Search Results - EGA European Genome-Phenome Archive

Malignant pheochromocytomas/paragangliomas harbor mutations in transport and cell adhesion genes

One out of ten patients with pheochromocytoma (PCC) and paraganglioma (PGL) develop malignant disease. Today there are no reliable pathological methods to predict malignancy at the time of diagnosis. Tumors harboring mutations in the succinate dehydrogenase subunit B (SDHB) gene often metastasize but the sequential genetic events resulting in malignant progression are not fully understood. The aim of this study was to identify somatic mutations that contribute to the malignant transformation of PCC/PGL. We performed pair-wise (tumor-normal) whole-exome sequencing to analyze the somatic mutational landscape in five malignant and four benign primary PCC/sympathetic PGL (sPGL), including two biological replicates from each specimen. In total, 225 unique somatic mutations were identified in 215 genes, with an average mutation rate of 0.54 mutations/megabase. Malignant tumors had a significantly higher number of mutations compared to benign tumors (p<0.001). Three novel genes were identified as recurrently mutated; MYCN, MYO5B and VCL, and mutations in these genes were exclusively found in malignant sPGL tumors. Mutations in the MYO5B gene could be verified in two publicly available data sets. A gene ontology analysis of mutated genes showed enrichment of cellular functions related to cytoskeletal protein binding, myosin complex, and motor activity, many of which had functions in Rab and Rac/Rho GTPase pathways. Conclusively, we have identified recurrent mutations in genes related to intracellular transport and cell adhesion, and we have confirmed recurrent mutations of MYO5B in PCC/PGL cases with malignant potential. Our study suggests that deregulated Rab and Rac/Rho pathways may be important in PCC/PGL tumorigenesis.

Study EGAS00001001601

18 Whole Exome Sequencing for Radiation Induced-Meningiomas

Purpose: Majority of pediatric cancers require the irradiation of the central nervous system (CNS), and as more patients survive into adulthood from improved oncological therapy the sequelae of brain radiation are increasing in prevalence. Radiation-induced meningiomas (RIMs), one such secondary effect, demonstrate a clinically more aggressive behaviour than sporadic meningiomas (SMs). We aimed to describe the genomic mutational landscape of RIMs.Methods: We analyzed a principal cohort of 18 RIMs, with 31 RIMs overall, from patients who received childhood radiation therapy and 30 SMs, as a comparator population. We performed a multiplatform integrative genomic analysis; including methylation, whole exome and RNA sequencing. Results: RIMs exhibited a five-fold increase in copy number alterations, commonly the loss of chromosome 1p (17/18 RIMs) and 22q (17/18 RIMs), which was significantly more than observed in sporadic meningiomas. Furthermore, RNA sequencing data revealed an NF2 gene fusion event in 35.3% of RIMs. In all 6 cases, there was a complete NF2 exon spliced into a complete exon of a reciprocal gene, suggesting that the breakpoints of genomic rearrangement are intronic. All tumours with the NF2 fusion also possessed monosomy of chromosome 22q, rendering the cells with homozygous disruption of NF2. Clinically, RIMs with the NF2 fusion exhibited ill-defined borders and a tendency to develop in anatomic frontal location. Also, targeted sequencing panel confirmed that RIMs had fewer nonsynonymous NF2 mutations (6.5% vs. 30% in SM) and absence of mutations in TRAF7, SMO, KLF4, PIK3CA and AKT1, genes traditionally involved in SMs.Conclusion: Our study demonstrates that RIMs have distinct genomic drivers of oncogenesis as compared to SMs, specifically NF2 inactivation through fusion event. Radiation therapy possibly triggers genomic structural rearrangements through error-prone repair of double-stranded DNA breaks.

