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• Tumor suppressor miR-133a modulates the prostate cancer epigenome by repressing BAZ2A

  Our study revealed a new subgroup of prostate tumors defined by the expression of a novel prognostic marker, BAZ2A, and the first time to show the establishment of CIMP via an microRNA-epigenetic interaction in prostate tumors.

  Study EGAS00001000568

• Integrated genetic and epigenetic analysis of myxofibrosarcoma

  Myxofibrosarcoma (MFS) is a common histological subtype of adult soft tissue sarcoma characterized by an infiltrative growth pattern and a high propensity for local recurrence. We underwent whole exome sequencing, RNA sequencing, and methylation analysis of MFS.

  Study EGAS00001002889

• Whole exome sequencing of Congenital Cataract

  Whole exome sequencing to identify potentially relevant mutations of congenital cataract in a Chinese girl. The novel PAX6 mutation (c.221G>A) is associated with congenital cataract, and the WFS1 mutation (c.2070_2079del) interactively aggravates this process.

  Study EGAS00001005673

• RNA seq before and after cold pressor test

  The cold pressor test (CPT) is a widely used pain provocation test to investigate both pain tolerance and cardiovascular responses. Twenty-two females were phenotypically assessed before and after a CPT, and blood samples were taken for RNA-sequencing.

  Study EGAS00001006690

• DETECT-A NGS Data Batch 3

  This batch is a subset of the full DETECT-A dataset, containing 29294 fastq files generated from 3653 subjects. All sequencing was conducted using Illumina HiSeq 4000 and Illumina MiSeq platforms. Note that the division into batches follows no specific criteria and that the sequencing data for each subject has multiple files which may span multiple datasets. Thus, for a comprehensive analysis, it is recommended to request access to all datasets that comprise this study.

  Dataset EGAD00001008597

• DETECT-A NGS Data Batch 2

  This batch is a subset of the full DETECT-A dataset, containing 498 fastq files generated from 71 subjects. All sequencing was conducted using Illumina HiSeq 4000 and Illumina MiSeq platforms. Note that the division into batches follows no specific criteria and that the sequencing data for each subject has multiple files which may span multiple datasets. Thus, for a comprehensive analysis, it is recommended to request access to all datasets that comprise this study.

  Dataset EGAD00001008591

• Clonal cultures of T memory cells

  Sequence data (bam files) of two RRBS samples for paper "A comprehensive analysis of 195 DNA methylomes reveals shared and cell specific features of partially methylated domains". Short Description: CD4+ T memory cells (CD3+ CD4+ CD45RA- CD45RO+ CD25-) from donors were sorted by flow-cytometry either as a bulk culture ('ex vivo' sample) or in a single-cell format into 96 well-plates ('clone' sample) in the presence of a TCR stimulus.

  Dataset EGAD00001004303

• DETECT-A NGS Data Batch 1

  This batch is a subset of the full DETECT-A dataset, containing 43963 fastq files generated from 3024 subjects. All sequencing was conducted using Illumina HiSeq 4000 and Illumina MiSeq platforms. Note that the division into batches follows no specific criteria and that the sequencing data for each subject has multiple files which may span multiple datasets. Thus, for a comprehensive analysis, it is recommended to request access to all datasets that comprise this study.

  Dataset EGAD00001008415

• Longitudinal sequencing of a recurrent paediatric high grade neuroepithelial tumour

  We have studied a unique case of astroblastoma arising in a 6 year-old girl, with multiple recurrences over a period of 10 years, with the pathognomonic MN1:BEND2 fusion 11 surgical samples from either fresh frozen of paraffin embedded material and 1 blood sample were subjected to Illumina short read whole exome sequencing using Agilent SureSelect whole exome v4. Data is provided as 15 BAM files aligned to hg19 with bwa.

  Dataset EGAD00001004118

• Colorectal Adenoma Gene Screen

  A pilot to establish the feasability of using a custom Agilent targeted pulldown of 110 genes implicated in colorectal tumourigensis to sequence for driver mutations in a set of 30 FFPE colorectal adenomas. If successful, we propose to sequence an additional 350 adenomas as part of a MRC research study in order to define the pattern of driver mutations across the spectrum of pathological subtypes including coventional adenomas, serrated adenomas and hyperplastic polyps

  Dataset EGAD00001001879

• DETECT-A NGS Data Batch 5

  This batch is a subset of the full DETECT-A dataset, containing 12740 fastq files generated from 3211 subjects. All sequencing was conducted using Illumina HiSeq 4000 and Illumina MiSeq platforms. Note that the division into batches follows no specific criteria and that the sequencing data for each subject has multiple files which may span multiple datasets. Thus, for a comprehensive analysis, it is recommended to request access to all datasets that comprise this study.

