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• A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma

  Osteosarcoma is the most common primary bone cancer. It can be cured by aggressive surgery and chemotherapy, but outcomes for metastatic or chemoresistant disease remain dismal. Cancer sequencing studies have shown that the p53 pathway is dysregulated in nearly every case, often by translocation; however, no studies of osteosarcoma evolution or intratumor heterogeneity have been done to date. We studied a patient with chemoresistant, metastatic disease over the course of three years. We performed exome sequencing on germline DNA and DNA collected from tumor at three separate timepoints. We compared variant calls and variant allele frequencies between different samples. We identified subclonal driver mutations in several different genes in the primary tumor sample and found that one particular subclone dominated subsequent tumor samples at relapse. This clone was marked by a novel TP53-KPNA3 translocation and loss of the opposite-strand wild-type TP53 allele. Future research must focus on functional significance of such clones and strategies to eliminate them.

  Study EGAS00001001805

• Single_Cell_RNAseq_at_various_stages_of_HiPSCs_differentiating_toward_definitive_endoderm_and_endoderm_derived_lineages

  When comparing the differentiation capacities of pluripotent stem cell lines that have different genetic backgrounds, batch to batch experimental variablility poses a significant challenge, especially when trying to identify smaller effects. One way to address this issue is to differentiate several different lines in the same culture dish, thereby elimating experimental variation. In addition, it allows researchers to analyze many more lines with less experiments. Parallel single cell RNA-Seq exploits that individual cells are tagged and hence each cell can be reliably assigned to the donor of origin based on the genetic variants it contains. In addition, analyzing the genetic signature of single cells within a differentiating population can reveal differentation stages that are not easily detected in bulk RNAseq data. 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 EGAS00001002278

• Genomic landscape and PD-1 blockade in Natural-killer/T cell lymphoma

  Natural killer/T-cell lymphoma (NKTL) is an aggressive malignancy with a predilection for Asian, Mexican and South American populations. With the exception of Japan, it is the most common mature T-cell lymphoma in Asia. NKTL presents as extranodal disease and mostly affects the upper aerodigestive tract. Neoplastic cells are invariably infected by the Epstein-Barr virus (EBV) and characterized by a cytotoxic phenotype. The genetic landscape of NKTL has been recently unraveled by discoveries describing recurring mutations altering the JAK-STAT pathway, epigenetic modifiers, the DDX3X gene and genetic predisposition in the HLA-DPB1 gene.The genomic landscape of NKTL has been interrogated by whole-exome sequencing, targeted sequencing and single nucleotide polymorphism arrays, but has yet been studied with whole-genome sequencing (WGS). In this study, we will use a combination of WGS, targeted-capture sequencing (TCS) and RNA sequencing data to explore the genetic landscape and its relevance to immunotherapy in NKTL

  Study EGAS00001003828

• Single_cell_analysis_of_cytokine_induced_T_cell_states

  We isolated T cells from healthy platelet donors and cultured them in resting and stimulated conditions with addition of a range of cytokines. We performed scRNA sequencing to assess the variability of polarization in different cytokines treated cells. Cytokines affect T cell responses by polarising them to different phenotypes. Given that the inflammation and and autoimmune tissue distruction is driven by the local production of cytokines, we investigated cytokine induced changes in T cells by using a combination of immunological and genomics approaches. To characterize, the efficacy of cytokine induced porization, here we stimulated naive and memory CD4+ T cells in the presence of cytokine polarizing coctails and profiled single cell transcriptome five days following polarization. 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 EGAS00001003215

• Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

  SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn’s disease (CD), suggesting a role in inflammation. We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD68+ CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte differentiation into inflammatory macrophages and lipopolysaccharide (LPS)-induced inflammatory activation. SP140 preferentially occupies transcriptional start sites (TSS) in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduced SP140 binding and thereby expression of SP140-bound genes. GSK761 inhibited the spontaneous expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal-mucosa. This study identifies SP140 as a druggable epigenetic therapeutic target for CD.

  Study EGAS00001004460

• Genome-wide discovery of somatic coding and regulatory variants in Diffuse Large B-cell Lymphoma

  Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3'UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NFκB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.

  Study EGAS00001002936

• Gut metagenome associations with extensive digital health data in a volunteer-based EstMB cohort

  Microbiome research is starting to move beyond the exploratory phase towards interventional trials and therefore well-characterized cohorts will be instrumental for generating hypothesis and providing new knowledge. As part of the Estonian Biobank, we established the Estonian Microbiome Cohort which includes stool, oral and plasma samples from 2,509 participants and is supplemented with multi-omic measurements, questionnaires, and regular linkages to national electronic health records. In this study, we analyzed stool data from deep metagenomic sequencing together with rich phenotyping, including 71 diseases, 136 medications, 21 dietary questions, 5 procedures, and 19 other factors. The data revealed numerous relationships with different microbiome features. Additionally, the long-term antibiotic usage, independent from recent administration, has a significant impact on the microbiome composition, partly explaining the common associations between diseases. Overall, this study extends the understanding of microbiome–host interactions and facilitates the development of microbiome-related studies.