Study EGAS00001002317

Proteom characterization in primary colorectal cancer and corresponding liver metastasis

Colorectal adenocarcinomas (CRC) are one of the most commonly diagnosed tumors worldwide. Colorectal adenocarcinomas primarily metastasize into the liver and (less often) into the peritoneum. Patients suffering from CRC-liver metastasis (CRC-LM) typically present with a dismal overall survival compared to non-metastasized CRC patients. The metastasis process and metastasis promoting factors in patients with CRC are under intensive debate. However, CRC studies investigating the proteome biology are lacking. Formalin-fixed paraffin-embedded (FFPE) tissue specimens provide a valuable resource for comprehensive proteomic studies of a broad variety of clinical malignancies. The presented pilot study compares the proteome of primary CRC and patient-matched CRC-LM. The applied protocol allows a reproducible and straightforward identification and quantification of over 2,600 proteins within the dissected tumorous tissue. Subsequent unsupervised clustering reveals distinct proteome biologies of the primary CRC and the corresponding CRC-LM. Statistical analysis yields multiple differentially abundant proteins in either primary CRC or their corresponding liver metastases. A more detailed analysis of dysregulated biological processes suggests an active immune response in the liver metastases, including several proteins of the complement system. Proteins with structural roles, e.g. cytoskeleton organization or cell junction assembly appear to be less prominent in liver metastases as compared to primary CRC. Immunohistochemistry corroborates proteomic high expression levels of metabolic proteins in CRC-LM. We further assessed how the in vitro inhibition of two in CRC-LM enriched metabolic proteins affected cell proliferation and chemosensitivity. The presented proteomic investigation in a small clinical cohort promotes a more comprehensive understanding of the distinct proteome biology of primary CRC and their corresponding liver metastases.

Study EGAS00001005641

European BestAgeing Study on microRNA candidates for cardiovascular disease

Background: Circulating miRNAs have emerged as promising biomarker candidates due to their stability and their role in regulating key pathological pathways in cardiovascular disease (CVD). Yet, large-scale, multicenter studies examining their diagnostic and prognostic potential are scarce. This study evaluates the potential of miRNA expression profiles to inform disease classification and risk stratification across major CVD phenotypes, including acute coronary syndrome (ACS), chronic coronary artery disease (CAD), dilated cardiomyopathy (DCM), and ischemic cardiomyopathy (ICM), in a large, multicenter European cohort. Methods: We assessed genome-wide miRNA expression profiles in a total of 1,209 cardiovascular patients and 848 controls in a uniform, standardized fashion, which renders this study one of the largest prospective miRNA studies. To focus on only the most biologically plausible miRNAs for clinical translation, we mined all original studies of miRNA candidates in CVD and performed differential miRNA expression and enrichment analysis. We then trained disease-specific binary classification models to evaluate the diagnostic potential of miRNA signatures. Finally, we evaluated prognosis and disease severity based on distinct miRNA levels. Results: 634 original abstracts were identified, detailing 166 ACS, 181 CAD, 56 DCM, and 182 ICM miRNAs. Without further optimization, the signatures of a priori miRNAs already yielded very good diagnostic performance with ROC AUC of 0.83 – 0.95. There was an improvement when considering additional miRNAs in a discovery setting. Interestingly, in ACS, CAD and DCM we observed a significantly worse prognosis in probands with higher scores in the miRNA signatures, indicating additional prognostic information. Conclusions: The European BestAgeing miRNA study reveals emerging associations of several miRNA signatures with cardiovascular disease discrimination and prognostication, providing a foundation for future external validation and potential clinical translation of this class of markers.

Study EGAS00001008346

Evaluation of somatic mutations in urine samples as a non-invasive method for the detection and molecular classification of endometrial cancer