  Dataset EGAD00001015426

• DETECT-A NGS Data Batch 4

  This batch is a subset of the full DETECT-A dataset, containing 25210 fastq files generated from 3040 subjects. All sequencing was conducted using Illumina HiSeq 4000 and Illumina MiSeq platforms. Note that the division into batches follows no specific criteria and that the sequencing data for each subject has multiple files which may span multiple datasets. Thus, for a comprehensive analysis, it is recommended to request access to all datasets that comprise this study.

  Dataset EGAD00001015360

• DETECT-A NGS Data Batch 6

  This batch is a subset of the full DETECT-A dataset, containing 9 fastq files generated from 8 subjects. All sequencing was conducted using Illumina HiSeq 4000 and Illumina MiSeq platforms. Note that the division into batches follows no specific criteria and that the sequencing data for each subject has multiple files which may span multiple datasets. Thus, for a comprehensive analysis, it is recommended to request access to all datasets that comprise this study.

  Dataset EGAD00001015458

• Improved Sezary cell detection and novel insights into immunophenotypic and molecular heterogeneity in Sézary syndrome

  We performed a prospective investigation in Sézary syndrome by the application of a standardized multiparameter flow cytometry, FACS-cell sorting, and RNA-sequencing for an in-depth immunophenotypic and transcriptional profiling of Sézary cells.

  Study EGAS00001005229

• Immune microenvironment and lineage tracing help deciphering Rosette-forming GlioNeuronal Tumors: a multi-omic analysis of 9 cases

  Rosette-forming GlioNeuronal Tumor (RGNT) is a rare central nervous system neoplasm containing two components, glial and neuronal. The delineation of histological diagnosis of RGNT from similar low-grade tumors such as pilocytic astrocytoma (PA) and ganglioglioma (GG) may be challenging. We performed here a comprehensive molecular analysis of a cohort of tumors with same histology features to identify molecular characteristics of RGNT. A cohort of 9 rosette-forming tumors histologically-diagnosed were analyzed at molecular level using multimodal approaches as Whole Exome Sequencing (WES), RNAseq and methylome. In our cohort, 3 tumors were plotted within the Methylation Class-RGNT (MC-RGNT) characterized by FGFR1 mutation associated with PIK3CA or NF1 mutations. Transcriptome analysis was performed in 7 cases. RNAseq identified a “Hot” and a “Cold” transcriptomic group; the latter includes the 3 MC-RGNT and 1 MC-Pilocytic Astrocytoma and exhibited a “Cold” immune tumor microenvironment in comparison with the “Hot” group. The distinct immune cell content of both groups was confirmed by quantitative immunostainings. Get Set Enrichment Analysis showed that the “Cold” group had upregulated NOTCH pathway and mainly oligodendrocyte precursor cell and neuronal phenotypes while the “Hot” group exhibited predominantly astrocytic and neural stem cell phenotypes. In silico deconvolution identified the cerebellar granule cell lineage as a putative origin and as the cell context to understand the effects of genetic alterations and NOTCH signaling. Histological diagnosis of rosette-forming tumors encompasses heterogeneous tumor entities. Our study identified distinct tumor cell contexts and microenvironments as key features to better understand and manage these neoplasms.

  Study EGAS00001006502

• Cohort A germline exome sequencing

  Cohort A includes glioma tumors of varied grading and pathology from male and female individuals. Germline DNA was isolated from whole blood.

  Study EGAS50000000952

• WGS of a Li-Fraumeni patient's HSPCs

  WGS data of clonally expanded HSPCs from a Li-Fraumeni patient at the time of second cancer (Burkitt lymphoma and <5% t-MN) after primary osteosarcoma diagnosis and a reference MSC bulk.

  Dataset EGAD00001011257

• Systemic Lupus Erythematosus Serum Stimulation of Human Intestinal Organoids Induces Barrier Leakiness and Changes in Goblet Cell Differentiation

  Human intestinal epithelial cells are the interface between potentially harmful luminal content and basally residing immune cells. Their role is not only nutrient absorption but also the formation of a tight monolayer that constantly secretes mucus creating a multi-layered protective barrier. Alterations in this barrier can lead to increased gut permeability which is frequently seen in individuals with chronic extraintestinal autoimmune diseases, such as Systemic Lupus Erythematosus (SLE). Despite recent advances in identifying alterations in gut microbiota composition in SLE patients, not much attention has been given to the epithelial barrier itself. To date, it remains largely unexplored which role and function intestinal epithelial cells have in SLE pathology. Here, we present a unique near-physiologic in vitro model specifically designed to examine the effects of SLE on the epithelial cells. We utilize human colon organoids that are stimulated with serum obtained from SLE patients. Combining bulk and single-cell RNA transcriptomic analysis with functional assays revealed that SLE serum stimulation induced a unique expression profile marked by a reduction of goblet cell marker expression and mucus composition. Additionally, organoids exhibited imbalanced cellulat composition along with enhanced paracellular permeability,mitochondrial function, and a type I interferon gene signature. Similarly, transcriptomic analysis of SLE human colon biopsies revealed a downregulation of epithelial secretory markers. Our work uncovers a crucial connection between SLE and intestinal homeostasis that might be promoted in vivo through the blood, offering insights into the causal connection of barrier dysfunction and autoimmune diseases.