  Study EGAS00001005900

• Detection of cell-free DNA fragmentation and copy number alterations in cerebrospinal fluid from glioma patients

  Glioma is difficult to detect or characterise using current liquid biopsy approaches. Detection of cell-free tumor DNA (cftDNA) in cerebrospinal fluid (CSF) has been proposed as an alternative to detection in plasma. We used shallow whole-genome sequencing (sWGS, at a coverage of < 0.4x) of cell-free DNA from the CSF of 13 patients with primary glioma to determine somatic copy number alterations and DNA fragmentation patterns. This allowed us to determine the presence of cftDNA in CSF without any prior knowledge of point mutations present in the tumor. We also showed that the fragmentation pattern of cell-free DNA in CSF is different from that in plasma. This low-cost screening method provides information on the tumor genome and can be used to target those patients with high levels of cftDNA for further larger-scale sequencing, such as by whole-exome and whole-genome sequencing.

  Study EGAS00001003255

• A Proteogenomic Analysis of Clear Cell Renal Cell Carcinoma in a Chinese Population

  Clear cell renal cell carcinoma (ccRCC) is a common and aggressive subtype of renal cancer. Here we conduct a comprehensive proteogenomic analysis of 232 tumor and adjacent non-tumor tissue pairs from Chinese ccRCC patients. By comparing with tumor adjacent tissues, we find that ccRCC shows extensive metabolic dysregulation and an enhanced immune response. Molecular subtyping classifies ccRCC tumors into three subtypes (GP1–3), among which the most aggressive GP1 exhibits the strongest immune phenotype, increased metastasis, and metabolic imbalance, linking the multi-omics-derived phenotypes to clinical outcomes of ccRCC. Nicotinamide N-methyltransferase (NNMT), a one-carbon 38 metabolic enzyme, is identified as a potential marker of ccRCC and a drug target for GP1. We demonstrate that NNMT induces DNA-dependent protein kinase catalytic subunit (DNA-PKcs) homocysteinylation, increases DNA repair, and promotes ccRCC tumor growth. This study provides insights into the biological underpinnings and prognosis assessment of ccRCC, revealing targetable metabolic vulnerabilities.

  Study EGAS00001006005

• Combined gene expression and digital pathology identifies molecular mediators of T cell exclusion and immune suppression in ovarian cancer

  Close proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what determines the spatial distribution of T cells in the tumour microenvironment is not well understood. Coupling digital pathology and transcriptome analysis on a large ovarian tumour cohort, we develop a machine learning approach to molecularly classify and characterize tumour-immune phenotypes. Our study identifies two important hallmarks characterizing T cell excluded tumours: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFb and activated stroma. Furthermore, we identify TGFb as a key mediator of T cell exclusion. TGFb reduces MHC-I expression in ovarian cancer cells in vitro; TGFb also activates fibroblasts and induced extracellular matrix (ECM) production as a potential physical barrier to hinder T cell infiltration. Our findings indicate that targeting TGFb may represent a promising strategy to overcome T cell exclusion and improve clinical benefits of cancer immunotherapy.

  Study EGAS00001003487

• Phase 1 CX-5461 Trial (Canadian Cancer Trials Group Trial IND.231)

  CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination (HR) deficient models. In this multicentre Phase Ib trial in patients with solid tumors, 40 patients were treated across 10 dose levels (50 - 650 mg/m2) to determine the recommended phase II dose (RP2D), and evaluate safety, tolerability, pharmacokinetics. Defective HR was explored as a predictive biomarker. CX-5461 was generally well tolerated, with a RP2D of 475 mg/m2 d1, 8 and 15 every 4 weeks, and dose limiting toxicities of phototoxicity. Responses were observed in 10% of patients, primarily in patients with defective HR (ORR 14%). Reversion mutations in PALB2 and BRCA2 were detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization showed this toxicity is related to the CX-5461 chemotype, independent of G4 synthetic lethality. These results establish clinical proof-of-concept for this first-in class G4 stabilizer.