Purpose: Current diagnostic methods for endometrial cancer lack specificity, leading to many women undergoing invasive procedures. The aim of this study was to evaluate somatic mutations in urine to accurately discriminate endometrial cancer patients from controls. Experimental Design: Overall, 72 samples were analyzed using next-generation sequencing with molecular identifiers targeting 47 genes. We evaluated urine supernatant samples from women with endometrial cancer (n=19) and age-matched controls (n=20). Cell pellets from urine and plasma samples from seven cases were sequenced; further, we also evaluated paired tumor samples from all cases. Finally, immunohistochemical markers for molecular profiling were evaluated in all tumor samples. Results: Overall, we were able to identify mutations in DNA from urine supernatant samples in 100% of endometrial cancers. In contrast, only one control (5%) showed variants at a variant allele frequency (VAF)≥2% in the urine supernatant samples. The molecular classification obtained by using tumor samples and urine samples showed good agreement. Analyses in paired samples revealed a higher number of mutations and VAFs in urine supernatants than in urine cell pellets and blood samples. Conclusions: Evaluation of somatic mutations using urine samples may offer a user-friendly and reliable tool for endometrial cancer detection and molecular classification. The diagnostic performance for endometrial cancer detection was very high, and cases could be molecularly classified using these noninvasive and self-collected samples. Additional multi-center evaluations using larger sample sizes are needed to validate the results and understand the potential of urine samples for the early detection and prognosis of endometrial cancer.

Study EGAS00001007396

DNA Methylation Markers and Pancreatic Cancer Risk in 3 Cohort Studies (NHS, PHS, HPFS)

Pancreatic cancer is the 4th leading cause of cancer deaths in the US. Due to the lack of early symptoms, pancreatic cancer is difficult to identify at early stages and no screening is available for the general population. Identifying pancreatic cancer at earlier stages could significantly improve survival with increased opportunities for surgery. New high-dimensional arrays designed to measure DNA methylation levels at hundreds of thousands of CpG sites throughout the genome have opened opportunities to examine the role of DNA methylation in cancer risk using blood samples. Using this method, archived samples from prospective studies can be used to examine early changes in the DNA methylation levels in individuals who develop cancer months or years later, providing new opportunities to better understand biological mechanisms and, perhaps, identify biomarkers for early detection. Pancreatic cancer cases and matched controls were obtained from 3 large cohort studies, the Nurses' Health Study (NHS), the Physician's Health Study (PHS), and the Health Professionals Follow-up Study (HPFS), to measure DNA methylation in stored buffy coats using a nested case-control study design.

Study phs001917

Next Generation Mendelian Genetics: Neonatal Diabetes

The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases. Neonatal diabetes mellitus (ND) is a rare form of monogenic diabetes (90,000-260,000 live births) that is diagnosed in the first 6 months of life. The disease has been classified as transient or permanent and although it can be inherited, more frequently is sporadic as a result of 'de novo' mutations. Defects in 12 genes have been found as responsible for the disease (defects in the paternally imprinted chromosomal region 6q24, IPF1, SLCA2A, INS, EIF2AK3, GCK, FOXP3, GLIS3, PTF1A, HNF1Beta, KCNJ11 and ABCC8). The two subunits of the ATP-sensitive K channel (ABCC8 and KCNJ11) and the insulin gene (INS), account for almost half of the cases and similar to CHI, the other half, remains genetically unexplained. We became part of this study when we submitted 4 DNA samples for exome sequencing, from patients with NDM of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations or genetic variants in new genes.

Study phs000542

High response rate to anti PD-1 therapy in desmoplastic melanoma

Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, but is highly associated with ultraviolet light DNA damage. We analysed 60 patients with advanced DM treated with programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1) blocking antibody therapy. Objective tumor responses were observed in 42 of the 60 patients (70%, 95% confidence interval 57-81%), including 19 patients (32% overall) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF-1 mutations (14 out of 17 cases). Immunohistochemistry (IHC) analysis from 19 DM and 13 non-DM revealed a higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with increased CD8 density and PD-L1 expression in the tumor invasive margin. Therefore, patients with advanced DM derive significant clinical benefit from PD-1/PD-L1 immune checkpoint blockade therapy despite being a cancer defined by its dense desmoplastic fibrous stroma. The benefit is likely derived from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.

