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• Highly differentiated, fusion-negative rhabdomyosarcoma.

  Sequencing was performed using OncoPanel v.2 (OPv2), an Agilent SureSelect custom designed bait set consisting of the coding regions of 504 genes, previously linked to human cancer. Sequencing wa sperformed on an Illumina HiSeq 2500. 14 highly differentiated, fusion-negative rhabdomyosarcoma tumor samples, and 8 non-matched normal skeletal muscle samples weer sequenced. BAM files are available for download.

  Dataset EGAD00001003746

• NIHR BioResource Rare Diseases WGS project - Intrahepatic Cholestasis of Pregnancy (ICP) Rare Disease domain

  Short read whole genome sequencing (WGS) CRAM files for the NIHR BioResource Rare Diseases WGS project.Participants from the Intrahepatic Cholestasis of Pregnancy (ICP) Rare Disease domain

  Dataset EGAD00001004515

• Dataset Gene-Breakpoint Panel

  In this study we analysed patients with metastatic prostate cancer to scan their tumor genomes noninvasively in plasma DNA. We enriched 1.3 Mbp of seven plasma DNAs (4 CRPC cases: CRPC1-3 and CRPC5; 3 CSPC cases: CSPC1-2 and CSPC4) including exonic sequences of 55 cancer genes and 38 introns of 18 genes, where fusion breakpoints have been described using Sure Select Custom DNA Kit.

  Dataset EGAD00001000365

• ECCO-GEN Valve Methylation Dataset (non-diseased)

  The valve methylation dataset consists of 12 bam files of human non-diseased valve tissue samples that are free from calcification (6 aortic and 6 mitral valves - matched; 10 males: 2 females; age range 42 – 64 years, mean age 52.2 years, SD 9.9682). Donor hearts are free from cardiovascular and valvular complications.

  Dataset EGAD00001006303

• Amplicon sequencing of IPC-298 and MelJuso parental cell lines and Belvarafenib resistant IPC-298 colony

  Amplicon seqeuencing of (1) wildtype IPC298 cell line grown for 3-4 weeks with DMSO, amplified for ARAF exon 11 (2) IPC298 cells treated for 3-4 weeks with 10uM belvarafenib, isolated colony 9, amplified for ARAF exon 11 (3) MelJuso cell line grown with DMSO, amplified for ARAF exon 11

  Dataset EGAD00001007061

• ChIP-seq bulk

  This dataset gather ChIP-seq data produced by immunoprecipitating CTCF factor in own laboratory in MM.1S cell line in EtOH and Dex conditions. It also gather ChIP-seq dataset produced by external laboratory (Active Motif) for H3K27ac mark and GR transcription factor in same cell line and conditions ( MM.1S ETOH/Dex)

  Dataset EGAD00001011136

• National Institute of Mental Health (NIMH) Duke Cognition Cohort

  The overall goal is to identify genetic variants influencing normal variation between humans, with a focus on cognitive and neurosensory traits. Because of the focus of funding agencies on disease, very few studies of the genetics of non-disease traits have been performed. The genetic variation underlying the vast majority of differences between humans therefore remains not only undiscovered, but also unexplored. We have assessed >1,200 healthy volunteers for >70 diverse, non-disease phenotypes, with a focus on cognitive and neurosensory traits that are understudied and seem to have a strong biological basis. Our study includes measurements of face recognition, night vision, cognitive performance, auditory pitch discrimination, contagious yawn susceptibility, time perception, sense of direction, taste preferences, personality, sexual behaviors, sleep habits, acne, headache locations, synesthesia, and teeth sensitivity. This method is very different from the focus of most studies on collecting cohorts of patients with disease and controls with minimal phenotypic information. Because we phenotype the same healthy volunteers for multiple highly variable yet heritable traits, we can perform genetic analyses on a large number of phenotypes by just investing once in sequencing the DNA of these participants. An additional >2,000 participants in our cohort have been measured just for cognitive performance instead of for the more extensive phenotyping. Most of the genetic studies in this cohort have been about cognitive perfromance. The number of participants with genetic data generated who have undergone the more extensive phenotyping is limited. Our studies of the more novel traits like contagious yawning have therefore focused more on correlations between different phenotypes until we have a sufficient sample size to truly attempt to make genetic discoveries. . The dataset also includes two small challenge studies. In one study, the cognitive performance of 150 healthy volunteers was measured before and after an acute dose of the antiepileptic drug topiramate. In the other study, the cognitive performance of 13 healthy volunteers was measured before and after 24 hours of sleep deprivation.

  Study phs001406

• Identification of Somatic Changes in Tumors from Fanconi Anemia Patients

  This study focused on the identification of genomic signatures present in tumors from Fanconi anemia patients. Fanconi anemia is a rare hereditary disease caused by defects in DNA interstrand crosslink repair. The primary patient phenotypes are bone marrow failure and cancer predisposition. We concentrated on squamous cell carcinomas and used whole genome Illumina sequencing (22 tumor samples and 12 normal samples) , whole exome sequencing (37 tumor samples and 33 normal samples), PacBio long-read whole-genome (nine tumor and four normal samples),10X linked-read whole-genome sequencing, 10x single-cell/nuclei 3’ RNA sequencing (three tumor samples), 10x Visium spatial transcriptomics (one tumor sample), EPIC 850K methylation array (six samples), and bulk RNAseq (six tumor samples) to identify somatic changes present in tumors. The study aimed to identify changes that drive tumorigenesis in Fanconi anemia, give insight into the early development and aggressive nature of these tumors, and suggest therapeutic avenues for these patients. Another goal was to compare the genomic changes identified in tumors from Fanconi anemia patients with sporadic head and neck cancers. This study demonstrated that the tumors from Fanconi anemia individuals are generally not driven by HPV. Instead, they acquire mutations in the p53 tumor suppressor. The main characteristic of the tumors is the presence of a high number of structural variants in the form of small deletions, unbalanced translocations, and fold-back inversions, which often form complex rearrangements. These rearrangements result in amplifications and deletions of a multitude of oncogenes and tumor suppressors, respectively. The study also shows that lack of the Fanconi anemia DNA repair pathway leads to an epithelial-to-mesenchymal transition in a mouse model and in human samples that may influence the behavior of tumors in Fanconi anemia. Finally, comparing genomic changes in Fanconi anemia and sporadic tumors of the head and neck, we propose that the structural variants present in sporadic cancer result in a functional deficiency of the Fanconi anemia DNA repair pathway.

