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• Blina_Tumour_project

  The aim of this study is to reconstruct the embryology of childhood tumours.

  Study EGAS00001006486

• Low_input_LC__WGS_

  R&D project to develop low input library construction methods.

  Study EGAS00001001855

• Whole_Genome_sequencing_of_rhabdomyosarcoma_tumour_tissue

  The aim of this study is to investigate the genomic landscape of human cancer.

  Study EGAS00001008274

• OAC WGS

  Please see our related publication, 'Molecular profiling to predict immunochemotherapy outcomes in esophageal adenocarcinoma'

  Study EGAS00001006470

• The Institute for Genomic Medicine at Nationwide Children's Hospital Pediatric Cancer and Blood Disorder Project

  The aim of this study is to enable the unification of the clinical and research arms of comprehensive genomic profiling in the setting of cancer and hematologic disease. Increasingly, studies of the genomic etiology of cancer and hematologic diseases are being utilized for patient management, including prognostication, informing diagnosis, and evaluating eligibility for targeted therapeutics and clinical trials. Clinically available testing can be limited in scope and follow-up, and thus assessment of the impact on patient outcomes is difficult to ascertain. N-of-1 studies have the ability to more broadly impact our understanding of the mechanisms of cancer and hematologic disease, and can have benefit for the individual as well as the larger population of patients with these diseases. Thus, we seek to study and characterize the genomic underpinnings of cancer and hematologic disease through genomic profiling studies bridging both clinical and research components. We will rigorously perform and vet research sequencing and genomic studies protocols for the purpose of transitioning these assays to clinically valid testing for use in clinical patient care. We have been enrolling patients onto this comprehensive genomic profiling study since January 2018. As part of the genomic workup for these patients, we have been performing tumor and normal whole genome sequencing, whole exome sequencing and RNA-Seq. The project is largely supported by the Nationwide Children's Foundation, and we anticipate adding another 50-70 cases per year. This protocol is significant in that it expands our understanding of the etiology of cancer and hematologic disease through a comprehensive analysis aimed at detecting a broad scope of genomic aberrations. Additionally, it improves our understanding of the clinical utility of genomic profiling and has the potential to ultimately improve patient management and surveillance at both level of an individual and general populations of patients affected by these diseases. Primary Objectives: Aim 1: Use diagnostic, relapse, and/or germline samples for augmented whole exome sequencing to characterize the spectrum of germline and somatic genomic alterations in pediatric malignancies and hematologic disease. Aim 2: Examine gene expression and fusion events using whole RNA-seq "transcriptome" analysis or targeted RNA-seq analysis such as the Archer FusionPlex technology. Aim 3: Compare the results of our enhanced molecular profiling vs. that which is detectable by traditional methods as related to cytogenetic, molecular, and minimal residual disease analyses performed as part of standard of care. Aim 4: Examine the utility of comprehensive genomic profiling by collection and evaluation of outcomes data as related to enhancement/alteration in diagnosis, prognosis, treatment management, and clinical benefit. Secondary Objective: Aim 1: Use and clinically validate expanded laboratory methodologies and bioinformatic approaches to more broadly assess genomic complexity (e.g. whole genome sequencing, transcriptome sequencing, in vitro analyses, minimal residual disease testing, clonality assays, proteomics) in the setting of hematologic and oncologic disease. In so doing, we aspire to make novel discoveries and associations, as related to disease phenotypes and subtypes, variant causality, therapeutic targeting, and cancer biology.

  Study phs001820

• BLUE CORAL: Biology and Longitudinal Epidemiology of PETAL COVID-19 Observational Study

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Available Data: Long Term Follow-up data has been added with version 2. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL BLUE CORAL include: Bronchial Lavage, Plasma, Tracheal Aspirate, Urine, Whole Blood Buffy Coat, DNA, Plasma, Serum, Urine, and Whole Blood. Please note that use of biospecimens is tiered for both non-genetic and genetic research.Objectives: To measure the incidence and changes over time in symptoms, disability, and financial status after COVID-19–related hospitalization.Background: For many individuals, the effects of COVID-19 persist after the acute phase and result in prolonged symptoms and disability. This has led to widespread efforts to characterize the epidemiologic characteristics of such post-COVID-19 sequelae. However, accurate data were limited, hindering the ability to counsel patients, caregivers, and policy makers and to plan relevant recovery-focused clinical research. Thus, the BLUE CORAL study was intended to address the knowledge gaps and provide critical data to help guide clinical care, public health, and scientific efforts.Participants: A total of 1376 COVID-19 patents were enrolled, with 825 (444 male, and 379 female) that completed at least one follow-up survey.A subset of the BLUE CORAL adult participants were enrolled in the extension study, FIRE CORAL. FIRE CORAL was a multicenter prospective cohort study of participants recovering from COVID-19 disease after discharge from the hospital. Design: BLUE CORAL was a prospective cohort study. Participants were enrolled between August 24, 2020, and July 20, 2021, with follow-up occurring through March 30, 2022. Posthospital surveys were administered by trained interviewers in English or Spanish to patients or their proxies at 1, 3, and 6 months after enrollment. Cardiopulmonary symptoms were assessed using the Airways Questionnaire 20, the Kansas City Cardiomyopathy Questionnaire, and the Seattle Angina Questionnaire. Fatigue was assessed using the Patient Health Questionnaire-9. Disability was assessed by self-report of limitations in activities of daily living (ADLs) or instrumental activities of daily living (IADLs). Financial problems were assessed using the World Health Organization Disability Assessment Schedule 2.0 question and questions regarding job changes, time off work, and insurance coverage developed with the Mi-COVID-19 study using qualitative interviews. Quality of life was measured using the European Quality of Life 5-dimension 5-level instrument.The primary outcomes were new or worsened cardiopulmonary symptoms, financial problems, functional impairments, perceived return to baseline health, and quality of life. Symptoms that were not present before hospitalization or specifically reported as increased in severity were counted as new or worsened. Conclusions: The findings of this cohort study of people discharged after COVID-19 hospitalization suggest that recovery in symptoms, functional status, and fatigue was limited at 6 months, and some participants reported new problems 6 months after hospital discharge.

  Study phs003419

• Lung Plasma rearrangement screen

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from lung cancer patients and subjected to short paired end sequencing on the llumina platform. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions.

  Dataset EGAD00001000367

• A model for predicting response to PD-1 inhibitors in NSCLC

  Whole exome sequencing was used to examine the impact of human leukocyte antigen B44 in a non-small cell lung cancer cohort treated with single agent pembrolizumab with over five years of follow-up.