Study phs001469

Development of CMT Peds Scale for Children with CMT

Information about how different forms of CMT affect children is not readily available because there are not good methods to measure impairment of children with CMT. The purpose of this project is to develop and test such a method and to then test this scale to ensure that it is an effective measurement of impairment of CMT in children, that the children tolerate it well, that different investigators using this method obtain similar results and that changes over time with the scale allow measurement of progression of CMT in the children. Primary Objective: To develop and test the CMT Peds scale (CMTPedS) in children with CMT in order to refine the scoring for future natural history and therapeutic trials. Secondary Objective: We propose to test the sensitivity of the CMT Peds Scale in a longitudinal study and compare the CMT Peds Scale with the Children's Quality of Life scale CHQ-PF50. 2000 patients <21 years of age with various forms of CMT will be evaluated at baseline and at subsequent annual follow up visits when possible. This first study release makes available data of n=208 study participants.

Study phs001553

Efficacy of Bitter Taste Blockers on Flavor Acceptance in a Human Population

The goal of this project is to determine variation in human bitter perception and the effectiveness of bitter blockers in individuals of different genotypes. The project is based on the parent project titled "Efficacy of bitter taste blockers on flavor acceptance in pediatric population", which addresses how bitter taste perception affects medication compliance. As a part of the parent project, mothers and their children were recruited from the general population of metropolitan Philadelphia through print and internet media as well as from a database of past research participants. Adults (mothers) were evaluated in the laboratory for bitter taste perception for a variety of "Generally Recognized As Safe" (GRAS) bitter compounds using the general Labeled Magnitude Scale (gLMS) which allows subjects to rate sensory intensity. Mothers were also evaluated for perception of the liquid formulation of the drug KaletraTM, a recommended 1st line treatment for infants with HIV infection, whose taste is rejected by some children and accepted well by others. DNA samples from mothers were genotyped as a part of this study to identify (1) novel genes associated with human bitter perception and (2) the ability of compounds to block bitterness.

Study phs000839

Detecting and Subtyping Lung Cancer Through Analysis of Circulating Tumor DNA

Small cell lung cancer (SCLC) is among the most aggressive tumors with poor clinical outcomes. Tumors are rarely resected, which is a major barrier to molecular profiling of tumor tissue; therefore, non-invasive approaches using circulating tumor DNA (ctDNA) from liquid biopsies are needed to help advance research and clinical care for patients with SCLC. We developed a targeted capture panel that profiles SCLC genes and transcriptional regulation sites, including transcription start sites (TSS) and transcription factor binding sites (TFBS). This is a single assay that detects genomic mutations and transcriptional regulation activity based on ctDNA fragment patterns reflecting epigenetic nucleosomal positions. We applied this assay to sequence patient-derived xenograft (PDX) and patient plasma samples. We also performed whole genome sequencing (WGS) for a subset of the PDX plasma samples to validate the capture data. We developed new algorithms to quantify activity of key SCLC marker genes of ASCL1, NEUROD1, POU2F3, and ATOH1 and to classify SCLC subtypes based on activity of these markers. Furthermore, we developed a model to classify SCLC from non-small cell lung cancer (NSCLC), which has potential important applications for monitoring transdifferentiation and tumor plasticity.

Study phs003570

Genetic Studies of Homologous Recombination Deficiency in Hispanic Gastric Cancer

Approximately 10% of gastric cancer cases show familial clustering and a hereditary cause is likely, however, only 1-3% cases result from known hereditary syndromes – which are predominantly associated with CDH1 and CTNNA1 genes. Hispanics are > 2 times more likely to be diagnosed and to die from gastric cancer compared to non-Hispanic whites. Not only does gastric cancer precision medicine lag behind other cancers – there is an urgent need to understand its etiology. Germline mutations in homologous recombination genes have been implicated as important risk factors for gastric cancer. The purpose of this study is to continue to generate knowledge to improve gastric cancer outcomes and disparities by 1) characterizing prevalence of germline mutations in homologous recombination genes and identify new genes associated with gastric cancer 2) perform molecular characterization of gastric tumors in Hispanic patients. Participants for germline analysis were enrolled from Chile, Colombia, Mexico, Portugal, Spain, Uruguay.Whole exome sequence capture was performed for all germline and somatic samples using Agilent SureSelect Human All Exon v7 Kit. All sequencing was performed on an Illumina NovaSeq 6000. Germline Analysis: Whole exome sequencing was performed on 536 Hispanic patients (290 males, 246 female)