  Study phs002652

• Bacterial Vaginosis, Cervical Immune Cells and HIV Susceptibility

  This was a cross-sectional study to characterize cervical immune cell composition and activation status in the presence versus absence of bacterial vaginosis (BV) using bulk messenger RNA sequencing (mRNA-Seq). Women enrolled in a longitudinal, open cohort study and engaged in a sex work in Mombasa, Kenya, were eligible. On the day of enrollment, participants self-collected vaginal swabs for generation of Gram-stained slide. The slides were scored from 0-10 using the method of Nugent and Hillier; in this system, women with scores of 0-3 are considered to have normal vaginal flora, those with scores of 4-6 are considered to have intermediate flora, and those with scores of 7-10 are considered to have BV. For this study, only women with normal flora (Nugent scores 0-3) or BV (Nugent scores 7-10) were eligible. Participants underwent speculum-assisted pelvic examination and collection of cervical biopsy specimens using Tischler forceps. Biopsies were placed immediately in ice cold medium and transferred to the laboratory where they were weighed and transferred to freezing medium (10% DMSO + fetal bovine serum) and cooled slowly overnight. Samples were shipped from Kenya to the United States in liquid nitrogen dry shippers, collagenase digested into single cell suspensions, and sorted on a FACS aria to enrich for a population of live, CD45+ cells. Sorted samples (N=17 with BV and N=13 without BV) were immediately lysed and processed using the Takara SMART-Seq v4 Ultra Low Input RNA Kit for sequencing. Library generation was completed using the manufacturer's instructions and sequencing performed on an Illumina NextSeq500 platform using Illumina NextSeq 500/550 High Output v2.5 (150 Cycles). The FASTQ files generated and BV status (N=9 with BV and N=12 without BV that passed quality control) of the donor sample will be available on dbGaP. We identified over 1000 differentially expressed genes between women with versus without BV at an adjusted p-value of <0.05 (listed under "gene names" below).

  Study phs002329

• NHLBI TOPMed: Lung Tissue Research Consortium (LTRC)

  Chronic obstructive pulmonary disease (COPD), a disease state characterized by airflow limitation that is not fully reversible, is the third leading cause of death in the U.S. COPD is a heterogeneous syndrome, with affected individuals demonstrating marked differences in lung structure (emphysema vs. airway disease); physiology (airflow obstruction); and other clinical features (e.g., exacerbations, co-morbid illnesses). Multiple genomic regions influencing COPD susceptibility have been identified by genome-wide association studies (GWAS), and rare coding variants can also influence risk for COPD. However, only a small percentage of the estimated heritability for COPD risk can be explained by known genetic loci. Like most complex diseases, COPD is influenced by multiple genetic determinants (each with modest individual effects). Emerging evidence supports the paradigm that complex disease genetic determinants are part of a network of interacting genes and proteins; perturbations of this network can increase disease risk. To identify this network, multiple Omics data will need to be analyzed with methods to account for nonlinear relationships and interactions between key genes and proteins. Our overall hypothesis is that integrated network analysis of genetic, transcriptomic, proteomic, and epigenetic data from biospecimens ranging from lung tissue to nasal epithelial cells to blood in highly phenotyped subjects will provide insights into COPD pathogenesis and heterogeneity. We will leverage the well-phenotyped, NHLBI-funded Lung Tissue Research Consortium (LTRC) to address these questions. We will perform multi-omics analysis in 1548 lung tissue and blood samples from the LTRC. With these multi-omics data, we will utilize a systems biology approach to understand relationships between multiple genetic determinants and multiple types of Omics data. We will begin by performing single Omics analyses in COPD vs. control lung, nasal, and blood samples. Next, we will integrate single Omics data with genetic variants identified by WGS to assist in fine mapping genetic determinants of COPD. We will then perform integrated network analysis of COPD with genetic and multiple Omics data using correlation-based, gene regulatory, and Bayesian networks. Subjects were recruited from Mayo Clinic, Universities of Colorado, Michigan, and Pittsburgh, and Temple University.

  Study phs001662

• UK10K NEURO IOP COLLIER

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The Genetics and Psychosis (GAP) set consists of samples from subjects with schizophrenia, ascertained as a new-onset sample. This set is of UK origin, with data on cognition, brain imaging and other endophenotypes. The Maudsley twin series consists of probands ascertained from the Maudsley Twin Register, defined as patients of multiple birth who had suffered psychotic symptoms. This set is of UK origin, with data on cognition, brain imaging and other endophenotypes, with DNA available from an MZ or DZ affected or unaffected co-twin. The Maudsley family study (MFS) consists of over 250 families who have a history of schizophrenia or bipolar disorder Within the Maudsley Family Study, biological markers of psychosis include neuropsychological tests, Evoked Response Potentials Tests (ERPs), MRI scans, dermatoglyphics and eye tracking. Early risk factors for psychosis and clinical symptoms are also investigated. This set is of UK origin, with DNA available from both affected and unaffected relatives in many of the probands. For further information on this study please contact David Collier (david.collier@kcl.ac.uk).

  Study EGAS00001000121

• Germline elongator mutations in sonic hedgehog medulloblastoma

  Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHHa subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