  Study phs002244

• Whole-genome sequencing with complement C1s deficiency linked to systemic lupus erythematosus

  This dataset includes two FASTQ files (R1 and R2) from an Illumina germline nuclear DNA whole-genome sequencing run of a single sample. The sample corresponds to a 34-year-old male with a rare deficiency in complement component C1s, linked to systemic lupus erythematosus (SLE). Genomic analysis revealed two novel mutations in the C1S gene.

  Dataset EGAD50000000988

• Novel genome editing strategies to uncover genotype-phenotype correlations in Polycystic Kidney Disease: a proof-of-concept

  Bulk RNA-seq of genome-edited HEK293T cell lines engineered to model specific PKD1 variants. This dataset enables the exploration of genotype-phenotype correlations in Polycystic Kidney Disease (PKD)

  Study EGAS50000001188

• GILD-ExomeSeq-PTNHL

  This study is meant to gain further knowledge in haematological cancers. Patients samples (mainly DNAs or PCR products) from haematolocical cancer patients will be sequenced, and the outputs will be correlated to their diagnosis and/or prognosis; the findings may also add more insight into the understanding of biology in this type of tumour. We will be sequencing Primary Testicular Lymphomas (PTL) to identify genetic drivers of this rare cancer

  Dataset EGAD00001001986

• POT1 splice site mutant analysis

  We are interested in the contribution mutations in the Shelterin complex protein POT1 may have to the development of melanoma. We have identified a patient who carries a splice site mutation in POT1 and as part of our analysis of this gene we aim to sequence the transcriptome of this patient to see how this mutation influences splicing. RNA has been obtained from lymphocytes collected from the patient.

  Dataset EGAD00001000786

• PLCRC study

  Genomic libraries (500 bps) will be generated from total genomic DNA derived from Colorectal cancer patients and subjected to short paired end sequencing on the llumina platform. Paired reads will be mapped to build 37 of the human reference genome to facilitate the generation of genome wide copy number information, and the identification of novel rearranged cancer genes and gene fusions.

  Dataset EGAD00001000947

• Center for Common Disease Genomics [CCDG] - Cardiovascular: Genetic and Phenotypic Determinants of Blood Pressure and Other Cardiovascular Risk Factors

  This study is a part of NHGRI's Center for Common Disease Genomics, which is a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation, congestive heart failure and type 2 diabetes. Atrial fibrillation will affect between 6-12 million individuals in the US by 2050. AF also is associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1. Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules. Source: ccdg.rutgers.edu The GAPP study is an ongoing national population-based prospective cohort study conducted in the Principality of Liechtenstein. Between 2010 and 2014, all inhabitants of Liechtenstein aged 25-41 years old were asked to participate in the study, and 2170 could be enrolled. The aim of the study is to identify the determinants of blood pressure and other cardiovascular risk factors and their progression over time. A large number of baseline characteristics and health information as well as several blood, urinary and genetic markers were collected. The samples were sent to The Broad Institute of MIT and Harvard to generate genetic data using whole exome sequencing and whole genome genotyping (Infinium Global Screening Array); all samples serving as controls.

  Study phs002236

• The genomic complexity of early T-cell progenitor acute lymphoblastic leukemia

  CREST The accurate identification of structural variations using whole-genome DNA sequencing data generated by next-generation sequencing technology is extremely difficult. To address this challenge, we have developed CREST, an algorithm that uses sequencing reads with partial alignments to the reference human genome (so-called soft-clipped reads) to directly map the breakpoints of somatic structural variations. We applied CREST to paired tumor/normal whole genome sequencing data from five cases of T-lineage acute lymphoblastic leukemia (T-ALL). A total of 110 somatic structural variants were identified, >80% of which were validated by genomic PCR and Sanger sequencing. The validated structural variants included 31 inter-chromosomal translocations, 19 intra-chromosomal translocations, one inversion, 22 deletions and 16 insertions. A comparison of the results generated with CREST to those obtained using the traditional paired-end discordant mapping methods demonstrate CREST to have a much higher sensitivity and specificity. In addition, application of CREST to publicly available whole-genome sequencing data from the human melanoma cancer cell line COLO-829 demonstrated the identification of 50 novel structural variations not detected using the standard methods, 20 of which were selected for validation with a 90% success rate. These data demonstrate that direct mapping of soft-clipped reads offers an improved method for detecting structural variants at the nucleotide level of resolution. T-ALL Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

  Study phs000340

• Kids First: Congenital Heart Defects and Laterality Birth Defects

  Laterality defects occur in approximately 1:10,000 newborns and are associated with a range of structural birth defects and abnormalities of organ positioning. Gut malrotation, biliary atresia, asplenia or polysplenia, complex cardiovascular malformations, and midline defects such as neural tube defects, vertebral anomalies and rib fusions are found in various combinations in patients with laterality defects. In addition, a subset of laterality defects caused by abnormalities of cilia position or function are associated with additional medical problems such as chronic sinusitis and bronchiectasis that require specific preventive care; however these patients frequently are undiagnosed until late in disease course. The goal of this project is to elucidate the genetic architecture of laterality disorders in order to inform medical management and risk stratification and to prevent complications. Laterality disorders are genetically heterogeneous and we and others have previously identified single nucleotide variants inherited in an X-linked or autosomal recessive manner as explanations for a minority of cases. In addition, we have demonstrated copy number variants (CNVs) as a mechanism of disease that requires additional investigation. We hypothesize that the majority of cases result from complex genetic inheritance. We propose to investigate this hypothesis using a multifaceted analysis approach in our extremely well phenotyped cohort of 538 probands with laterality disorders. Nested within this cohort are 105 trios who have not had previous sequencing, probands who have had exome sequencing and are excellent candidates for gene discovery via whole genome sequencing (WGS), and families with multiple affected family members for family-based analysis. All trios will be analyzed by transmission disequilibrium test (TDT) including rare variant TDT. De novo mutations will also be identified from trios for potential gene discovery. Using all probands, we will identify the prevalence of pathogenic CNVs. In addition, we will perform burden analyses to identify genes, gene interactions, and pathways important for susceptibility to laterality disorders. Finally, our rare families with multiple affected members will be studied using family based segregation analysis. This comprehensive genetic analysis in patients with laterality disorders is necessary to identify the appropriate clinical diagnostic testing for risk stratification, to elucidate underlying genetic architecture and facilitate novel gene discovery, and to provide essential knowledge about genes and pathways impacting the development of laterality disorders.