Study phs003251

Federated discovery and sharing of genomic data using Beacons

The Beacon Project is a Global Alliance for Genomics & Health (GA4GH) initiative that enables genomic and clinical data sharing across federated networks. The project is working toward developing regulatory, ethics and security guidance to ensure proportionate safeguards for distribution of data according to the GA4GH-developed “Framework for Responsible Sharing of Genomic and Health-Related Data”. Within this Nature Biotechnology Correspondence a description of the Beacon protocol and how it can be used as a model for the federated discovery and sharing of genomic data is offered to the community. A Beacon is defined as a web-accessible service that can be queried for information about a specific allele. A user of a Beacon can pose queries of the form “Have you observed this nucleotide (e.g., C) at this genomic location (e.g., position 32,936,732 on chromosome 13)?” to which the Beacon responds with either “yes” or “no.” In this way, a Beacon allows allelic information of interest to be discovered by a remote searcher with no reference to a specific sample or patient, thereby mitigating privacy risks. The Beacon API (represented as a RESTful web application) provides a technical specification that a Beacon server must implement. The specification is open source and available online here. To simplify the process of lighting a Beacon, a free, open-source reference implementation of the latest specification has been developed. GA4GH is promoting different levels of data access (open, registered, and controlled) for convenience and for compatibility across its projects. Each so-called access tier has distinct visibility and requirements for authorization. For example, ‘open access’ Beacons are accessible to anonymous users of the internet, whereas ‘registered access’ Beacons are accessible to registered users (for example, bona fide researchers and clinicians) who have agreed to a set of conditions of data use. Many of the largest genomic archives, such as dbGaP, the European Genome-phenome Archive and the European Variation Archive, have provided access to variation data through Beacons for some or all of their datasets. Beacons can be interconnected through the Beacon Network, a directory and search engine for Beacons. Although individual Beacons answer the question “Have you observed this allele?”, the Beacon Network answers the question “Who has observed this allele?”. Beacons can be freely registered to the Beacon Network and can be searched independently or in aggregate with other connected Beacons.

Blog federated-discovery-using-beacons

What is the cBio Portal

EGA cBioPortal What is the EGA cBioPortal? EGA hosts a dedicated cBioPortal instance that enables authorized researchers to explore and visualize selected cancer datasets archived at EGA. Data submitters can also contribute cancer datasets to be made available through the portal. The platform provides interactive tools to analyse genomic and clinical data once access has been granted by the relevant Data Access Committee (DAC). How to find and access an EGA cBioPortal Dataset 1. Register as an EGA user 2. Go to the dataset page of interest. You can use the Search function to find datasets available in cBioPortal. If the dataset is available on the EGA cBioPortal Instance, the cBioPortal icon will be displayed on the dataset page, as shown below: On the dataset page, you will find information about access requirements. For more details, please visit how to request access. 3. Once access has been granted Go to the EGA cBioPortal instance and log in with your EGA user accountThe approved dataset will be listed in cBioPortalSelect the dataset to start exploring the data What you can do in cBioPortal The EGA cBioPortal is designed for interactive exploration and visualization of controlled-access cancer datasets, including: Visualising genomic alterationsAnalysing mutation patternsFiltering by clinical attributesComparing molecular profilesGenerating plots and summaries Important Notes Datasets are only visible in cBioPortal after DAC approvalAccess requests must always be submitted through the EGA website If you encounter any issues gaining access to a dataset, please contact EGA Support.If your question is related to the cBioPortal features, please reach out to: cbioportal@googlegroups.com. The EGA Helpdesk does not support this platform. How to link a dataset to the EGA cBioPortal instance during a submission STEP 1 – cBioPortal File Upload to EGA Files must be uploaded to the SFTP INBOX. The supported cBioPortal file types are: Raw data (e.g., VCF files)cBioPortal-specific formats (e.g., MAF files) STEP 2 – Register the cBioPortal dataset in the Submitter Portal Register the cBioPortal files in an analysis objectRegister a dataset with the title “cBioPortal Metadata” and include the analysis and nothing else Please note that cBioPortal is not directly supported by the EGA Helpdesk. For questions about the platform, please visit the cBioPortal website or contact the cBioPortal support team at cbioportal@googlegroups.com. The EGA does not support this platform.