  Study EGAS50000000012

• DNA Methylomic Profiling of Preeclampsia Across Pregnancy

  Preeclampsia (PE) is a hypertensive, multi-system disorder of pregnancy that significantly impacts maternal and infant morbidity/mortality across the globe, as it increases risk of cardiovascular disease and remains a leading killer of women and babies. Despite PE's significant impact on morbidity/mortality, there are no clinically reliable biomarkers that predict PE. DNA methylation, a dynamic regulator of gene expression, represents a mechanism that is known to be impacted by the environment. Because PE stems from a dysfunctional placenta that releases debris into the maternal circulation, we hypothesized that the in-vivo environment created by the dysfunctional placenta will impact DNA methylation in the maternal circulation, and that these blood-based methylation profiles would serve as a systemic biomarker of the maternal response to placental dysfunction. Our overall objective of this pilot study was to longitudinally characterize DNA methylation profiles across the three trimesters of pregnancy in the maternal blood at time points before and after clinically overt PE using a targeted (endoglin and endoglin-related genes) and a discovery-based approach. For this pilot study, 28 normotensive control participants and 28 PE case participants enrolled in the NICHD funded pregnancy study entitled Prenatal Exposures and Preeclampsia Prevention: Mechanisms of Preeclampsia and the Impact of Obesity (PEPP3; P01HD30367) were 1:1 frequency matched on self-reported race, pre-pregnancy BMI, smoking history, and gestational age at sample collection. Methylation data were collected with the Infinium® MethylationEPIC Beadchip. Methylation assay data collection were carried out at Johns Hopkins University Genetic Resources Core Facility, The SNP Center, Baltimore, MD, USA.

  Study phs001937

• Count Me In (CMI): The Angiosarcoma (ASC) Project (CMI-ASCproject)

  Count Me In - The Angiosarcoma Project: A Patient-Partnered Research Initiative to Accelerate Research in a Rare Sarcoma The Angiosarcoma Project (ASCproject) is a research study that directly engages angiosarcoma patients online and empowers them to accelerate cancer research by sharing medical information and clinical samples. Angiosarcoma is an exceedingly rare soft tissue sarcoma with an incidence of ~300 newly diagnosed cases per year in the United States. This low incidence has impeded large-scale research efforts in this disease that are strongly needed to catalyze research and improve clinical outcomes. The Angiosarcoma Project, launched in March 2017, has demonstrated the feasibility of directly engaging geographically dispersed patients to democratize research and establish a large patient cohort to characterize the genomic and clinical landscape of a rare disease. Angiosarcoma patients living in the US or Canada can access the study and consent online through an online portal (ASCproject.org). Enrolled patients are mailed saliva and blood draw kits, which can be used to extract germline DNA and cell-free DNA (cfDNA), respectively. The study team contacts participants' healthcare institutions to obtain medical records and a portion of archived tumor samples. All received tumor samples are subjected to centralized histological re-review by an expert pathologist to confirm a diagnosis of angiosarcoma. Whole exome sequencing is performed on tumor DNA, germline DNA, and cfDNA; transcriptome sequencing is performed on tumor RNA. De-identified data, including linked genomic, clinical, and patient-reported data, are shared via public databases on a recurring pre-publication basis. Participants are regularly provided updates on the study.

  Study phs001931

• Count Me In (CMI): The Metastatic Breast Cancer (MBC) Project (CMI-MBCproject)

  Count Me In - The Metastatic Breast Cancer Project: A Patient-Driven Research Initiative to Accelerate Metastatic Breast Cancer Research The Metastatic Breast Cancer Project is a research study that directly engages patients with metastatic breast cancer via social media and advocacy groups and empowers them to accelerate cancer research by sharing their samples and clinical information. Our goal is to create a publicly available dataset of genomic, molecular, clinical, and patient-reported data to enable research. Patients in the US or Canada may register online. Registered patients are sent an online consent form that asks for permission to obtain and analyze their medical records, tumor tissue, saliva, and blood samples. Once enrolled, patients are sent a saliva kit and asked to mail back a saliva sample, which is used to extract germline DNA. Study staff contact participants' medical providers and obtain medical records and a portion of their stored tumor biopsies. Patients may be asked to mail in a blood sample, which is used to extract cell free DNA (cfDNA). Whole exome sequencing (WES) is performed on tumor DNA, germline DNA, and cfDNA; transcriptome sequencing is performed on tumor RNA. Clinically annotated genomic data are used to study specific patient cohorts (including outliers) and to identify mechanisms of response and resistance to therapies. All de-identified data, including genomic, clinical, and patient-reported data, are shared via public databases on a pre-publication and recurring basis as it is generated. The latest data release in cBioPortal is available here. Study updates are shared with participants regularly.