  Study phs002589

• Effect of Crohn's Disease Risk Alleles on Enteric Microbiota

  This UH2/UH3 demonstration project entitled "Effects of Crohn's disease risk alleles on enteric microbiota" is focused on characterizing intestinal associated microbiota in patients with ileal Crohn's disease (ileal CD), ulcerative colitis (UC) and control patients without inflammatory bowel diseases (non-IBD). We hypothesize that genetic factors that affect Paneth cell function, contribute to compositional changes in intestinal microbiota. These changes in microbiota may lead to reduction of protective commensal organisms and increased numbers of aggressive organisms that incite intestinal inflammation. This hypothesis is being tested by high throughput 16S rRNA sequence analysis of de-identified ileal and colonic tissues that have been archived at Washington University St. Louis, University of North Carolina, Mount Sinai Hospital and the Cleveland Clinic. Multivariate analysis of the metagenomic data will be conducted with genotyping metadata (highly reproducible CD risk alleles, including NOD2 and ATG16L1) and phenotyping metadata (e.g. age, gender, race, body mass index, medications and smoking.) Shotgun sequencing will be performed on selected fecal specimens linked to ileal tissues to identify additional, or auxiliary, or synergistic pathogenic factors or other functional changes in the microbiome. Because members of this research team have observed that a chronic viral infection is required for the Paneth cell defect in Atg16l1 hypomorphic mice, a major focus of these studies will be towards identifying potential viral triggers for the defective Paneth cell phenotype in individuals harboring the ATG16L1 risk allele. Novel genetic probes for protective and aggressive organisms will be developed by mining bacterial genome and shotgun sequencing data. Genomic sequences will be produced for candidate protective and aggressive strains (e.g. adherent-invasive strains of E. coli) isolated from human intestinal tissues where there is limited existing genome information. Quantitative qPCR assays using the novel as well as established genetic probes will be conducted to test the hypothesis that an imbalance between protective and aggressive organisms is associated with genetic factors that affect Paneth cell function. Our combined expertise in multiple disciplines across multiple institutions, our demonstrated ability to collect a large number of well-phenotyped samples with longitudinal clinical information that will be linked to host response and morphologic studies, and our consortium's capacity for high-throughput sequencing will be used to investigate how alterations in human microbiome relate to CD risk alleles and CD pathogenesis.

  Study phs000255

• Phase II Study of Cryoablation and Post-Progression Immune Checkpoint Inhibition in Metastatic Melanoma

  Percutaneous cryoablation guided by imaging is a well-established, minimally invasive treatment for oncological conditions. We posited that cryoablation could alter the immune microenvironment by directly influencing the tumor, potentially eliciting an anti-tumor response in cases resistant to immune checkpoint inhibition (ICI). In this non-randomized phase II single-center study (NCT03290677), individuals with unresectable melanoma experiencing progression on ICI underwent cryoablation in a single progressing metastasis, while ICI was continued for at least two additional cycles. The main objectives were to assess safety and feasibility and to evaluate tumor response in non-ablated lesions. Between May 2018 and July 2020, 17 patients participated in the study. The treatment regimen proved safe, revealing an objective response rate of 23.5% and a disease control rate of 41% (comprising 4 partial responses and 3 stable diseases). In our investigation into the factors influencing response to cryoablation therapy in ICI-resistant melanoma, we conducted single-cell RNA sequencing (scRNA-seq) using both 10x Genomics and Smart-seq2 technologies on biopsies from metastatic sites of 15 patients. We collected pre-treatment samples from all patients and post-treatment samples from 5 patients, totaling 20 samples. After quality control, excluding cells specific to anatomical sites or rare cell types (e.g., alveolar type II, neurons), and batch correction, we analyzed 49,071 single cells spanning melanocyte, endothelial, stromal, T, myeloid, and B/plasma cell lineages. Differential gene expression (DGE) analysis between myeloid cells identified the genes MARCKS and IL10, two genes involved in anti-inflammatory responses that can inhibit macrophages activation to be associated with failed response. Moreover, DGE analysis of T cells identified the gene TXK, which acts as a Th1 transcription factor, and the gene CMKLR1 (chemerin-like-receptor-1), which triggers migration of CD8 T-cells to be upregulated in patients who benefited from cryoablation treatment. In contrast, MTHFD2 and GGH, two genes involved in one-carbon metabolism and the folate cycle, were upregulated in T cells from patients who did not respond to therapy. Our analysis revealed a significant increase in B/plasma cells in patients who responded positively to the therapy combination, along with an enrichment of oxidative phosphorylation in T cells among non-responsive patients with progressive disease. These findings advocate for further investigation into this innovative and synergistic therapeutic approach.

  Study phs003579

• Whole Blood Transcriptomics of Patients With Melioidosis

  Melioidosis is a neglected tropical infection caused by the Gram negative bacterium Burkholderia pseudomallei that is associated with high mortality rates in southeast Asia. The goal of this study was to a) identify human blood leukocyte transcriptomic features and pathways specific to melioidosis (vs other etiologies of infection), b) identify transcriptomic features and pathways specific to fatal melioidosis, and c) identify transcriptomic predictors of death in patients with melioidosis. This study used clinical data and whole blood leukocyte samples from a subset of participants in the Ubon Sepsis Study, a prospective single-center cohort study conducted at Sunpasitthiprasong Hospital, Ubon Ratchathani, Thailand between 2013 and 2017. Participants in the Ubon Sepsis Study had suspected or documented infection with accompanying systemic manifestations of infection and were enrolled, with blood sampling, within 24 hours of admission to the study hospital. Enrolled patients were followed over time and vital status was determined at 28 days after enrollment. The subset of participants from the parent Ubon Sepsis Study cohort selected for this study was comprised of 164 patients with melioidosis (defined as having a culture of clinical sample positive for B. pseudomallei), 35 patients with Gram negative bacteremia due to either Escherichia coli or Klebsiella pneumoniae, 16 patients with Gram positive bacteremia due to Staphylococcus aureus, and 19 patients who had negative blood cultures and no clinical sample culture-positive for B. pseudomallei. Fifty uninfected control patients with or without diabetes were recruited from the outpatient department and blood donation center at Udon Thani hospital, Udon Thani, Thailand from 2018 to 2019. Blood was collected at the time of enrollment in Tempus Blood RNA tubes. RNA was extracted using the Tempus Spin RNA Isolation kit. RNA sequencing (RNA-Seq) was performed at the University of Washington Northwest Genomics Center. Analysis was performed using a variety of statistical methods. The main finding of the study was that the transcriptomes of melioidosis patients, compared to patients with other infections, were characterized by upregulation of interferon signaling. The transcriptomes of patients with fatal melioidosis were notable for upregulation of inflammatory and type 2 immune responses and downregulation of genes related to T-cell function. A five-gene (EPHB1, SYCP2L, MERTK, IL5RA, and SPOCK1) predictive signature for death in melioidosis was developed.