  Study EGAS00001006173

• GENOMIC MUTATION LANDSCAPE OF SKIN CANCERS FROM DNA REPAIR-DEFICIENT XERODERMA PIGMENTOSUM PATIENTS

  Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis (TLS) DNA polymerase η (group V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to the general population. Here, we analyzed 38 skin cancer genomes from five XP groups. We found that the activity of NER determines heterogeneity of the mutation rates across skin cancer genomes and that transcription-coupled NER extends beyond the gene boundaries reducing the intergenic mutation rate. Mutational profile in XP-V tumors revealed the role of polymerase η in the error-free bypass of (i) rare TpG and TpA DNA lesions, (ii) 3’ nucleotides in pyrimidine dimers, and (iii) TpT photodimers. Our study unravels the genetic basis of skin cancer risk in XP and provides insights into the mechanisms reducing UV-induced mutagenesis in the general population.

  Study EGAS00001006732

• Multi-omics identify falling LRRC15 as a COVID-19 severity marker and persistent pro-thrombotic signals in convalescence

  Patients with end-stage kidney disease (ESKD) are at high risk of severe COVID-19. Here, we perform longitudinal blood sampling of ESKD haemodialysis patients with COVID-19, collecting samples pre-infection, serially during infection, and after clinical recovery. Using plasma proteomics, and RNA-sequencing and flow cytometry of immune cells, we identify transcriptomic and proteomic signatures of COVID-19 severity, and find distinct temporal molecular profiles in patients with severe disease. Supervised learning reveals that the plasma proteome is a superior indicator of clinical severity than the PBMC transcriptome. We show that a decreasing trajectory of plasma LRRC15, a proposed co-receptor for SARS-CoV-2, is associated with a more severe clinical course. Strikingly, we observe that two months after the acute infection, patients still display dysregulated gene expression related to vascular, platelet and coagulation pathways, including PF4 (platelet factor 4), which may explain the prolonged thrombotic risk following COVID-19.

  Study EGAS00001006778

• Gene Expression and Biomarker Utility in Post-Mortem Samples

  The FAA Functional Genomics Team examined the feasibility of analyzing gene expression profiles using post-mortem brain, lung, muscle, and blood samples collected from aviation accident fatalities, with the goal of validating post-mortem extracted RNA for use in RNA sequencing. We compared the RNA sequencing results obtained from THC-positive and THC-negative samples to determine whether RNA sequencing on samples collected from aviation accident fatalities was possible and if any differences in gene expression associated with THC consumption were detectable post-mortem. The study population included 57 males of indeterminant age who perished in general aviation accidents and for whom post-mortem toxicological testing identified delta-9-THC or its primary or secondary metabolites, as well as negative controls. We determined that RNA sequencing on post-mortem aviation accident fatality samples is possible, and further identified genes showing differential expression in lung and muscle between THC-positive and THC-negative samples. We conclude that post-mortem tissue samples collected from aviation accident fatalities are suitable for gene expression profiling, but caution researchers that such samples have low RNA integrity numbers and some degree of microbial contamination is both probable and to be expected. Raw sequencing files (.fastq) from this study are available in dbGaP.

  Study phs003546

• Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers

  Ovarian cancer is the leading cause of death from gynecological cancers worldwide. No effective screening methods exist, and tumors are commonly detected at advanced stages where treatment is much less effective. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women from the European Union or the United States with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model that incorporated multi-analyte fragmentome data and protein measurements, we detected ovarian cancer with high specificity >99% and sensitivity of 72%, 69%, 87%, and 100% for stages I–IV, respectively (AUC=0.96, 95% CI: 0.94-0.99), including 90% of high grade serous ovarian cancers. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I–IV (p=0.001, two-sided test of equal proportions). Additionally, our approach distinguished benign masses from ovarian cancers with high accuracy (AUC of 0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.

  Study EGAS50000000484

• 3D tissue engineered human skeletal muscle modelling Facioscapulohumeral Muscular Dystrophy

  acioscapulohumeral muscular dystrophy (FSHD) is caused by sporadic misexpression of the transcription factor double homeobox 4 (DUX4) in skeletal muscles. So far, monolayer cultures and animal models have been used to study the FSHD disease mechanism and for FSHD therapy development, but these models do not fully recapitulate the disease and there is a lack of knowledge on how DUX4 misexpression leads to skeletal muscle dysfunction. To overcome these barriers, we have developed a 3D tissue engineered skeletal muscle (3D-TESM) model by generating genetically matched myogenic progenitors (MPs) from human induced pluripotent stem cells of three mosaic FSHD patients. 3D-TESMs derived from genetically affected MPs recapitulate pathological features including DUX4 and DUX4 target gene expression, smaller myofiber diameters, and reduced absolute forces upon electrical stimulation. RNA sequencing data illustrates increased expression of DUX4 target genes in 3D-TESMs compared to 2D myotubes, and cellular differentiation was improved by 3D culture conditions. Treatment of 3D-TESMs with small molecules identified in drug development screens in 2D muscle culture showed no improvements in contractile force and sarcomere organization, highlighting the potential benefit of 3D-TESMs for preclinical drug potency screening by eliminating false-positive compounds for FSHD research and drug development.