  Study EGAS00001004126

• HCA_Thymus_Disease_DiGeorge_Transplant_RNA

  Single cell transcriptomics study of thymic transplant biopsies Allogeneic thymus transplantation is the only curative therapy for complete DiGeorge Syndrome (cDGS), a rare severe primary immunodeficiency characterised by athymia. GOSH is one of only two centres worldwide to offer this treatment. Despite a lack of major histocompatibility complex (MHC)-matching between donor and host, transplanted thymus becomes repopulated by recipient bone marrow derived precursor cells and supports development of functional T-cells. The mechanisms underlying thymopoiesis in this context are poorly understood, but over time we observe reconstitution of T-cell immunity, with the ability to produce host naïve T-cells showing a broad T-cell receptor (TCR) repertoire and to generate MHC-restricted T-cell proliferative responses. Although lifesaving, the achieved immunological reconstitution is typically not complete with circulating T-cell numbers usually remaining below the age related normal ranges. Additionally, we observe persistence of donor-derived T-cells of unknown clinical significance. To gain more insight into the mechanisms by which MHC-mismatched transplanted thymus supports T-cell development with self-tolerance, as well as into the basis of suboptimal T-cell immunity, we now aim to investigate immune reconstitution after thymus transplantation in further detail by using single-cell transcriptomics, applied to thymic transplant biopsies and peripheral blood samples collected during standard post-transplant patient care. By identifying which lineages of host- derived cells repopulate the thymic tissue after transplantation, we will be able to address the role of MHC in positive and negative T-cell selection during T-cell differentiation. We will also be able to clarify the exact ontogeny of the persistent donor T-cells, as well as their possible role. Understanding the mechanisms of action of HLA-mismatched transplanted thymus will contribute to treatment optimisation. Additionally, our research provides a unique opportunity to further investigate key immunological concepts, such as tolerance and autoimmunity, challenging existing paradigms in thymus immunology. 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 EGAS00001004025

• ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA

  Background Liquid biopsies, and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in somatic copy-number alterations (SCNAs), which have been associated with poor outcome and metastasis, using ctDNA is challenging. Pancreatic adenocarcinoma is a disease which has been considered to harbour early punctuated events in its evolution, leading to an early fitness peak, with minimal further subclonal evolution. Methods To interrogate the role of SCNAs in pancreatic adenocarcinoma cancer evolution, we applied whole-exome sequencing of 55 longitudinal cell-free DNA (cfDNA) samples taken from 24 patients (including 8 from whom a patient-derived xenograft (PDX) was derived) with metastatic disease prospectively recruited into a clinical trial. We developed a method, Aneuploidy in Circulating Tumour DNA (ACT-Discover), that leverages haplotype phasing of paired tumour biopsies or PDXs to identify SCNAs in cfDNA with greater sensitivity. Results SCNAs were observed within 28 of 47 evaluable cfDNA samples. Of these events, 30% could only be identified by harnessing the haplotype-aware approach leveraged in ACT-Discover. The exceptional purity of PDX tumours enabled near-complete phasing of genomic regions in allelic imbalance, highlighting an important auxiliary function of PDXs. Finally, although the classical model of pancreatic cancer evolution emphasises the importance of early, homogenous somatic events as a key requirement for cancer development, ACT-Discover identified substantial heterogeneity of SCNAs, including parallel focal and arm-level events, affecting different parental alleles within individual tumours. Indeed, ongoing acquisition of SCNAs was identified within tumours throughout the disease course, including within an untreated metastatic tumour. Conclusions This work demonstrates the power of haplotype phasing to study genomic variation in cfDNA samples and reveals undiscovered intra-tumour heterogeneity with important scientific and clinical implications. Implementation of ACT-Discover could lead to important insights from existing cohorts, or underpin future prospective studies seeking to characterise the landscape of tumour evolution through liquid biopsy.

  Study EGAS00001007077

• Patient-derived tumor organoids for personalized medicine in a rare case of hepatocellular carcinoma with neuroendocrine differentiation.

  Dac EGAC00001002458

• Analysis of recent shared ancestry in a familial cohort identifies coding and noncoding autism spectrum disorder variants

  Dac EGAC00001002558

• Single cell transcriptomics of hESC-derived midbrain dopaminergic neurons generated by a new human development-based protocol

  Dac EGAC00001002707

• A population specific reference genome defined from the analysis of 153 United Arab Emirates nationals.

  Study EGAS00001004537

• Transcriptome Analysis Offers a Comprehensive Illustration of the Genetic Background of Pediatric Acute Myeloid Leukemia

  Study EGAS00001003701

• High coverage sequencing of a single sample can account for the problem of intratumor heterogeneity

  Study EGAS00001004200

• : Centromeric cohesion failure invokes a conserved choreography of chromosomal mis-segregations in pancreatic neuroendocrine tumours

  Study EGAS00001004239

• IN UTERO ORIGIN OF MYELOFIBROSIS PRESENTING IN ADULT MONOZYGOTIC TWINS AFTER A PROLONGED DISEASE LATENCY

  Study EGAS00001005744

• A capture-based next-generation sequencing panel for the molecular characterization of chronic lymphocytic leukemia

  Study EGAS00001006975

• Altered neutrophil and granulopoiesis biology underlie a poor outcome sepsis endotype

  Study EGAS00001006283

• Oncolytic virotherapy mediated anti-tumor response in primary cutaneous B-cell lymphoma: a single-cell perspective

  Study EGAS00001004904

• IG-MYC rearrangement defines a high-risk subgroup of B-cell precursor acute lymphoblastic leukaemia

  Study EGAS00001005111

• Better Outcomes for Children: GWAS from Cincinnati Children's Hospital Medical Center (CCHMC) - eMERGE Phase II data - (dbGaP Deposit 1)