  Study phs003724

• Multiple_myeloma_precursor_genomics

  Whole genome sequencing of up to 45 multiple myeloma precursor samples and matched normals pairs.

  Study EGAS00001006312

• OAC RNASeq

  Please see our related publication, 'Molecular profiling to predict immunochemotherapy outcomes in esophageal adenocarcinoma'

  Study EGAS00001006468

• Molecular Tumor Board to Inform on Personalized Medicine for a Man with Advanced Prostate Cancer

  Purpose: Molecular profiling of cancer is increasingly common as part of routine care in oncology, and germline and somatic profiling may provide insights and actionable targets for men with metastatic prostate cancer. However, all reported cases are of deidentified individuals without full medical and genomic data available in the public domain. Patient and Methods: We present a case of whole genome tumor and germline sequencing in a patient with advanced prostate cancer, who has agreed to make his genomic and clinical data publicly available in an accompanying personal testimonial. Results: We describe an 84-year-old Caucasian male with a Gleason 10 oligometastastic hormone-sensitive prostate cancer. Whole-genome sequencing provided insights into his tumor’s underlying mutational processes and the development of an SPOP mutation. It also revealed an androgen-receptor dependency of his cancer which was reflected in his durable response to radiation and hormonal therapy. Potentially actionable genomic lesions in the tumor were identified through a personalized medicine approach for potential future therapy, but at the moment, he remains in remission, illustrating the hormonal sensitivity of his SPOP-driven prostate cancer. We also placed this patient in the context of a large prostate-cancer cohort from the PCAWG (Pan-cancer Analysis of Whole Genomes) group. In this comparison, the patient's cancer appears typical in terms of the number and type of somatic mutations, but it has a somewhat larger contribution from the mutational process associated with aging. Conclusion: We combined the expertise of medical oncology and genomics approaches to develop a molecular tumor board to integrate the care and study of this patient, who continues to have an outstanding response to his combined modality treatment. This identifiable case potentially helps overcome barriers to clinical and genomic data sharing.

  Study EGAS00001004648

• Deep single-cell RNA sequencing data for 11138 T cells from tumour, adjacent normal tissue and peripheral blood of treatment-naive CRC patients. The DATA ACCESS AGREEMENT is provided at https://github.com/zhangyybio/single-T-cell-data-access. Applicants can request access to the data by directly downloading it or by sending an email to cancerpku@pku.edu.cn. The process that is used to approve an application includes verifying the institution, participants and research purposes of the application. In general this process will take about two weeks. In principal, any scientific research program complying with the laws and bioethic regulation policies of China will be approved.

  T cells are central players in cancer immunotherapy1, yet some of their fundamental properties such as development and migration within tumours remain elusive. The enormous T cell receptor (TCR) repertoire, required for recognising foreign and self-antigens2,3, could serve as lineage tags to track these T cells in tumours4. Here, we obtained transcriptomes of 11,138 single T cells from 12 colorectal cancer (CRC) patients and developed STARTRAC (Single T-cell Analysis by Rna-seq and Tcr TRACking) indices to quantitatively analyse dynamic relationships among 20 identified T cell subsets with distinct functions and clonalities. While both CD8+ effector and “exhausted” T cells exhibited high clonal expansion, they were independently connected with tumour-resident CD8+ effector memory cells, implicating a TCR-based fate decision. Of the CD4+ T cells, the majority of tumour-infiltrating Tregs showed clonal exclusivity, whereas certain Treg clones were developmentally linked to multiple TH clones. Notably, we identified two IFNG+ TH1-like clusters in tumours, the GZMK+ TEM and CXCL13+ TH1-like clusters, which were associated with distinct IFN-γ-regulating transcription factors, EOMES/RUNX3 and BHLHE40, respectively. Only CXCL13+BHLHE40+ TH1-like cells were preferentially enriched in tumours of microsatellite-instable (MSI) patients, which might explain their favourable response rates to immune-checkpoint blockade. Furthermore, we found IGFLR1 to be highly expressed in both CXCL13+BHLHE40+ TH1-like and CD8+ exhausted T cells and possessed co-stimulatory functions. Our integrated STARTRAC analyses provides a powerful avenue to comprehensively dissect the T cell properties in CRC, which could shed new insights into the dynamic relationships of T cells in other cancers

  Study EGAS00001002791

• Nanopore sequencing enables allelic phasing of FLG loss-of-function variants, intragenic copy number variation and methylation status in atopic dermatitis and ichthyosis vulgaris

  Loss-of-function (LoF) variants in the FLG gene are associated with ichthyosis vulgaris (IV) and atopic dermatitis (AD). IV and AD patients with two FLG LoF variants are reported to have a more severe disease course. However, subsets of compound heterozygous patients display phenotypic heterogeneity despite a prediction of a severe phenotype from their genotype. The underlying genetic mechanism of this phenotypic variability is unknown. One possibility is that two LoF FLG variants could be located in cis (on the same allele), thus altering the predicted gene dosage. To investigate the allelic contribution of compound heterozygous FLG LoF mutations to IV phenotypic variability, we employ long reads from Oxford Nanopore Technologies, utilising two methodologies to phase the entire coding region of FLG into parental alleles: an amplicon-sequencing approach and an adaptive-sampling strategy. We investigated the allelic phasing of FLG LoF variants and intragenic-repeat copy-number variations (CNV) of 21 subjects with known compound heterozygous genotypes and mixed IV severity. Our results suggest that IV severity is not linked to the presence of cis variants in our IV patient cohort. Nanopore reads enabled detection and accurate phasing of CNVs and LoF variants into parental alleles, providing a framework for future in-depth genetic analysis. These results highlight the usefulness of utilising long reads for interrogating the FLG gene and other highly repetitive genes for genetic stratification related to clinical phenotypes.