  Study EGAS50000000502

• Microbiomic and immunogenic biomarkers of adjuvant chemotherapy efficacy in stage III colorectal cancer

  The standard treatment for stage III colorectal cancer (CRC) is surgery, followed by adjuvant chemotherapy (AC). However, the efficacy of AC is limited, and approximately 30% of patients experience recurrence. Therefore, easily assessable molecular biomarkers that can predict response to AC are needed. Here, we aimed to identify predictive biomarkers of response to AC using tumor transcriptomic data. Tumor specimens from 253 patients who underwent surgery for stage III CRC between 1997 and 2019 were analyzed using RNA sequencing. Transcriptional subtyping and analyses of gut microbiome, immune cell fractions, and T-cell receptor (TCR) were performed to identify factors associated with recurrence-free survival (RFS) in patients treated with or without AC. Of 253 patients, 118 (46.6%) received AC. Twenty phyla and 799 species of the microbiomes were identified, among which Fusobacteria were identified in 247 patients (97.6%). Multivariable Cox proportional hazards regression analysis of patients who received AC showed that intratumoral Fusobacterium and M1 macrophage abundance and diversity of TCR alpha and delta (TRAD) were independently associated with RFS. Fusobacterium and M1 macrophage abundance, and TRAD diversity were associated with the response to AC, suggesting that these factors could serve as biomarkers for personalized treatment in stage III CRC.

  Study JGAS000875

• Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy

  Background: Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits including cardiovascular diseases.Results: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 149 (97)* patients with dilated cardiomyopathy and 113 (108)* non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage and allele specific expression. Systematic annotation of genome wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome wide association signals in two independent cohorts.Conclusions: RNA transcription, splicing and allele specific expression are each important determinants of the DCM phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics. (*) numbers in parentheses represent samples that the publication is based on.

  Study EGAS00001002454

• Negligible impact on missing heritability of autoimmune-locus rare coding-region variants

  Genome wide association studies (GWAS) have identified common variants of modest effect size at hundreds of loci for common autoimmune diseases - however a substantial fraction of heritability remains unexplained, and to which rare variants may contribute. To discover rare variants and test them for association with a phenotype, the majority of studies re-sequence a small initial sample size and then genotype the discovered variants in a larger sample set. This approach will fail to analyse a large fraction of the rare variants present in the entire sample set. Here we perform simultaneous amplicon sequencing-based variant discovery and genotyping for coding exons of 25 GWAS risk genes in 41,911 white-European origin UK subjects comprising 24,892 subjects with six autoimmune disease phenotypes and 17,019 controls, and show that rare coding-region variants at known loci play a negligible role in common autoimmune disease susceptibility. These results do not support the rare variant - synthetic genome-wide association hypothesis. Many known autoimmune disease risk loci contain multiple independent common and low frequency variant association signals, and so genes in these loci are a priori stronger candidates to harbor rare coding-region variants than other genes. Our data suggest that the missing heritability for common autoimmune diseases may not lie in the rare coding-region variant portion of the allelic spectrum, but perhaps as others have proposed in very many common variant signals of weak effect.

  Study EGAS00001000476

• CRC organoid RNA-seq data access committee

  This DAC is responsible for granting access to RNA-seq data (paired-end FASTQ files) from 10 patient-derived colorectal cancer organoid patients. The data was ad hoc generated as part of the development of NovumRNA, a non-canonical tumor-specific antigen prediction pipeline.

  Dac EGAC50000000406

• WGS dataset for malignant pleural and peritoneal mesothelioma

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

  Dataset EGAD50000001343

• Boyes Lab - DAC policy

  Access to this data is controlled. Upon request from a third party for access to the data, a separate Data Sharing Agreement would be put in place between the University of Leeds and the third party prior to EGA granting access to the data to the third party.

  Dac EGAC50000000283

• RNA-seq of multi-regional CRC samples

  BAM files of RNA sequencing (RNA-seq) experiment on multi-regional colorectal cancer (CRC) samples. 58 samples corresponding to 16 patients were sequenced and there is one BAM file for each sample.

  Dataset EGAD00001006164

• Prognostic factors in prostate cancer: deep sequencing pilot project TAPG

  This is a pilot project to determine whether the TAPG FFPE DNA's are suitable for deep sequencing. If successful an investigation of SNP distribution in a larger cohort will follow.

  Dataset EGAD00001001237

• TCS validation of 11 lung adenos

  This is the targeted capture deep sequencing (TCS) data for validation of the mutations discovered in the WES step. There are 58 bam files of TCS data including 48 tumor samples and 10 peripheral blood WBC samples.

  Dataset EGAD00001000985