  This submission includes genotyping data from 6 separate cohorts (named A-E here), each is described in separate paragraphs below. Cohort A) Autism is a neurodevelopmental disorder that affects 1.5 million people in the United States, at an estimated lifetime cost of $4 million. It is part of Pervasive Developmental Disorder characterized by impairments in communication, language and reciprocal social interaction, and by unusual patterns of restricted and repetitive interests or behaviors. Autism, or autistic disorder, is the most severe form of the disease which has a wide range of symptom severity encompassed by the more inclusive term, Autism Spectrum Disorder (ASD). The prevalence of Autistic Disorder is currently estimated to be 4 per 1000, affecting 4 times more boys than girls. Susceptibility to autism is clearly attributable to genetic factors but the extensive clinical and genetic heterogeneity within the disorder have hindered efforts at genetic dissection. Identifying the genetic variants that contribute to this highly heritable disease is crucial to advancing research on autism. Reported concordance rates among monozygotic twins range from 60% &#8722; 90% and heritability of autism has been estimated to be 90% or greater. Identifying genetic variants that contribute to this highly heritable disease is crucial to advancing research on autism. Cohort B) The long-term objective of this research is to determine the molecular genetic basis of Cardiovascular (CV) disease in the young; this study seeks to identify gene mutations that cause "structural heart defects". Every year in the USA, 32,000 individuals are born with CV malformations; approximately 20% die during the first year of life. Another 30,000 young people develop a disturbance of cardiac rhythm or conduction. In addition, the life expectancy of another 40,000 young people is shortened by other forms of CV disease. It is becoming more apparent that in spite of the success in diagnosis and treatment, very little is known about the causes of CV disease in the young; understanding the causes will permit insight into the pathophysiologic basis of disease and allow definition of disease risk - two critical elements for disease prevention. Disease prevention and/or risk modification promises to be the new frontier in the management of CV disease in the young. Cohort C) Eosinophilic Esophagitis (EE) is one of the manifestations of eosinophilic gastrointestinal inflammation which have profound effects on a patient&#39;s health and development. Results of epidemiologic studies performed through our center demonstrate that eosinophil-associated gastrointestinal disease is not an uncommon entity. While the epidemiology of eosinophilic esophagitis has not been thoroughly studied until recently, there appears to be a significant increase in the diagnosis of EE in the last decade. Based on our research, this mainly reflects increased disease recognition, but there is also a bona-fide increase in disease incidence which coincides with the increasing incidence of asthma and allergic diseases in the industrialized world. In addition, many patients with intractable symptoms thought in the past to represent atypical GERD or other disorders are now being recognized as having EE. Diagnosis of EE requires endoscopy and biopsies to document the characteristic histologic findings of esophageal eosinophilia. In general, this study proposed to elucidate the mechanisms underlying eosinophil growth, survival, migration, and function, and to investigate and further characterize the pathophysiology of, clinical manifestations of, and spectrum of disease severity of eosinophilic esophagitis in humans. Cohort D) Juvenile idiopathic arthritis (JIA) is a debilitating complex genetic disorder characterized by inflammation of the joints and other tissues and shares histopathological features with other autoimmune diseases. It is considered a complex genetic disorder. There are more than 50,000 children with JIA in the USA, approximately 1 per 1000 births, which is about the same incidence as juvenile diabetes. It is believed that genes in the major histocompatibility complex (MHC) play a role in defining genetic risk, and it can be hypothesized that loci in other chromosomal regions are involved in conferring risk in JIA. These candidate chromosomal regions can be identified using genome wide association analyses. The long-term goal is a comprehensive understanding of the genetic basis of these disabling arthropathies for which the molecular basis is not presently understood. The results of recent GWAS for Caucasian JIA were recently published in Arthritis Rheum. 2012 Feb 21 (Published online, PMID=22354554). Cohort E) Childhood Absence Epilepsy (CAE) is characterized by very frequent (several to many per day) absence seizures in an otherwise normal child with an EEG usually demonstrating 3 Hz bilateral, synchronous, symmetrical spikewaves pattern with normal background activity. CAE occurs in 10% to 15% of all children with epilepsy with an annual incidence of 6.3 to 8/100,000 in children &lt;15 years of age. Females are more affected than males. Epilepsy onset is typically between the ages of 4 to 8 years with a peak incidence of 6 to 7 years. CAE does not start after age 13 years. The primary objective of this study is: To identify the optimal anticonvulsant (i.e. the antiepileptic drug (AED) with highest rate of seizure control and lowest incidence of treatment limiting toxicity) used for the initial treatment of children with Childhood Absence Epilepsy (CAE). The secondary objectives are: To determine the pharmacogenetic and other non-heritable factors underlying the interindividual variation in anticonvulsant response efficacy and toxicity. To define and contrast the effects of ethosuximide, lamotrigine, and valproic acid monotherapy on cognition (attention), behavior and quality of life in children with Childhood Absence Epilepsy. Cohort F) Cincinnati Controls. These are local healthy children selected to be representative of the population of Cincinnati with respect to gender and ancestry. Cohort G) Cytogenetics cases are ascertained by the clinical request to obtain cytogenetic analysis. The platform used included genotyping data which are then available for genome wide association analysis

  Study phs000494

• A Genome-Wide Association Study of Lung Cancer Risk

  Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types genotyping 515,922 single nucleotide polymorphisms (SNPs) in 5,739 incident lung cancer cases and 5,848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from 10 additional studies for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication resulting in 3,333 adenocarcinomas (AD), 2,589 squamous cell carcinomas (SQ), and 1,418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT) on chromosome 5p15.33, was associated with risk of adenocarcinoma (OR=1.23, 95%CI=1.13-1.33, P=3.02x10-7), but not other histologic types (OR=1.01, P=0.84, and OR=1.00, P=0.93, for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR=1.24, 95%CI=1.17-1.31, P=3.74x10-14 for AD and OR=0.99, P=0.69 and OR=0.97, P=0.48, for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma. Note: The lung study dataset to be released to dbGaP and caBIG excludes 47 individuals from the PLCO cohort who consented to participate only in cancer research projects and 22 individuals because of updated QC. Thus, the released dataset is derived from 11517 subjects, 5699 cases and 5818 controls. After the updated QC, the dataset to be released to dbGaP and caBIG includes 506062 SNPs.

  Study phs000336

• A circulating biomarker for severity of facioscapulohumeral muscular dystrophy

  Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable skeletal myopathy. Clinical trials for FSHD are hindered by heterogeneous biomarkers poorly associated with clinical severity, requiring invasive muscle biopsy. Macroscopically FSHD presents with slow fatty replacement of muscle, rapidly accelerated by inflammation. Mis-expression of the transcription factor DUX4 is currently accepted to underlie FSHD pathogenesis and mechanisms including PAX7 target gene repression have been proposed. Here we perform RNA-sequencing on MRI guided inflamed (n=24) and isogenic non-inflamed (n=24) muscle biopsies from the same clinically characterised FSHD patients, alongside isogenic peripheral blood mononucleated cells from a subset of patients (n=13), and unaffected controls. We employ multivariate models to evaluate the clinical associations of 5 published FSHD transcriptomic biomarkers. We demonstrate that PAX7 target gene repression can discriminate control, inflamed and non-inflamed FSHD muscle independently of age and sex (p&lt;0.013), while the discriminatory power of DUX4 target genes is limited to distinguishing FSHD muscle from control. Importantly, the level of PAX7 target gene repression in non-inflamed muscle associates with clinical assessments of FSHD severity (p=0.04). DUX4 target gene biomarkers in FSHD muscle show associations with lower limb fat fraction and D4Z4 array length, but not clinical assessment. Lastly, PAX7 target gene repression in FSHD muscle correlates with the level in isogenic peripheral blood mononucleated cells (p=0.002). A refined PAX7 target gene biomarker comprising 143/601 PAX7 target genes computed in peripheral blood (the FSHD muscle-blood biomarker) associates with clinical severity in FSHD patients (p&lt;0.036). Our new circulating biomarker validates as a classifier of clinical severity in an independent data set of 54 FSHD patient blood samples, with improved power in older patients (p=0.03). In summary, we present the minimally invasive FSHD muscle-blood biomarker of FSHD clinical severity valid in patient muscle and blood, with potential utility in routine disease monitoring and clinical trials.