  Study EGAS50000000166

• Characterizing the Role of the Immune Microenvironment in Multiple Myeloma Progression at a Single Cell Level

  The plasma cell disease multiple myeloma (MM) is highly dependent on its bone marrow microenvironment (BMME). Early alterations within the bone marrow microenvironment that contribute to the progression of multiple myeloma (MM) from its precursor stages could hold the key to identifying novel therapeutic approaches, yet the intrinsic variability in cellular populations between patients together with differences in sample processing and analysis methods have made it difficult to identify consistent changes between datasets. Here, we used single-cell RNA sequencing of BM cells from precursor stages, monoclonal gammopathy of unknown significance (MGUS), smoldering MM (SMM) and newly diagnosed MM and analyzed our data in combination with a previously published dataset that used a similar patient population and sample processing. Despite vast interpatient heterogeneity, some alterations were seen consistently in both datasets. We identified changes in immune cell populations as disease progressed that were characterized by a substantial decrease in memory and naïve CD4 T cells and an increase in CD8+ effector T cells and T-regulatory cells. These alterations were further accompanied by an enrichment of non-clonal memory B cells and an increase of CD14 and CD16 monocytes in MM compared to its precursor stages. These results provide crucial information of the immune changes associated with the progression to clinical MM and can help to develop immune based strategies for patient stratification and early therapeutic intervention. 

  Study phs002756

• Cell-Free, Methylated DNA in Blood Samples Reveals Tissue-Specific, Cellular Damage from Radiation Treatment

  Radiation therapy is an effective cancer treatment, although damage to surrounding healthy tissues can also occur. Cell-type specific DNA methylation patterns can be used to decode the cellular origins of cell-free DNA fragments, allowing for minimally-invasive monitoring of tissue damage. To evaluate whether changes in cell-free DNA methylation can indicate damages to tissues in patients treated with radiation, we collected serum samples from 15 breast cancer patients at three timepoints during their standard-of-care radiation therapy after surgery. A baseline sample was taken for each patient before onset of radiation therapy and a second End-Of-Treatment (EOT) sample was taken 30 minutes after the last treatment fraction. Finally, a recovery sample was taken one month after completion of radiation therapy. From serum samples, cell-free DNA was isolated and bisulfite capture-sequencing DNA methylation data were generated. Bisulfite capture-sequencing DNA methylation data were also generated from buffy coat and tissue-specific endothelial gDNA samples as well as from serum/plasma samples of healthy controls. The analysis of serum samples from breast cancer patients undergoing radiation treatment revealed distinct tissue-specific epithelial and endothelial responses to radiation across multiple organs. In conclusion, as a proof of concept we show that cell-type specific methylation signatures can be applied to detect cellular injury from radiation treatment using minimally invasive cell-free DNA in blood samples.

  Study phs003290

• RNA-Sequencing of B-Lymphoblastic Leukemia with Glucocorticoids and PI3K Delta Inhibition

  Mononuclear cells were isolated from bone marrow or peripheral blood of 7 pediatric subjects with B-lymphoblastic leukemia at the time of diagnosis. To determine the effect of PI3K delta inhibition on glucocorticoid-induced gene regulation, B-lymphoblastic leukemia cells were treated with glucocorticoids +/- the PI3K delta inhibitor, idelalisib, for 24 hours prior to RNA extraction and sequencing. Biological replicates were performed for 4 of the 7 subjects; 2 of these subjects had specimens demonstrating an additive response to the combination of glucocorticoids and idelalisib in viability testing in vitro, and 2 subjects' specimens demonstrated a synergistic response. All 7 subjects were analyzed together and the 4 specimens with biological replicates were also evaluated in an additional analysis. An average of 40 million reads per specimen and treatment condition were obtained. We compared gene expression in each treatment condition to vehicle-treated cells and expression in glucocorticoid or idelalisib only treated cells to combination treated cells. Using a high dose of dexamethasone (25 or 50 nM) and an equivalent dose of prednisolone, we found that the addition of idelalisib (500 nM) enhanced prednisolone-induced gene regulation but not dexamethasone-induced gene regulation. Surprisingly, the specimens with additive response to combination therapy demonstrated enhancement of prednisolone-induced gene regulation with the addition of idelalisib, while the specimens with synergistic responses did not. Raw sequencing data (FASTQ) and count tables will be available through dbGaP.

  Study phs003085

• Systems genetics in human endothelial cells identifies non-coding variants modifying enhancers, expression, and complex disease traits

  Identification of causal variants and mechanisms underlying complex disease traits in humans requires strategies to locate and fine-map functional regulatory variants in disease-relevant cell types. To discover functional regulatory variants in primary aortic endothelial cells (ECs) from humans, we collected genetic, transcriptomic, and four epigenomic phenotypes in a population of 153 human donors representing individuals of both sexes and three major ancestries. We found thousands of EC eQTLs that were not present in GTEx at all ranges of effect sizes, indicating novel functional variants not observable from tissue data. We performed several epigenetic assays across 53 donors' EC to enable molecular QTL mapping, which included chromatin accessibility, histone modification, and transcription factor binding of proteins ERG and NF-kB/p65 in two activation states. We discovered over 3000 regulatory elements where cis-regulatory variants associated to significant differences in epigenetic marks. Co-localization with our eQTLs, TF motif mutations, and 3D confirmation capture data in ECs enabled our discovery of hundreds of high-confidence functional regulatory elements that perturb endothelial molecular phenotypes. Furthermore, this set of variants is enriched at GWAS loci for Coronary Artery disease and other disease traits, with some SNPs demonstrating pleiotropic effects. Together, our dataset and analytical approach provide the genetics and vascular biology communities with specific variants affecting EC biology and serves as a proof-of-principle for how to detect functional regulatory variants in human cells with relevance to complex traits.

  Study phs002057

• Gabriella Miller Kids First Pediatric Research Program in Craniofacial Microsomia

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Craniofacial microsomia (CFM), also termed hemifacial microsomia or oculo-auricular-vertebral spectrum, is the third most common congenital craniofacial condition. CFM comprises a variable phenotype and the most common features include malformations of the ear (i.e. microtia) and lower jaw (i.e. mandibular hypoplasia) on one or both sides. Microtia in the absence of other anomalies is believed to represent the mildest form of CFM. The cause of CFM is unknown for most affected individuals. We have established a cohort through previous studies and collected DNA to identify the genetic contributions to CFM, which could facilitate diagnosis, tailored treatments and guide prevention strategies. Successful completion of this proposal will advance knowledge in the genetic architecture of susceptibility to CFM and will provide insight about the biological mechanisms underlying craniofacial development. The results from this study have the potential to further research on the etiology of other craniofacial conditions, and the pathogenesis of typical and atypical craniofacial development.