  Study phs001709

• Healthspan and lifespan extension by fecal microbiota transplantation in progeroid mice

  The gut microbiome is emerging as a key regulator of several metabolic, immune and neuroendocrine pathways. Gut microbiome deregulation has been implicated in major conditions such as obesity, type 2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease or cancer, but its precise role in aging remains to be elucidated. Here, we characterize the gut microbiome profile of accelerated aging and show that its external modulation is sufficient to extend healthspan and lifespan. We found that two different mouse models of progeria present with intestinal dysbiosis, which is characterized, among other alterations, by an increment in proteobacteria, cyanobacteria and a loss in verrucomicrobia, whereas long-lived humans (i.e., centenarians) exhibit a remarkable increase in verrucomicrobia and a reduction in proteobacteria. Fecal microbiota transplantation proved to be effective to enhance healthspan and lifespan in both progeroid mouse models and, more importantly, the solely transplantation with the verrucomicrobia Akkermansia muciniphila was sufficient to exert beneficial effects. Our results demonstrate that intestinal dysbiosis is a phenotype associated with accelerated aging and its correction provides health benefits. Moreover, metabolomic analysis of ileal content points to the restoration of secondary bile acids as a possible mechanism for the beneficial outcome of reestablishing a healthy microbiome. Our results suggest the existence of a link between gut aging and the microbiota, and can help to gain insight into the rationale for microbiome-based interventions against age-related diseases. Mouse sequence data have been deposited in ENA (https://www.ebi.ac.uk/ena) under accession number PRJEB34214

  Study EGAS00001003656

• Robust methylation-based classification of brain tumours using nanopore sequencing

  Background: DNA methylation-based classification of cancer provides a comprehensive molecular approach to diagnose tumours. In fact, DNA methylation profiling of human brain tumours already profoundly impacts clinical neuro-oncology. However, current implementations using hybridization microarrays are time-consuming and costly. We recently reported on shallow nanopore whole-genome sequencing for rapid and cost-effective generation of genome-wide 5-methylcytosine profiles as input to supervised classification. Here, we demonstrate that this approach allows to discriminate a wide spectrum of primary brain tumours. Results: Using public reference data of 82 distinct tumour entities, we performed nanopore genome sequencing on N=382 tissue samples covering 46 brain tumour (sub)types. Using bootstrap sampling in a cohort of N = 56 cases, we find that a minimum set of 1,000 random CpG features is sufficient for high-confidence classification by ad hoc random forests. We implemented score recalibration as confidence measure for interpretation in a clinical context and empirically determined a platform-specific threshold in a randomly sampled discovery cohort (N = 185). Applying this cut-off to an independent validation series (N = 184) yielded 148 classifiable cases (sensitivity 80.4%) and demonstrated 100 % specificity. Cross-lab validation demonstrated robustness with concordant results across four laboratories in 10/11 (90.9%) cases. In a prospective benchmarking (N = 15), median time to results was 21.1 hours. Conclusions: In conclusion, nanopore sequencing allows robust and rapid methylation-based classification across the full spectrum of brain tumours. Platform-specific confidence scores facilitate clinical implementation for which prospective evaluation is warranted and ongoing.

  Study EGAS00001006540

• Chronic lymphocytic leukemia IGHV somatic hypermutation detection by targeted capture next-generation sequencing

  Somatic hypermutation (SHM) status of the immunoglobulin heavy variable (IGHV) gene locus plays a crucial role in determining the prognosis and treatment of patients with chronic lymphocytic leukemia (CLL). A common approach for determining SHM status is multiplex PCR of the IGH gene followed by Sanger sequencing; however, this technique is low throughput, vulnerable to failure, and does not allow multiplexing with other molecular diagnostic assays. Here we designed and validated a DNA targeted capture approach that allows the assessment of IGHV SHM status as a sub-module of a larger next-generation sequencing (NGS) assay. We developed an end-to-end assay that takes as input raw FASTQ files and outputs a report containing IGHV SHM status and V-allele usage following the guidelines of the European Research Initiative on CLL (ERIC). We validated the approach on 35 CLL patient samples, 34 of which were previously characterized using Sanger sequencing. The targeted capture NGS panel identified the SHM status of 34 of 35 CLL patients. We showed 100% sensitivity and specificity among the 33 CLL samples with both NGS and Sanger calls. Furthermore, we demonstrated that this panel can be combined with additional targeted capture panels to detect common and prognostically important CLL single nucleotide variants (SNV) and insertion/deletion (indel) variants as well as copy number variants (del17p). Thus, a targeted capture approach to IGHV SHM detection can be easily integrated into broader sequencing panels, allowing broad CLL prognostication in a single molecular assay.