  Study EGAS00001007350

• Molecular features of adenomas predicting metachronous colorectal cancer: a nested-case control study

  "Background &amp; Aims: Current morphological features defining advanced adenomas (size ≥10 mm, high grade dysplasia or &gt;25% villous component) cannot optimally distinguish individuals at high-risk or low-risk of metachronous colorectal cancer (me-CRC), which may result in suboptimal surveillance. Certain DNA copy number alterations are associated with adenoma-to-carcinoma progression (cancer-associated events; CAEs). We aimed to evaluate whether CAEs can better predict an individual’s risk of me-CRC than the morphological advanced adenoma features. Methods: In this nested case-control study, 529 individuals with a single adenoma at their first colonoscopy were selected from a Norwegian adenoma cohort. DNA copy number profiles were determined, by means of low-coverage whole genome sequencing. We assessed the prevalence of CAEs in advanced and non-advanced adenomas and its association with me-CRC. For the latter, cases (with CRC) were matched to controls (without CRC), with the same follow-up period as cases, as well as age and sex. Subsequently, odds ratios (OR) for the association of the presence of an advanced adenoma or a molecularly-defined high-risk adenoma with me-CRC were calculated. Results: Molecular high-risk features were observed in 85/267 (32%) of advanced adenomas and in 27/262 (10%) of non-advanced adenomas. Me-CRC was more strongly associated with advanced adenomas (OR 3.58; 95% CI 2.27-5.72) than with molecular high-risk adenomas (OR 1.90; 95% CI 1.14–3.16). After adjusting for other variables, only advanced adenoma remained significantly associated with me-CRC (OR 3.39; 95% CI 2.10–5.55). Conclusion: Molecularly-defined high-risk adenomas were associated with me-CRC, but the association of advanced adenoma with me-CRC was stronger. " Project goal: Evaluate the value of DNA copy numbers alterations detected in a baseline adenoma, in the prediction of risk of metachronous CRC

  Study EGAS00001007039

• GeneScreen, a Population Based, Targeted Genomic Screening Study

  The GeneScreen research study was based at the University of North Carolina (UNC) at Chapel Hill. It brought together researchers from different disciplines, including genetics, clinical medicine, bioethics, sociology, anthropology, psychology, and public health, to study the best ways to offer targeted genetic screening to the general adult population. DNA samples were collected from people who joined GeneScreen to look at a targeted panel of 17 genes. It tested for genetic differences (called mutations) that can cause one of 11 rare, but preventable or treatable conditions, including certain types of cancer and heart disease. Each condition has specific medical advice people can follow with their doctors to prevent or treat a serious health problem. The GeneScreen study was approved by the UNC Institutional Review Board and by the Kaiser Permanente Center for Health Research Institutional Review Board. GeneScreen is funded by the National Human Genome Research Institute of the National Institutes of Health.

  Study phs001817

• A Genome-wide Association Study (GWAS) of Risk for Osteosarcoma

  This is a genome-wide association study (GWAS) of osteosarcoma, the most common primary bone malignancy. Osteosarcoma typically occurs in adolescents and young adults. It occurs at increased frequency in several inherited cancer predisposition syndromes but the genetic contribution to sporadic osteosarcoma is largely unexplored. The objective of this study was to identify genetic risk factors for osteosarcoma by conducting a genome-wide association study. We developed collaborations with multiple institutions in order to attain the necessary sample size required to discover novel loci in the genome associated with osteosarcoma using the GWAS approach. Genomic DNA (either blood or buccal in source) derived from osteosarcoma cases was obtained from each participating institution or research group. De-identified blood or buccal cell DNA samples from osteosarcoma cases were derived from existing biobanks at the collaborative institutions. Control subjects were derived from existing NCI cohorts and matched by gender and ethnicity.

  Study phs000734

• The Microbial Ecology of Bacterial Vaginosis: A Fine Scale Resolution Metagenomic Analysis

  Archived self-collected vaginal swabs were utilized from a pilot study of vaginal douching cessation (NIH/NIAID R03-AI061131). Thirty-nine non-pregnant, reproductive-age women who reported the use of vaginal douche products in the two months prior to screening were enrolled. Thirty-three of these successfully completed the 16-week longitudinal study. Participants self-collected vaginal swabs and smears twice weekly. We report sequences based on the analysis of 16S rRNA gene sequences amplified from whole genomic DNA isolated from the swabs. Bacterial vaginosis (BV) is defined by Gram's stain of vaginal fluid (Nugent's score =7). The large body of information generated will facilitate understanding of vaginal microbial community dynamics, the etiology of BV, and drive the development of better diagnostic tools for BV. Furthermore, it is hoped that the information will enable a more personalized treatment of BV and ultimately, prevent adverse sequelae associated with BV.