Documentation submission/metadata/submission/cbioportal

The identification of genetic vulnerabilities in head and neck cancers for the development of novel treatments.

The global cancer burden is expected to double by the year 2030 and this will disproportionately affect the Asian continent. Head and neck squamous cell carcinoma (HNSCC) is endemic in Asia. It is the sixth most common cancer worldwide and the second most common in Malaysia, with approximately 600,000 new cases per year globally. Longterm survival remains less than 50%, underscoring the need for better therapeutic strategies. In this proposal we aim to bring new technological advancements in the identification of critical genes in HNSCC and the identification of compounds for the development of new therapies in HNSCC. We propose to genomically characterise 16 unique Asian H&N cancer cell lines, to classify sub groups where identification of essential genes that can be targeted for tumor control can be applied in a more rational way. Further, we propose to use zebrafish, an established drug discovery platform to identify promising pathway-specific compounds that could be further studied using CRISPR/Cas9 lethality screens and biological models to better identify novel therapeutic strategies to combat this major health problem in Asia.

Study EGAS00001002682

Genomic analysis of Smoothened inhibitor resistance in basal cell carcinoma

Smoothened inhibitors are currently being investigated for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). The majority of BCC patients treated with vismodegib experience significant clinical benefit, however, a small number of patients develop resistance. Knowledge of resistance mechanisms can generate predictive biomarkers and is critical for the design of additional therapeutic strategies aimed at circumventing resistance. To investigate mechanisms of resistance to vismodegib in BCC we sequenced and profiled biopsies from patients who initially responded to treatment and subsequently progressed on drug.We find that resistance is associated with re-activation of the Hedgehog (Hh) pathway through diverse mechanisms, including concurrent copy number alterations in the downstream Hh pathway components SUFU and GLI2, as well as novel SMO mutations that reduce sensitivity to vismodegib. The latter fall into two classes: those that activate SMO and those that directly affect the vismodegib-binding pocket. Additionally, we observe evidence of clonal selection of SMO mutations and intra-tumor heterogeneity of resistance mechanisms, which implies diverse and combinatorial strategies are required to overcome resistance.

Study EGAS00001000845

Spatial_transcriptome_analysis_of_Paediatric_Thymus

Cell atlas of Paediatric Thymus Cell atlas of Paediatric Thymus - The Human Cell Atlas initiative is an ambitious global research effort which aims to describe every cell in the human body across all developmental stages to generate a reference map to accelerate progress in science and medicine particularly relating to human development and disease. The initiative is led by investigators based at the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and funding support from the Wellcome and NIH. We aim to interrogate the cellular composition and molecular regulators underpinning a cells identity through; genetic and genomic analysis, expression analysis, non-identifiable video imaging and cell line and organoid production, as well as, computational algorithms to predict cellular developmental trajectories and cell-cell interactions. We will subsequently validate these findings in situ using spatial genomic and imaging technologies e.g. immunohistochemistry, RNAscope, in situ sequencing and spatial transcriptomic analyses. 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 EGAS00001004281

The demographic history and mutational load of African hunter-gatherers and farmers

The distribution of deleterious genetic variation across human populations is a key issue in evolutionary biology and medical genetics. However, the impact of different modes of subsistence on recent changes in population size, patterns of gene flow, and deleterious mutational load remains unclear. Here, we report high-coverage exomes from various populations of rainforest hunter-gatherers and farmers from central Africa. We find that the recent demographic histories of hunter-gatherers and farmers differed considerably, with population collapses for hunter-gatherers and expansions for farmers, accompanied by increased gene flow. We show that purifying selection against newly arising deleterious alleles is of similar efficiency across African populations, in contrast with Europeans where we detect weaker purifying selection. Furthermore, the per-individual mutation load of rainforest hunter-gatherers is similar to that of farmers, under both additive and recessive models. Our results indicate that differences in the cultural practices and demographic regimes of African populations have not resulted in large differences in mutational burden, and highlight the beneficial role of gene flow in reshaping the distribution of deleterious genetic variation across human populations.