  Study EGAS00001006887

• Whole Exome Sequencing data of six chRCC tumors corresponding to three patients

  Mammalian target of rapamycin (mTOR) is a central regulator of mammalian metabolism and physiology. Aberrant hyperactivation of the mTOR pathway promotes tumor growth and metastasis, and can also promote tumor resistance to chemotherapy and cancer drugs; this makes mTOR an attractive cancer therapeutic target. mTOR inhibitors have been approved to treat cancer; however, the mechanisms underlying drug sensitivity remain poorly understood. Here, whole exome sequencing of three chromophobe renal cell carcinoma (chRCC) patients with exceptional mTOR inhibitor sensitivity revealed that all three patients shared somatic mutations in the deubiquitinase USP9X. The clonal characteristics of the mutations, which were amassed by studying multiple patients’ primary and metastatic samples from various years, together with the low USP9X mutation rate in unselected chRCC series, reinforced a causal link between USP9X and mTOR inhibitor sensitivity. Rapamycin treatment of USP9X-depleted HeLa and renal cancer 786-O cells, along with the pharmacological inhibition of USP9X, confirmed that this protein plays a role in patients’ sensitivity to mTOR inhibition. USP9X was not found to exert a direct effect on mTORC1, but subsequent ubiquitylome analyses identified p62 as a direct USP9X target. Increased p62 ubiquitination and the augmented rapamycin effect upon bortezomib treatment, together with the results of p62 and LC3 immunofluorescence assays, suggested that dysregulated autophagy in USP9X-depleted cells can have a synergistic effect with mTOR inhibitors. In summary, we show that USP9X constitutes a potential novel marker of sensitivity to mTOR inhibitors in chRCC patients, and represents a clinical strategy for increasing the sensitivity to these drugs.

  Study EGAS00001007104

• What is a DAC?