  Study phs002130

• A New Pipeline to Predict and Confirm Tumor Neoantigens Predicts Better Response to Checkpoint Blockade

  Mutations that drive oncogenesis in cancer can generate neoantigens that may be recognized by the immune system. Identification of these neoantigens remains challenging due to the complexity of the major histocompatibility complex (MHC) antigen and T-cell receptor interaction. Here we describe the development of a systematic approach to efficiently identify and validate immunogenic neoantigens. Whole exome sequencing of tissue from a melanoma patient was used to identify nonsynonymous mutations, followed by MHC binding prediction and identification of tumor clonal architecture. The top 18 putative class I neoantigens were selected for immunogenicity testing via a novel in vitro pipeline in HLA-A201 healthy donor blood. Naive CD8 T cells from donors were stimulated with allogeneic dendritic cells pulsed with peptide pools and then with individual peptides. The presence of antigen-specific T cells was determined via functional assays. We identified one putative neoantigen that expanded T cells specific to the mutant form of the peptide and validated this pipeline in a subset of patients with bladder tumors treated with durvalumab (N = 5). Within this cohort, the top predicted neoantigens from all patients were immunogenic in vitro. Finally, we looked at overall survival in the whole durvalumab-treated bladder cohort (N = 37) by stratifying patients by tertile measure of tumor mutation burden (TMB) or neoantigen load. Patients with higher neoantigen and TMB load tended to show better overall survival.

  Study phs002269

• Trisomy 21 Dosage Compensation Map (T21DoCoMap)

  Excess gene dosage from human chromosome 21 (HSA21), due to trisomy or translocation of HSA21 material, causes Down syndrome (DS). We derived trisomy 21 (T21) induced pluripotent stem cells (iPSCs) alongside otherwise isogenic euploid controls from mosaic DS fibroblasts (GM00260, first described in Lubiniecki et al., PMID: 225951) of the NIGMS genetic cell repository, to enable analysis of whole-chromosomal and individual gene dosage imbalance in the context of in vitro models of DS development. Virtual karyotyping (by Infinium CytoSNP-850k), and phased genotyping (by linked-read whole-genome sequencing) of the resulting iPSC lines provide a deeply-characterized genomic platform for dissection of HSA21 gene dosage. We apply this highly unique resource to allelic analysis of mRNA sequencing of iPSCs and differentiated neural lineages, and demonstrate its utility in the context of inducible HSA21 dosage compensation. To this end, we equipped one distinct HSA21 copy with a doxycycline-inducible XIST transgene, which endogenously silences one X in 46,XX females. Standard and allele-specific RNA-seq analysis confirms mono-allelic T21 silencing to be virtually complete and irreversible, further supported by DNA methylation data (Infinium methylEPIC). This full-length HSA21 map of phased single-nucleotide and insertion/deletion variants enables allele-specific applications for gene-level dissection T21 dosage effects. Because our XIST remains inducible in post-mitotic T21 neurons and astrocytes, we perform single-nuclei RNA-seq to demonstrate XIST efficiently represses genes even after terminal differentiation.

  Study phs002397

• Spatio-temporal Profiling of a Rhabdoid Tumor Case Study

  Background Immune checkpoint inhibition (ICI) has revolutionized oncology, offering extended survival and long-term remission in previously incurable cancers. While highly effective in tumors with high mutational burden, lowly mutated cancers, including pediatric malignancies, present low response rate and limited predictive biomarkers. Patients and methods We present a framework for the identification and validation of tumor-reactive T cells as a biomarker to quantify ICI efficacy and as candidates for a personalized TCR-T cell therapy. Therefore, we profiled a pediatric malignant rhabdoid tumor patient with complete remission after ICI therapy using deep single-cell T cell receptor (TCR) repertoire sequencing of the tumor microenvironment (TME) and the peripheral blood. Results Tracking T cell dynamics longitudinally from the tumor to cells in circulation over a time course of 12 months revealed a systemic response and durable clonal expansion of tumor-resident and ICI-induced TCR clonotypes. We functionally validated tumor reactivity of TCRs identified from the TME and the blood by co-culturing patient-derived tumor cells with TCR-engineered autologous T cells. Here, we observed unexpectedly high frequencies of tumor-reactive TCR clonotypes in the TME and confirmed T cell dynamics in the blood post-ICI to predict tumor-reactivity. Conclusion These findings strongly support spatio-temporal tracking of T cell activity in response to ICI to inform therapy efficacy and to serve as a source of tumor-reactive TCRs for personalized TCR-T designs.

  Study EGAS00001008174

• Massively parallel nanowell-based single-cell gene expression profiling

  Technological advances have enabled transcriptome characterization of cell types at the single-cell level providing new biological insights. New methods that enable simple yet high-throughput single-cell expression profiling are highly desirable. Here we report a novel nanowell-based single-cell RNA sequencing system, ICELL8, which enables processing of thousands of cells per sample. The system employs a 5184-nanowell-containing microchip to capture ~1300 single cells and process them. Each nanowell contains preprinted oligonucleotides encoding poly-d(T), a unique well barcode, and a unique molecular identifier. The ICELL8 system uses imaging software to identify nanowells containing viable single cells and only wells with single cells are processed into sequencing libraries. Here, we report the performance and utility of ICELL8 using samples of increasing complexity from cultured cells to mouse solid tissue samples. Our assessment of the system to discriminate between mixed human and mouse cells showed that ICELL8 has a low cell multiplet rate (< 3%) and low cross-cell contamination. We characterized single-cell transcriptomes of more than a thousand cultured human and mouse cells as well as 468 mouse pancreatic islets cells. We were able to identify distinct cell types in pancreatic islets, including alpha, beta, delta and gamma cells. Overall, ICELL8 provides efficient and cost-effective single-cell expression profiling of thousands of cells, allowing researchers to decipher single-cell transcriptomes within complex biological samples.

  Study EGAS00001002320

• A no-stop mutation in MAGEB4 is a possible cause of rare X-linked azoospermia and oligozoospermia in a consanguineous Turkish family

  Purpose: The purpose of this study was to identify mutations that cause non-syndromic male infertility using whole exome sequencing of family cases.Methods: We recruited a consanguineous Turkish family comprising nine siblings with male triplets; two of the triplets were infertile as well as one younger infertile brother. Whole exome sequencing (WES) performed on two azoospermic brothers, identified a mutation in the MAGEB4 gene which was confirmed via Sanger sequencing and then screened for on control groups and unrelated infertile subjects. The effect of the mutation on mRNA and protein levels were tested after in vitro cell transfection. Structural features of MAGEB4 were predicted throughout the conserved MAGE domain.Results: The novel single base substitution (c.1041A>T) in the X-linked MAGEB4 gene was identified as a no-stop mutation. The mutation is predicted to add 24 amino acids to the C-terminus of MAGEB4. Our functional studies were unable to detect any effect either on mRNA stability, intracellular localization of the protein or the ability to homo / heterodimerize with other MAGE proteins. We thus hypothesize that these additional amino acids may affect the proper protein interactions with MAGEB4 partners. Conclusion: The whole exome analysis of a consanguineous Turkish family revealed MAGEB4 as a possible new X-linked cause of inherited male infertility. This study provides the first clue to the physiological function of a MAGE protein.