  Study phs000261

• ROCHE PD 92 Multiome dataset

  This dataset contains 10X Multiome data generated on post-mortem brain from 92 individuals (70 PD, 22 controls). For the Roche_PD dataset, nuclei were isolated using Nuclei Pure Prep Nuclei Isolation Kit (Sigma Aldrich) with the following modifications. The tissue was lysed in Nuclei Pure Lysis Solution with 0.1% Triton X, 1mM DTT and 0.4U/ul SUPERase-In™ RNase Inhibitor (ThermoFisher Scientific) freshly added before use and homogenized with the help first of a 23G and then of a 29G syringe. Cold 1.8M Sucrose Cushion Solution, prepared immediately before use with the addition of1mM DTT and 0.4U/ul RNase Inhibitor, was added to the suspensions before they were filtered through a 30μm strainer. The lysates were then carefully and slowly layered on top of 1.8M Sucrose Cushion Solution previously added in new Eppendorf tubes. Samples were centrifuged for 45 minutes at 16000xg at 4°C. Pellets were re-suspended in Nuclei Storage Buffer with RNase Inhibitor, transferred in new Eppendorf tubes and centrifuged twice for 5 minutes at 500xg at 4°C. Finally purified nuclei were re-suspended in Nuclei Storage Buffer with RNase Inhibitor, stained with trypan blue and counted using Countess II (Life technology). After count, nuclei permeabilization was carried out following the demonstrated protocol for single cell multiome ATAC + Gene Expression sequencing from 10x Genomics. A total of 12,000 estimated nuclei from each sample was used for the transposition step and then loaded on the Chromium Next GEM Single Cell Chip J. ATAC library and gene expression library construction was performed using the Chromium Next GEM Single Cell Multiome ATAC + Gene Expression kit according to the manufacturer’s instructions. Libraries were sequenced using Illumina NovaSeq 6000 System and NovaSeq 6000 S2 Reagent Kit v1.5 (100 cycles), aiming at a minimum sequencing depth of 30K reads/nucleus. Genotype was generated as previously described (Bryois et al, Nature Neuroscience, 2022).

  Dataset EGAD50000000964

• Aberrant RNA-splicing (neojunctions) offers a new source for targets, and our neoantigen discovery platform (SNIPP) characterizes a novel class of clonally-expressed splicing-derived neoantigens that elicit a CD8+ T-cell-mediated tumor killing response.

  RESULTS: Our pipeline identified 789 public neojunctions, with 32 neojunctions concurrently identified in transcriptomic and proteomic glioma data and predicted to be presented by HLA-A*02:01 with high confidence. IVS and subsequent 10x VDJ scRNA-seq identified TCR clonotypes reactive against neojunctions in RPL22 (n=7) and GNAS (n=1), the latter being highly intratumorally-conserved (detected in &gt; 90% of spatially-mapped biopsies across 17/56 patients (26.78%)). TCR-transduced T-cells demonstrated recognition and immunogenic activation against endogenously processed and presented neoantigens in multiple GBM PDX cell lines. Furthermore, IDH1-mutant oligodendroglioma samples demonstrated significantly elevated expression of neojunctions over IDH1-mutant astrocytoma and IDH1wt subtypes. Differential gene expression (DESeq2) identified decreased expression of splicing factors due to oligodendroglioma-specific co-deletion of Chromosomes 1p/19q. siRNA knockdown of these splicing factors (e.g. SF3A3, SNRPD2) in IDH1wt glioma cells resulted in significantly increased expression of corresponding neojunctions.

  Study EGAS00001007986

• WFS1 mutation screening in a large series of Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis

  A heterozygous mutation in the Wolfram syndrome type 1 gene (WFS1) causes autosomal dominant nonsyndromic hereditary hearing loss, DFNA6/14/38, or Wolfram-like syndrome. To date, more than 40 different mutations have been reported to be responsible for DFNA6/14/38. In the present study, WFS1 variants were screened in a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA6/14/38 and Wolfram-like syndrome. Massively parallel DNA sequencing of 68 target genes was performed in 2,549 unrelated Japanese HL patients to identify genomic variations responsible for HL. The detailed clinical features in patients with WFS1 variants were collected from medical charts and analyzed. We successfully identified 13 WFS1 variants in 19 probands: eight of the 13 variants were previously reported mutations, including three mutations (p.A684V, p.K836N, and p.E864K) known to cause Wolfram-like syndrome, and five were novel mutations.

  Study JGAS000123

• Quick Guide for data submission

  Quick Guide This is a quick guide to submit data to the EGA. Please select data type to display the right detailed instructions. Sequence data Array-based data Get your submission account You first need to create your EGA user. Then, once your account has been verified by the Help Desk team, request your submission account and provide details of the data type and platform(s) in your submission. Register Study/DAC Use Submitter Portal to register your study, samples, Data Access Committee (DAC) and Policy. Upload data Encrypt your data files using the and upload it to your inbox using SFTP. Register experiments and runs Associate each data file to a registered sample and study by Linking files to samples. Details of the experimental procedure you followed must be provided. Finalise your submission Group your runs/analysis into datasets and link them to your new or existing DAC and policy using DAC Portal. Data request are done at a dataset level, thus files within a datasets must share release conditions. Release and admin When finalising the submission, set a released date to instruct our Helpdesk to release your study. All registered studies are automatically placed on hold until the named submission or DAC contact instructs our Helpdesk for the study to be released. Get your submission account Fill the submission form and provide details of the data type and platform(s) in your submission. Register Study/DAC Use EGA Programmatic submission to register your study, samples, Data Access Committee (DAC) and Policy. Upload data Encrypt your data files using the EgaCryptor and upload it using default FTP clients or Aspera. Complete the Array-Format (AF) spreadsheet Download the AF spreadsheet and complete all four sections. Return the spreadsheet to the EGA helpdesk. Release and admin Instruct our Helpdesk to release your study. All registered studies are automatically placed on hold until the named submission or DAC contact instructs our Helpdesk for the study to be released.

  Documentation submission/quickguide

• A comprehensive human gastric cancer organoid biobank captures tumor subtype heterogeneity and enables therapeutic screening​

  Gastric cancer displays marked molecular heterogeneity with aggressive behavior and treatment resistance. Therefore, good in vitro models that encompass unique subtypes are urgently needed for precision medicine development. Here, we have established a primary gastric cancer organoid (GCO) biobank that comprises normal, dysplastic, cancer and lymph node metastases (n=63) from 34 patients, including detailed whole-exome and transcriptome analysis. The cohort encompasses most known molecular subtypes (including EBV, MSI, intestinal/CIN, and diffuse/GS, with CLDN18-ARHGAP6 or CTNND1-ARHGAP26 fusions or RHOA mutations), capturing regional heterogeneity and subclonal architecture, while their morphology, transcriptome, and genomic profiles remain closely similar to in vivo tumors, even after long-term culture. Large-scale drug screening revealed sensitivity to unexpected drugs that were recently approved or in clinical trials, including Napabucasin, Abemaciclib, and the ATR inhibitor VE-822. Overall, this new GCO biobank, with linked genomic data, provides a useful resource for studying both cancer cell biology and precision cancer therapy.