  What is a DAC? Given the complexity, scale, and diversity of global submitters and studies, the EGA operates a distributed data access model in which requests are made to the data controller, not to the EGA. The European Commission defines a data controller, in the General Data Protection Regulation (GDPR), as the person that determines the purposes for which and the means by which personal data is processed. A Data Access Committees, commonly referred to as DACs, comprise on or more individuals (or data controllers) that review data access requests and make decisions on who can access personally identifiable genetic, phenotypic, and clinical data deposited at the EGA. Therefore, the members of a DAC should be individuals who have the authority to approve data access requests. The animation describes how you can authorise access to your sensitive data with the help of Data Access Committee and Authorisation tool. Acknowledgement to CSC - IT Center for Finland, Elixir Finland, Elixir Europe. Frequently Asked Questions How can I create a Data Access Committee? How can I create a Data Access Committee? The members of a DAC can come from different areas of expertise, such as data management, data analysis, information technology, legal and compliance, subject matter experts, privacy and security, and representatives from the organisations or individuals that provide data to the DAC. The specific members of a DAC can vary depending on the needs of the organisation and the type of data being managed. The EGA strongly suggests checking with your organisation to align with its regulations How should a DAC be named? The chosen name must be informative to the applicant.  For example, internal identifiers, such as grant numbers, should not be used. Individual PI names should also not be used. DAC's are often named after the organisation or department of the data source.  Browse the full list of DAC names currently in the EGA. How can I become an EGA DAC contact? To register a DAC at the EGA you must create first as an EGA user. Once your EGA user has been approved by the Helpdesk team, you will be able to log in to the DAC Portal. How can I register a DAC? To register a DAC, follow the DAC Portal instructions.  You will be required to provide a DAC name, name of the individual(s) that make up your DAC and contact details for your DAC including your Institutional email(s). Wherever possible, the DAC should make sure that all points of contact are readily available and able to answer any initial data requests/queries in < 2 weeks.  Once your DAC is registered, you will have to wait upon the validation from our Helpdesk team. As soon as all the validations have been completed, your DAC will be activated. Alternatively, you can also establish a DAC at the EGA during a programmatic submission through Webin API. Which are the possible roles of a DAC contact? There are two possible roles for DAC contacts: member and admin. An admin has additional privileges compared to a member: An “admin” can manage data requests, create and edit policies, edit the content of the DAC, add or remove contacts, and decide the role of each contact. A “member” can manage data requests and create policies. However, a member does not have permission to modify DAC details, edit information from policies where they are not admins, or add/remove contacts. There is no limit to the number of admins in a DAC, and each admin is responsible for deciding who should have editing privileges. This allows for a more decentralised and democratic approach to managing the DAC. How can I modify the information of a DAC? To modify a DAC, follow the instructions here. Keep in mind that only DAC contact with an admin role can modify the information of a DAC. If your DAC was registered before the lauch of the DAC Portal, and its ID is EGAC0 (not EGAC5), you must use the programmatic submission to modify it. Please, do not hesitate to contact our Helpdesk team if you need help with this! To prevent potential data breaches and ensure adherence to GDPR regulations, it is essential that the European Genome-Phenome Archive (EGA) is informed via the Helpdesk team of any changes to the Data Access Committee (DAC). This should be done in addition to any changes being made on the DAC portal. Data Controllers (as per the definition in the DPA) are also responsible for notifying the previous DAC of any modifications. Without proper notification, changes might not be automatically updated in our system, leading to the risk of incorrect permissions being applied and potential data access issues. Therefore, it is imperative that all Data Controllers follow this protocol to maintain data integrity and security. What’s the link between DAC, policy and dataset? A dataset is linked to one single policy. At the same time, one policy has a one to one relationship with a DAC. In this example, you can see that in this dataset page, we are only showing the information of one DAC (1 dataset - 1 DAC). However, the ratio of objects does not work the same in the other direction. One DAC can own multiple policy objects. And each policy object can be reused in several datasets. Thus, one DAC can manage one or more datasets. In this example, you can see that in this DAC page, we are showing all the datasets that are managed by one DAC (1 DAC - >400 datasets). EGA Data Access Committee Best Practices Which are the EGA DAC best practices? Refer to DAC Best Practices What happens if a DAC member changes institutions? EGA is committed to the protection and ownership of the data stored in our systems. We respect the institution's ownership of the data, and as such, if a DAC member changes institutions, the ownership of the data will not be transferred to the new institution. Therefore, before changing institutions, we request that the DAC contact add a new member who will replace them once they no longer work at the institution. This ensures that the data remains protected and is accessible to authorised personnel at the institution. To prevent potential data breaches and ensure adherence to GDPR regulations, it is essential that the European Genome-Phenome Archive (EGA) is informed via the Helpdesk team of any changes to the Data Access Committee (DAC). This should be done in addition to any changes being made on the DAC portal. Data Controllers (as per the definition in the DPA) are also responsible for notifying the previous DAC of any modifications. Without proper notification, changes might not be automatically updated in our system, leading to the risk of incorrect permissions being applied and potential data access issues. Therefore, it is imperative that all Data Controllers follow this protocol to maintain data integrity and security. What happens if EGA detects an unresponsive DAC? EGA defines an unresponsive DAC as a DAC with one or more contacts who do not respond to data access requests. EGA has procedures in place to identify these types of DACs, escalate the issue, and attempt to reassign the DAC to a responsive contact. This is a crucial step in ensuring that data can be accessed and utilised by researchers. If EGA identifies an unresponsive DAC, the organisation will first try to resolve the issue by escalating it to the appropriate parties. This may involve attempting to reassign the DAC to a more responsive contact. Unfortunately, in situations where we cannot reassign the DAC, the dataset will be withdrawn from the public website and the files will be removed from our system. If an EGA ID is referenced in a publication, the EGA will take extra steps to ensure that the public is made aware of the data's unavailability. I don't want to receive an email notification for pending requests. How can I do that? If you are an EGA DAC with pending requests, you will always receive emails for new data access requests. However, the EGA understands that a request resolution can take some time, for this reason, if you add a comment (make sure you save it by clicking the APPLY button!) we will filter those requests at the time of sending the notification! How can I manage data access requests? What documentation does the DAC need to provide? Each dataset that is submitted to the EGA must be linked to a policy object. The policy is a Data Access Agreement (DAA), which defines the terms and conditions of using the dataset, such as how the data files should be stored once downloaded or details of publication embargoes that should be observed by the approved user. As part of the Data Access Agreement, information regarding the application can be captured to help inform the DAC when making its decision. For example, requestors could be asked to provide a proposed title for their research and a proposal of how the data will be used. By asking for provision of such information the DAC can be assured that the requestor fully understands any consents associated with the data. It is important that accounts created at the EGA, are created solely for those individuals that will be downloading the data from the EGA. As part of the data access request, we strongly encourage you to identify individuals that will need an account at the EGA in order to prevent sharing of login details, which is strictly prohibited under EGA user account policy. Such information can easily be captured in the DAA. NOTICE The data access agreement template below is provided for guidance only and should be adapted as you see fit to suit your own purpose. In the interest of promoting data sharing, we suggest that if an agreement cannot be met around clause 19 in this example that both parties should agree to remain silent, and that the clause should be removed from the agreement. Example DAA How can the DAC provide the DAA? The DAC should provide their own DAA when registering a policy. Data requestors will download this document and should fill it in and send it back to the DAC. Data access decisions should be based on such documentation. The DAA can be downloaded through the request data webpage. Once it has been filled in, the signed copy of the DAA can be uploaded back to the request data webpage and sent to the DAC for review. How can I grant access to the data? Once you receive a data access request, you can login to the DAC Portal. In this portal you will see all your pending requests and will be able to grant or decline access to the requestors. I am a member of the Data Access Committee. Could I approve somebody else to deal with the requests on my behalf? If you want to delegate data access decisions to someone else, make sure that the individual's account is officially registered as a member of the DAC. Remember that a DAC contact with an "admin" role can always add new members to an existing DAC, remove members, and modify contact details through the DAC Portal. Can I automatise the process of managing data access requests? The answer is yes! You can use a programmatic approach using our DAC API! Check out the DAC API specification! Data Breach What should a DAC do if they suspect a breach? If a DAC suspects a data breach of one or more of their datasets, they should immediately contact the EGA Helpdesk team at this link. The DAC must provide the following information when contacting the EGA Helpdesk team: A list of affected datasets An estimated date of the data breach (or interval of dates) A list of unauthorised users who accessed the data (if available). Otherwise, they can provide a list of authorised users for the affected datasets Any observations they would like to raise to the EGA team Once the DAC has contacted the EGA team, we will respond within 48 hours (please allow some leeway during peak times) and activate our data breach protocol. What can I expect from the EGA if they detect a breach? Once the EGA determines that a security incident has occurred, we will notify all DAC members that a data breach has been detected, and take steps to contain the incident. Containment approaches may include: Revoking a data provider's access to the EGA resources, such as by changing passwords. Removing affected EGA datasets from distribution, such as by withdrawing a dataset. Disabling certain functions or services, such as the EGA ingestion pipeline. Shutting down the system or disconnecting it from the network. After the incident has been contained, the EGA will determine whether it is necessary to eradicate components related to the incident. Finally, the EGA will enable recovery of the service to normal operation and confirm that all services are functioning normally.

