer genes, often with multiple drivers. Total and driver mutation burdens increase with age, but are also influenced by other factors, including body mass index and parity, and clones with drivers often originate during early decades of life. The somatic mutational landscapes of normal cells differ between cell types and are revealing the procession of neoplastic change leading to cancer.

  Dataset EGAD00001004547

• Integrated genomic characterization of adrenocortical carcinoma

  Adrenocortical carcinomas (ACC) are aggressive cancers originating in the cortex of the adrenal glands. Despite the overall poor prognosis, ACC outcome is heterogeneous. CTNNB1 and TP53 mutations are frequent in these tumors, but the complete spectrum of genetic changes remains undefined. Exome sequencing and SNP array analysis of 45 ACC revealed recurrent alterations in known drivers (CTNNB1, TP53, CDKN2A, RB1, MEN1) and genes not previously reported to be altered in ACC (ZNRF3, DAXX, TERT and MED12), which were validated in an independent cohort of 77 ACC. The cell-surface transmembrane E3 ubiquitin ligase ZNRF36 was the gene the most frequently altered (21%), and appears as a potential novel tumor suppressor gene related to the ß-catenin pathway.Our integrated genomic analyses led to the identification of two distinct molecular subgroups with opposite outcome. The C1A group of poor outcome ACC was characterized by numerous mutations and DNA methylation alterations, whereas the C1B group with good prognosis displayed a specific deregulation of two miRNA clusters. Thus, aggressive and indolent ACC correspond to two distinct molecular entities, driven by different oncogenic alterations.

  Dataset EGAD00001000764

• Somatic mutations and clonal dynamics in healthy and cirrhotic human liver

  Chronic liver injury predisposes to cirrhosis and hepatocellular carcinoma, but how somatic mutations accumulate in liver disease is unexplored. We sequenced whole genomes of 400 microdissections of 100-500 hepatocytes from 5 normal and 6 cirrhotic livers. Compared to normal liver, cirrhotic liver had higher mutation burden, especially structural variants, including chromothripsis. Cirrhotic nodules were oligoclonal; sometimes entirely derived from a single, recent common ancestor. Clonal expansions millimeters in diameter occurred in cirrhosis in the absence of known driver mutations. Endogenous mutational processes predominated, although signatures of polycyclic aromatic hydrocarbon and aristolochic acid exposure occurred in some samples. Up to 10-fold within-patient variation in activity of exogenous signatures existed between adjacent cirrhotic nodules, with both clone-specific and microenvironmental forces shaping this heterogeneity. Synchronous hepatocellular carcinomas drew from the same repertoire of mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease.

  Dataset EGAD00001004578