  Study EGAS00001002272

• UK10K COHORT TWINSUK

  The UK10K project proposes 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 directly analyse 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 TwinsUK samples will be part of the cohort study and will undergo whole genome sequencing. For further information with regard to this cohort please contact Brent Richards (brent.richards@kcl.ac.uk) or Nicole Soranzo (ns6@sanger.ac.uk).

  Study EGAS00001000108

• UK10K NEURO ASD BIONED

  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 BioNED (Biomarkers for Childhood onset neuropsychiatric disorders) study has been carrying out detailed phenotypic assessments evaluating children with an autism spectrum disorder. These assessments included ADI-R, ADOS, neuropsychology, EEG etc. There are 56 DNA samples from this study (25 extracted from blood). For further information with regard to this cohort please contact Patrick Bolton (patrick.bolton@kcl.ac.uk).

  Study EGAS00001000111

• RRBS sequencing of 7 tumour regions and a normal sample from a single TRACERx patient.

  Background: Epigenetic heterogeneity within a tumour can play an important role in tumour evolution and the emergence of resistance to treatment. It is increasingly recognised that the study of DNA methylation (DNAm) patterns along the genome - so-called `epialleles' - offers greater insight into epigenetic dynamics than conventional analyses which examine DNAm marks individually. Results: We have developed a Bayesian model to infer which epialleles are present in multiple regions of the same tumour. We apply our method to reduced representation bisulfite sequencing (RRBS) data from multiple regions of one lung cancer tumour and a matched normal sample. The model borrows information from all tumour regions to leverage greater statistical power. The total number of epialleles, the epiallele DNAm patterns, and a noise hyperparameter are all automatically inferred from the data. Uncertainty as to which epiallele an observed sequencing read originated from is explicitly incorporated by marginalising over the appropriate posterior densities. The degree to which tumour samples are contaminated with normal tissue can be estimated and corrected for. By tracing the distribution of epialleles throughout the tumour we can infer the phylogenetic history of the tumour, identify epialleles that differ between normal and cancer tissue, and define a measure of global epigenetic disorder. Conclusions: Detection and comparison of epialleles within multiple tumour regions enables phylogenetic analyses, identification of differentially expressed epialleles, and provides a measure of epigenetic heterogeneity.

  Study EGAS00001002484

• Partner-independent fusion gene detection by multiplexed CRISPR/Cas9 enrichment and long-read Nanopore sequencing

  Fusion genes are hallmarks of various cancer types and important determinants for diagnosis, prognosis and treatment possibilities. The promiscuity of fusion genes with respect to partner choice and exact breakpoint-positions restricts their detection in the diagnostic setting, even for known and recurrent fusion gene configurations. To accurately identify these gene fusions in an unbiased manner, we developed FUDGE: a FUsion gene Detection assay from Gene Enrichment. FUDGE couples target-selected and strand-specific CRISPR/Cas9 activity for enrichment and detection of fusion gene drivers (e.g. BRAF, EWSR1, KMT2A/MLL) - without prior knowledge of fusion partner or breakpoint-location - to long-read Nanopore sequencing. FUDGE encompasses a dedicated bioinformatics approach (NanoFG) to detect fusion genes from Nanopore sequencing data. Our strategy is flexible with respect to target choice and enables multiplexed enrichment for simultaneous analysis of several genes in multiple samples in a single sequencing run. We observe on average a 508-fold on-target enrichment and identify fusion breakpoints at nucleotide resolution - all within two days. We demonstrate that FUDGE effectively identifies fusion genes in cancer cell lines, tumor samples and on whole genome amplified DNA irrespective of partner gene or breakpoint-position in 100% of cases. Furthermore, we show that FUDGE is superior to routine diagnostic methods for fusion gene detection. In summary, we have developed a rapid and versatile fusion gene detection assay, providing an unparalleled opportunity for pan-cancer detection of fusion genes in routine diagnostics.

  Study EGAS00001003964

• Mutational Signature and Transcriptomic Classification Analyses as the Decisive Diagnostic Tools for a Cancer of Unknown Primary with Neuroendocrine Differentiation

  PURPOSE: Cancer of unknown primary (CUP) is a group of metastatic tumors in which the standard diagnostic work-up fails to identify the site of origin of the tumor. The potential impact of precision oncology on this group of patients is large since their tumors might have actionable driver mutations that can provide treatment options otherwise not available for patients with these fatal cancers. This study investigated if comprehensive genomics analyses could inform on the origin of the tumor. PATIENT AND METHODS: Here we describe a patient whose tumor was misdiagnosed at least three times. Next-generation sequencing, a PDX mouse model and bioinformatics was used to identify an actionable mutation, predict resistance development to the targeted therapy, and to correctly diagnose the origin of the tumor. The Cancer Genome Atlas was used to benchmark the bioinformatics workflow. RESULTS: Despite the lack of a known primary tumor site and the absence of diagnostic immunohistochemical markers, the origin of the patient's tumor was established using the novel bioinformatics workflow. This included a mutational signature analysis of the sequenced metastases and comparison of their transcriptomic profiles to a pan-cancer panel of tumors from The Cancer Genome Atlas. We further discuss the strengths and limitations of the latter approaches in the context of three potentially incorrectly diagnosed TCGA lung tumors. CONCLUSION: Comprehensive genomics analyses could inform on the origin of tumors in patients suffering from CUP.