  Documentation access/data-access-committee/what-is-dac

• A super-enhancer associated with CD47 links pro-inflammatory signaling to CD47 upregulation in breast cancer

  CD47 is a cell surface molecule that inhibits phagocytosis of cells that express it by binding to its receptor, SIRP&#945;, on macrophages and other immune cells. CD47 is expressed at different levels in normal cells, however, in cancer cells, CD47 transcript and protein expression is aberrantly increased. Here we sought to uncover the regulators of CD47 transcription, including active enhancers that increase its aberrant expression in cancer cells, in order to reveal mechanisms by which different neoplastic cells generate this dominant &#39;don&#39;t eat me&#39; signal. Enhancers are genomic regions, often referred to as "switches", that can turn on or off the transcription of target genes. Recently the discovery of super-enhancers (SEs) has given more insight into the regulatory architecture of key genes that are highly expressed in a specific cell type, during a particular developmental stage or in disease. By analyzing the CD47 regulatory genomic landscape, we discovered: i) A distinct super-enhancer (SE) is associated with CD47 upregulation in breast cancer cells ii) Disruption of CD47 SEs by using the BRD4 inhibitor JQ1 robustly reduces CD47 gene expression; and iii) The TNF-NFKB1 signaling pathway is directly involved in the regulation of CD47 by interacting with a distal downstream constituent enhancer located within a CD47-associated SE specific to breast cancer. Our results describe a novel mechanism that cancer cells have evolved to drive CD47 overexpression to escape immune surveillance.

  Study phs001264

• 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

• 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&gt;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

• The Medical Genome Reference Bank: a whole genome data resource of 4,000 healthy elderly individuals.

  Allele frequency data from human reference populations is of increasing value for filtering and assignment of pathogenicity to genetic variants. Aged and healthy populations are more likely to be selectively depleted of pathogenic alleles, and therefore particularly suitable as a reference populations for the major diseases of clinical and public health importance. However, reference studies of the healthy elderly have remained under represented in human genetics. We have developed the Medical Genome Reference Bank (MGRB), a large scale comprehensive whole genome dataset of confirmed healthy elderly individuals, to provide a publicly accessible resource for health related research, and for clinical genetics. It also represents a useful resource for studying the genetics of healthy aging. The MGRB comprises 4,000 healthy, older individuals with no reported history of cancer, cardiovascular disease or dementia, recruited from two Australian community based cohorts. DNA derived from blood samples will be subject to whole genome sequencing. The MGRB will measure genome wide genetic variation in 4,000 individuals, mostly of European decent, aged 60 to 95 years (mean age 75 years). The MGRB has committed to a policy of data sharing, employing a hierarchical data management system to maintain participant privacy and confidentiality, whilst maximizing research and clinical usage of the database. The MGRB will represent a dataset of international significance, broadly accessible to the clinical and genetic research community.