Study EGAS00001002457

Cryptic Relatedness in the Singapore Living Biobank Project

The Singapore Living Biobank is a collection of healthy population-based Chinese and Malay individuals, for the purpose of phenotype recall study of high-impact variant carriers. These individuals are sampled from two studies: Multi-Ethnic Cohort (MEC), and the Singapore Health 2012 (SH2012). The MEC is a population-based cohort initiated in 2007 to investigate the genetic and lifestyle factors that affect the risk of developing chronic diseases such as diabetes and cardiovascular outcomes in the three ethnic groups (Chinese, Malays, and Indians). The SH2012 study is a population-based cross-sectional survey conducted in Singapore between 2012 and 2013, with over-sampling of Malays and Indians. Participants in MEC and SH2012 completed a similar set of questionnaire components, health examination, and biochemisty panels. Description of the MEC and SH2012 studies can be found at http://blog.nus.edu.sg/sphs/. We generated whole-exome sequencing data and Illumina OmniExpress array genotyping data for 1,299 Chinese and 1,229 Malays from the Singapore Living Biobank. This study includes a subset of 762 individuals that were found to be closely related (≤3rd degree), including 263 Chinese and 499 Malays.

Study EGAS00001002619

SS18-SSX-mediated hijacking of BAF complexes drives synovial sarcoma

Synovial sarcoma (SS) is defined by a recurrent t(x;18) chromosomal translocation, which produces the hallmark SS18-SSX oncogenic fusion. Incorporation of SS18-SSX into BAF complexes renders BAF complexes aberrant in two distinct manners: the addition of 78aa of SSX onto SS18, and concomitant loss of BAF47 assembly. However, the importance and functional contributions of each of these perturbations on BAF complex targeting and gene expression regulation remain unclear. Here we use an integrative set of genomic approaches in human cancer cell lines and primary tumor samples to define the mechanistic consequences of the SS18-SSX fusion oncoprotein. We find that SS18-SSX hijacks BAF complexes to broad polycomb domains to activate bivalent genes, driving a unique gene expression program distinct from other loss-of-function BAF complex malignancies. Importantly, restoration of BAF47 rescues enhancer activation but is dispensable for proliferative arrest in cell lines. These results demonstrate that gain-of-function SS18-SSX-mediated BAF complex targeting and gene activation is the driving event in SS, and present a mechanism by which distinct functions of BAF complexes can be co-opted to drive oncogenesis.

Study EGAS00001002920

Kidney_transplant_nephrectomy_scRNAseq

Single cell transcriptomics study of tissue from human kidney transplant nephrectomies Tissue is acquired from kidney transplant nephrectomies, homogenised and disaggregated to a single cell suspension prior to droplet encapsulation single cell RNAseq (10X protocol) or plate based single cell RNAseq (SS2 protocol). Human tissues, including the kidney are seeded with a tissue resident immune cell network throughout life. These cells may self renew in situ or be replaced by circulating precursors which enter the tissue in response to tissue specific niche and inflammatory signals. We are using single cell RNA sequencing of kidney transplant nephrectomy tissue to 1) understand the immune cell populations which are resident within the human kidney 2) identify which of these populations is donor or recipient derived. 3) Uncover the temporal dynamics of donor/recipient chimerism in the the human kidney following transplantation. 4) Understand transcriptional differences between organs removed for a variety of reasons (infection, chronic rejection, vascular emergencies) 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 EGAS00001003935

Mutational bias in spermatogonia impacts the anatomy of regulatory sites in the human genome