  Study EGAS00001003145

• Epigenomics and Single-cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis

  Langerhans cell histiocytosis (LCH) is a rare neoplasm predominantly affecting children. It occupies a hybrid position between cancers and inflammatory diseases, and it provides an attractive model for studying cancer development. To explore the molecular mechanisms underlying the pathophysiology of LCH and its characteristic clinical heterogeneity, we investigated the transcriptomic and epigenomic diversity in primary LCH lesions. Using single-cell RNA sequencing, we identified multiple recurrent types of LCH cells within these biopsies, including putative LCH progenitor cells and several subsets of differentiated LCH cells. We confirmed the presence of proliferative LCH cells in all analysed biopsies using immunohistochemistry, and we defined an epigenomic and gene-regulatory basis of the different LCH cell subsets by chromatin accessibility profiling. In summary, our single-cell analysis of LCH uncovered an unexpected degree of cellular, transcriptomic, and epigenomic heterogeneity among LCH cells, indicative of complex developmental hierarchies in LCH lesions.

  Study EGAS00001003822

• A novel subset of human CD33+ haematopoietic stem cells characterized at single-cell resolution

  Elucidation of the identity and diversity of mechanisms that sustain long-term human blood cell production remains an important challenge. Previous studies indicate that, in adult mice, this property is ultimately vested in cells uniquely identified by their ability to clonally regenerate detectable levels of mature blood cells in serially transplanted recipients. We now present a combined multi-parameter analysis of the molecular features of very primitive human cord blood cells that display different cell output activities in vitro and in vivo. These analyses identified a new, prospectively separable, but still functionally heterogeneous, subset of long-term human blood-forming cells. Single-cell measurements of their transcriptional, DNA methylation and 40-protein content and of closely related phenotypes revealed numerous subtle, but consistent differences both within and between each subset analyzed. These results suggest that multiple regulatory mechanisms underlie the functional heterogeneity exhibited by clonally tracked human blood cell precursors with long-term output abilities.

  Study EGAS00001002826

• Single cell RNA sequencing and Whole Genome Sequencing on different cells from the same sample for a triple negative patient derived xenograft and ovarian cancer cell lines.

  Measuring gene expression of genomically defined tumour clones at single cell resolution would associate functional consequences to somatic alterations, as a prelude to elucidating pathways driving cell population growth, resistance and relapse. In the absence of scalable methods to simultaneously assay DNA and RNA from the same single cell, independent sampling of cell populations for parallel measurement of single cell DNA and single cell RNA must be computationally mapped for genome-transcriptome association. Here we present clonealign, a robust statistical framework to assign gene expression states to cancer clones using single-cell RNA-seq and DNA-seq independently sampled from an heterogeneous cancer cell population. We apply clonealign to triple-negative breast cancer patient derived xenografts and high-grade serous ovarian cancer cell lines and discover clone-specific dysregulated biological pathways not visible using either DNA-Seq or RNA-Seq alone.

  Study EGAS00001003387

• A Universal Gut Metagenomic-Derived Signature Predicts Cirrhosis

  Dysregulation of the gut microbiome has been implicated in the progression of nonalcoholic fatty liver disease (NAFLD) to advanced fibrosis and cirrhosis. To determine the diagnostic capacity of this association, stool microbiomes were compared across 163 well-characterized participants encompassing non-NAFLD controls, NAFLD-cirrhosis patients and their first-degree relatives. Interrogation of shotgun metagenomic and untargeted metabolomic profiles using the Random Forest machine learning algorithm and differential abundance analysis identified discrete metagenomic and metabolomic signatures that were similarly effective in detecting cirrhosis (diagnostic accuracy 0.91, AUC). Combining the metagenomic signature with age and serum albumin levels accurately distinguished cirrhosis in etiologically and genetically distinct cohorts from geographically separated regions. Additional inclusion of serum aspartate aminotransferase levels, which are increased in cirrhosis patients, enabled discrimination of cirrhosis from earlier stages of fibrosis. These findings demonstrate that a core set of gut microbiome species may offer universal utility as a non-invasive diagnostic test for cirrhosis.

  Study EGAS00001004600

• A Single-Cell Atlas of the Multicellular Ecosystem of Primary and Metastatic Hepatocellular Carcinoma

  Hepatocellular carcinoma (HCC) represents a paradigm of the relation between tumor microenvironment (TME) and tumor development. Here, we generated a single-cell atlas of the multicellular ecosystem of HCCs from four relevant sites. Antitumor central memory T (TCM) cells were found in tertiary lymphoid structures (TLSs). Chronic HBV/HCV infection increases infiltration of CD8+ T cells in tumors but aggravates T cell exhaustion. We identified CD11b+ macrophages to be terminally differentiated tumor-associated macrophages (TAMs) and two distinct differentiation trajectories contribute to their accumulation. We further demonstrated CD11b+ TAMs promote HCC cells invasion and migration, and angiogenesis. We characterized the heterogeneous subpopulations of malignant hepatocytes and their multifaceted roles in shaping the immune microenvironment. Finally, we identified seven TME subtypes that can predict patient prognosis. Collectively, this large-scale atlas deepens our understanding of the ecosystem in primary and metastatic HCCs, might facilitating the development of new immune therapy strategies for this malignancy.

  Study EGAS00001004468

• Ductal keratin 15+ luminal progenitors in normal breast exhibit a basal-like breast cancer transcriptomic signature

  Normal breast luminal epithelial progenitors have been implicated as cell of origin in basal-like breast cancer, but their anatomical localization remains understudied. Here, we combine micro-collection of uncultured organoids and single cell mRNA sequencing (scRNA-seq) of FACS-sorted luminal epithelial cells with multicolor imaging to profile ducts and terminal ductal lobular units (TDLUs) and compare them with breast cancer subtypes. Unsupervised clustering reveals eleven distinct clusters and a differentiation trajectory starting with keratin 15+ (K15+) progenitors enriched in ducts. Spatial mapping of luminal progenitors is confirmed at the protein level by staining with critical duct markers. Comparison of the gene expression profiles of normal luminal cells with those of breast cancer subtypes reveals a strong correlation between normal breast K15+ ductal progenitors and basal-like breast cancer. We propose that K15+ basal-like breast cancers originate in ductal progenitors, which emphasizes the importance of not only lineages but also cellular position within the ductal-lobular tree.