  Study EGAS00001003026

• Disease and phenotype relevant genetic variants identified from histone acetylomes in human hearts

  Identifying genetic markers for heterogeneous complex diseases such as heart failure has been challenging, and may require prohibitively large cohort sizes in genome-wide association studies (GWAS) in order to demonstrate statistical significance1. On the other hand, chromatin quantitative trait loci (QTL), elucidated by direct epigenetic profiling of specific human tissues, may contribute towards prioritising variants for disease-association. Here, we captured non-coding genetic variants by performing enhancer H3K27ac ChIP-seq in 70 human control and end-stage failing hearts, mapping out a comprehensive catalogue of 47,321 putative human heart enhancers. 3,897 differential acetylation peaks (FDR < 0.05) pointed to recognizable pathways altered in heart failure (HF). To identify cardiac histone acetylation QTLs (haQTLs), we regressed out confounding factors including HF disease status, and employed the G-SCI test2 to call out 1,680 haQTLs (FDR < 0.1). A subset of these showed significant association to gene expression, either in cis (180), or through long range interactions (81), identified by Hi-C and Hi-ChIP performed on a subset of hearts. Furthermore, a concordant relationship was found between the gain or disruption of specific transcription factor (TF) binding motifs, inferred from alternative alleles at the haQTLs, associated with altered H3K27ac peak heights. Finally, colocalisation of our haQTLs with heart-related GWAS datasets allowed us to identify 62 unique loci. Disease-association for these new loci may indeed be mediated through modification of H3K27-acetylation enrichment and their corresponding gene expression differences.

  Study EGAS00001003586

• Analysis of Papilloma Infiltrating T cells from an Exceptional Responder to Immunotherapy

  This data corresponds to single cell RNA-seq data of TIL from a young woman with recurrent respiratory papillomatosis who was treated with PD-L1 blockade and experienced durable disease control over a 4+ year period. A HPV6 E2-specific, HLA-B*55 restricted TCR was identified and shown to be present in both the immediate post treatment and 4 year TIL, with a gene expression profile indicative of being a tissue resident memory T cell. 

  Study phs002826

• Evolution of Chronic Lymphocytic Leukemia to Richter's Syndrome (RS)

  Richter's syndrome arising from chronic lymphocytic leukemia is a striking example of an aggressive malignant histology that emerges from indolent cancer. To understand this process, we reconstructed phylogenies based on whole exome sequencing of matched normal, CLL and RS samples. We computationally deconvoluted CLL and RS clones and identified drivers of transformation. We additionally performed whole genome sequencing, whole transcriptome sequencing and single-cell transcriptome sequencing to understand the mutational signatures, genome-wide events and gene expression changes associated with transformation.

  Study phs002458

• Genomic Data Access Committee for Early and Late Onset Colorectal Cancer Study

  This Data Access Committee (DAC) manages access to genomic data generated from the study "A Clinically and Genomically Annotated Early Onset Colorectal Cancer and Late Onset Colorectal Cancer." The study focuses on identifying the distinct genomic profiles of early-onset colorectal cancer (EOCRC) compared to late-onset colorectal cancer (LOCRC) through whole-genome sequencing (WGS) of both tissue and blood samples. The DAC is responsible for reviewing and approving access requests from researchers who wish to utilize this data for non-commercial, academic purposes related to colorectal cancer research. The committee ensures that all data access is granted in compliance with ethical standards and that the data is used solely for the approved research objectives. Researchers requesting access to this data must provide a detailed research proposal, institutional review board (IRB) approval, and demonstrate relevant expertise in genomic research. All data will be stored in secure, encrypted environments, and any further sharing or use of the data requires additional DAC approval.

  Dac EGAC50000000359

• Observational studies using advanced analytical techniques to understand the biological functions of kidney component cells

  The purpose of this study is to establish a foundation for understanding the functions of kidney component cells and the biology of renal disease. Single cell and spatial transcriptome analyses of human kidney component cells will be performed to analyze the gene expression profiles of those cells and explore their relationship between the gene expression profiles and clinical parameters. The research foundation established here is worthwhile for understanding disease mechanisms in the kidney or discovering novel therapeutic drugs for renal disease.

  Study JGAS000736

• RNA sequencing of CD8 T cells from melanoma patients prior to and during checkpoint immunotherapy and untreated healthy controls

  We are interested in inter-individual variation in transcriptional response to immune checkpoint blockade. We have analysed poly A purified RNA expression from CD8 T cells (297 transcriptomes in total) isolated from metastatic melanoma patients (n=106) prior to and during treatment with either single agent (Pembrolizumab) or combination (Ipilimumab/ Nivolumab) immune checkpoint blockade. We compare expression at different stages of treatment and additionally contrast this with that from healthy controls (n=68).

  Study EGAS00001004081

• Investigating genetic susceptibility to rheumatic heart disease in Oceania

  This case-control study investigated susceptibility to rheumatic heart disease in over 3,000 individuals recruited across eight Oceanian countries. Cases were patients with rheumatic heart disease and controls were members of the general population. In addition to the Illumina HumanCore-24 BeadChip genotyping, a subset of 128 samples were analysed using the higher density Illumina HumanOmniExpressExome BeadChip of which 64 were also analysed using low coverage sequencing with the Illumina HiSeq 4000 platform.

  Study EGAS00001001881

• The mutational landscape of human somatic and germline cells

  During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

  Dataset EGAD00001006643

• The mutational landscape of human somatic and germline cells

  During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

  Dataset EGAD00001006642

• Lung cancer organoids addition

  Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here we describe a method to establish long-term culture conditions of human airway epithelial organoids that contain all major cell populations and allow personalized human disease modelling. We collected macroscopically inconspicuous lung tissue from non-small-cell lung cancer (NSCLC) patients undergoing medically indicated surgery and isolated epithelial cells to engineer 3D organoids. We exploit the potential to derive sub-clones from AOs to demonstrate the feasibility of CRISPR gene editing. Finally, we show that AOs readily allow modelling of viral infections such as RSV and for the first time demonstrate the possibility to study neutrophil-epithelium interaction in an organoid model. Taken together, we anticipate that human AOs will find broad applications in the study of adult human airway epithelium in health and disease.

  Dataset EGAD00001004943

• Genetics of gene expression in human macrophage response to Salmonella

  Understanding how cells sense and respond to their environment, and how these responses are modulated by genetic variation, are fundamental biological problems, particularly for understanding how pathogenic organisms invade and manipulate the cells of the human immune system. Macrophages recognize and respond to many important human pathogens including HIV-1, Mycobacteria tuberculosis and Salmonella. This study will focus on the cellular response of human macrophages to Salmonella infection and how this response is modulated by the genetic bacground of the individual as well as additional pro-inflammatory stimulus (interferon-gamma priming). We will acquire 100 human induced pluripotent stem cell lines from the HipSci project, differentiate the cells in vitro into macrophages and expose them to four environmental conditions: (i) no stimulation, (ii) interferon-gamma (18h), (iii) Salmonella typhimurium SL1344 (5h), (iv) interferon-gamma (18h) + Salmonella (5h).Subsequently, we will isolate RNA from the samples for sequencing.

  Dataset EGAD00001003204