Mutation in the germline is the ultimate source of genetic variation, but little is known about the influence of germline chromatin structure on mutational processes. Using ATAC-seq, we profile the open chromatin landscape of human spermatogonia, the most proliferative cell-type of the germline, identifying transcription factor binding sites (TFBSs) and PRDM9-binding sites, a subset of which will initiate meiotic recombination. We observe an increase in rare structural variant (SV) breakpoints at PRDM9-bound sites, implicating meiotic recombination in the generation of structural variation. Many germline TFBSs, such as NRF, are also associated with increased rates of SV breakpoints, apparently independent of recombination. Singleton short insertions (>=5 bp) are highly enriched at TFBSs, particularly at sites bound by testis active TFs, and their rates correlate with those of structural variant breakpoints. Short insertions often duplicate the TFBS motif, leading to clustering of motif sites near regulatory regions in this male-driven evolutionary process. Increased mutation loads at germline TFBSs disproportionately affect neural enhancers with activity in spermatogonia, potentially altering neurodevelopmental regulatory architecture. Local chromatin structure in spermatogonia is thus pervasive in shaping both evolution and disease.

Study EGAS00001005366

DNA methylation landscape of prostate cancer

Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy thanks to improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles are associated with the mutually exclusive SPOP mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of 42 patients with prostate cancer brain metastases (PCBM), with matched primary samples available for 17 patients, we carried out DNA methylation analysis using Illumina EPIC array. We examined the epigenetic distinction between primary PCa and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM in particular. Multiregion sampling of PCBM revealed epigenetic heterogeneity in metastases. We found aberrant methylation in PCBM is associated with mutational background, PRC2 complex activity and upregulation of EZH2, an effect that is particularly pronounced in SPOP mutant PCBM. While we detected a hypermethylator phenotype in PCBM, we also observed hypomethylation occurring at the promoters of genes involved in neuroactive ligand-receptor interactions or the calcium signalling pathway, such as GABRB3 and GRM5, a change not observed in non-brain prostate cancer metastases.

Study EGAS00001006670

RNAseq

Familial Mediterranean Fever (FMF) is a prototypical periodic fever syndrome caused by genetic variation in MEFV. While it is known that especially IL-1β responses are dysregulated in FMF, its innate immune landscape has not been comprehensively described. Therefore, we extensively characterized the function of monocytes and neutrophils in patients with FMF in between disease attacks, as well as their circulating inflammatory proteome. We found that monocyte IL-1 and IL-6 production was enhanced following a range of stimulations, in concordance with alterations in the plasma inflammatory proteome. In contrast, neutrophil function in FMF was normal. Additionally, ATAC-seq and RNA-seq analyses revealed important epigenetic and transcriptional reprogramming arguing for monocyte function dysregulation. Interestingly, chromatin-accessibility was down-regulated in genomic regions related to cellular responses. This argues that the primary immune dysregulation in monocytes due to MEFV mutations leads to a chronic inflammatory profile that is subsequently associated with counterregulatory epigenetic and transcriptional changes reminiscent of tolerance (rather than trained immunity) induction. These data increase our understanding of the innate immune changes in FMF, that can be used in the design of novel approaches to manage chronic inflammation of these patients.

Study EGAS00001007165

Massively parallel functional dissection of schizophrenia associated non-coding genetic variants

Schizophrenia (SCZ) is a severe mental disorder affecting 1% of the world population. SCZ is characterized by an underlying genetic architecture that is highly polygenic. Genome wide association studies have identified thousands of genetic variants that are statistically linked to the disease. However, the translation of these associations into insights on the pathomechanisms has been challenging because the causal genetic variants, their molecular function, and their target genes remain largely unknown. To address these questions, we combined induced pluripotent stem cell technology with a massively parallel variant annotation pipeline (MVAP) to functionally characterize 35,000 SCZ associated non-coding genetic variants. This approach identified a set of 620 (1.7%) single nucleotide polymorphisms as functional on the molecular level in a highly cell type and condition specific fashion. Subsequent multi-modal integration of epigenomic data combined with CRISPR screening in human neurons enabled us to systematically translate SCZ variant associations into target genes, biological processes, and ultimately alterations of neuronal physiology. These results provide a new high-resolution map of functional variant-gene combinations and offer comprehensive biological insights into the developmental context and stimulus dependent molecular processes modulated by SCZ genetic variation beyond statistical association.

Study EGAS00001007542

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