  Study EGAS00001005963

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

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

  Dataset EGAD00001009087

• Diagnostic utility of whole genome sequencing in adults with B-other acute lymphoblastic leukemia

  Genomic profiling at diagnosis of B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) in adults is used to guide disease classification, risk stratification and treatment decisions. Patients for which diagnostic screening fails to identify disease defining or risk stratifying lesions are classified as B-other ALL. We screened a cohort of 652 BCP-ALL cases enrolled in UKALL14 to identify and perform whole genome sequencing (WGS) on paired tumor-normal samples. For 52 B-other patients we compared WGS findings to data from clinical and research cytogenetics. WGS identifies a cancer associated event in 51/52 cases, this includes an established subtype defining genetic alteration in 5/52 that were previously missed by standard-of-care genetics. Of the 47 true B-other ALL we identified a recurrent driver in 87% (41).  Complex karyotype by cytogenetics emerges as a heterogeneous group, underlied by distinct genetic alterations associated with either favorable (DUX4-r) or poor outcomes (MEF2D-r, IGK::BCL2). For a subset of 31 cases, we integrate findings from RNA-sequencing (RNA-seq) analysis to include fusion gene detection, and classification by gene expression. Compared to RNA-seq, WGS was sufficient to detect and resolve recurrent genetic subtypes, however RNA-seq can provide orthogonal validation of findings. In conclusion, we demonstrate that WGS can identify clinically relevant genetic abnormalities missed by standard-of-care testing and identify leukemia driver events in virtually all cases of B-other ALL.

  Dataset EGAD00001009304

• Ancestry and somatic profile predict acral melanoma origin and prognosis – WXS

  Acral melanoma, which is not ultraviolet (UV)-associated, is the most common type of melanoma in several low- and middle-income countries including Mexico. Latin American samples are significantly underrepresented in global cancer genomics studies, which directly affects patients in these regions as it is known that cancer risk and incidence may be influenced by ancestry and environmental exposures. To address this, we characterise the genome and transcriptome of 123 acral melanoma tumours from 92 Mexican patients, a population notable because of its genetic admixture. Compared with other studies of melanoma, we found fewer frequent mutations in classical driver genes such as BRAF, NRAS or NF1. While most patients had predominantly Amerindian genetic ancestry, those with higher European ancestry had increased frequency of BRAF mutations and a lower median number of structural variants. The tumours with activating BRAF mutations have a transcriptional profile more similar to cutaneous non-volar melanocytes, suggesting that acral melanomas in these patients may arise from a distinct cell of origin compared to other tumours arising in these locations. KIT mutations were found in a subset of these tumours, and quadruple wild-type samples (non BRAF/NRAS/NF1/KIT) differed from mutated samples in their structural genomic profile and overall and recurrence-free survival patterns. Transcriptional profiling defined three expression clusters; these characteristics were associated with recurrence-free and overall survival. We highlight potential novel low-frequency drivers, such as PTPRJ, NF2 and RDH5. Our study enhances knowledge of this understudied disease and underscores the importance of including samples from diverse ancestries in cancer genomics studies.

  Dataset EGAD00001015755

• Spiradenocarcinoma (2018-10-29)

  Spiradenocarcinoma is a rare cutaneous sweat gland adnexal cancer with potential for aggressive behaviour. They are classified histologically into low- and high-grade tumours, with morphologically low-grade tumours thought to behave more favourably. However, limited information is available, with only 18 published cases. We have collected morphologically low-grade spiroadenocarcinomas (one with a lung metastasis) and high-grade spiroadenocarcinomas, as well as some spiradenomas (benign lesions), cylindromas (another type of malignant cutaneous sweat gland adnexal tumour) and hybrid spiradenoma-cylindromas. H&amp;E-stained sections were reviewed, follow-up was obtained, and immunohistochemistry for Ki-67, p53 and, MYB has been performed. The tumours were solitary, measuring 0.8-7?cm (median: 2.7?cm), with a predilection for the head and neck of elderly patients (median age: 72 years; range 53-92) without gender bias. Histologically, the tumours were multinodular and located in deep dermis and subcutis. A pre-existing spiradenoma was present in all cases. The malignant component was characterized by expansile growth with loss of the dual cell population, up to moderate cytological atypia and increased mitotic activity (median: 10/10 HPF; range 1-28). Additional findings included squamoid differentiation (n=9), necrosis (n=7), and ulceration (n=5). P53 expression was variable and no significant differences were noted in the benign compared with the malignant parts of the tumours. In contrast, in the malignant components the Ki-67 proliferative index was slightly increased, and MYB expression was lost. Follow-up (median: 67 months; range: 13-132) available for 16 patients (84%) revealed a local recurrence rate of 19% but no metastases or disease-related mortality. Here we wish to exome sequence these cases to define the first genomic landscape for this malignancy. This dataset contains all the data available for this study on 2018-10-29.

  Dataset EGAD00001004426

• Determination of cell specific regulatory enhancers in hematopoetic models

  The BLUEPRINT project is a large-scale project investigating epigenetic mechanisms involved in blood formation, in health and disease. The human variation workpackage (WP10, led by NS) 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. Units of 475 ml of AB will be obtained from consenting volunteers of the Cambridge BioResource (CBR), a panel of 10,000 healthy volunteers local to Cambridge who have already consented to participate in biomedical research and of whom biological samples (DNA, plasma, serum) and lifestyle data have been deposited in a repository and database, respectively. We are requesting funding from the Human Diversity project to sequence the genomes of the 200 CBR volunteers at low pass (6x coverage). Nuclei, DNA and RNA will be recovered from the purified cells and made available for RNA-seq, DNA-seq and ChIP-seq and genomic DNA for entire genome sequencing will be recovered from the DNA repository.

  Dataset EGAD00001002205

• A National Translational Science Network of Precision-Based Immunotherapy for Primary Liver Cancer (PLC)

  The primary objective of the NCI-CLARITY study is to establish a biospecimen repository for genomic, genetic and epigenetic analysis to study the biology of primary liver cancer (PLC) development and progression. Secondary objectives include predicting overall and progression-free survival following immunotherapy. In the retrospective phase, anonymous archival tissue from PLC patients was obtained from five participating sites. Whole exome and transcriptome sequencing was generated and used to predict overall survival in response to immunotherapy.

  Study phs003074