  Study EGAS00001003511

• A novel orthotopic patient-derived xenograft model of radiation-induced glioma following medulloblastoma

  Radiation-induced glioma (RIG) is a highly aggressive brain cancer arising as a consequence of radiation therapy. We report a case of RIG that arose in the brain stem following treatment for paediatric medulloblastoma, and the development and characterisation of a matched orthotopic patient-derived xenograft (PDX) model (TK-RIG915). Patient and PDX tumours were analysed using DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing. While initially thought to be a diffuse intrinsic pontine glioma (DIPG) based on disease location, results from methylation profiling and WGS were not consistent with this diagnosis. Furthermore, clustering analyses based on RNA expression suggested the tumours were distinct from primary DIPG. Additional gene expression analysis demonstrated concordance with a published RIG expression profile. Multiple genetic alterations that enhance PI3K/AKT and Ras/Raf/MEK/ERK signalling were discovered in TK-RIG915 including an activating mutation in PIK3CA, upregulation of PDGFRA and AKT2, inactivating mutations in NF1, and a gain-of-function mutation in PTPN11. Additionally, deletion of CDKN2A/B, increased IDH1 expression, and decreased ARID1A expression were observed. Detection of phospho-S6, -4EBP1 and -ERK via immunohistochemistry confirmed PI3K pathway and ERK activation. Here, we report one of the first PDX models for RIG, which recapitulates the patient disease and is molecularly distinct from primary brain stem glioma. Genetic interrogation of this model has enabled the identification of potential therapeutic vulnerabilities in this currently incurable disease.

  Study EGAS00001004709

• Clonal heterogeneity leads to secondary resistance in a melanoma patient after adoptive cell therapy with tumor-infiltrating lymphocytes

  Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is effective in melanoma patients, although long-term responses seem restricted to patients with complete remissions. Many patients develop secondary resistance to TIL-ACT but involved mechanisms are unclear. Here, we describe a case of secondary resistance to TIL-ACT likely due to intratumoral heterogeneity and selection of a resistant tumor cell clone via transferred T cells. This is the first case of clonal selection of a pre-existing non-dominant tumor cell clone and demonstrates a new mechanism involved in secondary resistance to TIL-ACT and could potentially change current clinical practice, because it advocates for T cell collection from different tumor sites and analysis of tumor heterogeneity before the treatment with TIL-ACT.

  Study EGAS50000000279

• A benchmarking resource for NGS testing of cancer predisposition genes

  A benchmarking resource of 639 individuals, to assess the analytical sensitivity of cancer predisposition gene (CPG) testing.The dataset includes sequencing data generated using the TruSight Cancer Panel (TSCP) a targeted NGS assay for analysis of CPGs and orthogonally generated data supporting at least one pathogenic variant in a CPG for a total of 645 pathogenic CPG variants.The set of pathogenic CPG variants includes strong representation of some of the most challenging types of pathogenic variants, with 339 indels, including 16 complex indels and 24 insertions or deletions with length greater than 5bp, and 74 exon CNVs, including 23 single exon CNVs. There are 502 pathogenic variants in BRCA1 or BRCA2, making this an important first-line validation dataset for laboratories performing NGS testing of BRCA1 and BRCA2.

  Study EGAS00001002993

• The Research Institute at Nationwide Children's Hospital Genetics of Congenital Heart Disease (CHD)

  Congenital heart disease (CHD) is the most common type of birth defect, but the cause for the majority of cardiac birth defects remains unknown. Numerous epidemiologic studies have demonstrated evidence that genetic factors likely play a contributory, if not causative, role in CHD. A few genes have been identified by us and other investigators using traditional genetic approaches, but these genes only account for a small portion of the non-syndromic CHDs. Therefore, we are now utilizing whole exome sequencing (WES) and whole genome sequencing (WGS), with the addition of more traditional genetic techniques such as chromosomal microarray or traditional linkage analysis, to identify genetic causes of familial and isolated CHD. With WES/WGS, we are able to sequence all of the genes of an individual and apply different data analysis techniques based on whether we are analyzing a multiplex family or a cohort of trios (mother, father and child with CHD) with a specific isolated CHD. Therefore, WES/WGS is a robust method for identification of novel genetic causes of CHD, which will have important diagnostic and therapeutic consequences for these children. Subjects provided blood samples, skin biopsy, or saliva samples for DNA extraction and creation of cell lines. Tissue remaining after surgical procedures was also collected. Medical records were searched for detailed phenotype data and subjects were followed longitudinally for outcome.

  Study phs002010

• ApoA-1 and Atherosclerosis in Psoriasis

  Apolipoprotein A-1 is a protein localized to high-density lipoprotein that functions to remove cholesterol from tissues for transport back to the liver. Psoriasis is a systemic inflammatory disease associated with poor high-density lipoprotein function and accelerated non-calcified burden by coronary computed tomographic angiography. In this study, 310 psoriasis patients from The Psoriasis, Atherosclerosis, and Cardiometabolic Disease Initiative (PACI) were studied at baseline to determine if levels of circulating apolipoprotein A-1 predict early onset coronary artery disease in inflammatory conditions. Of the 310 participants, 124 were followed for four years to determine if apolipoprotein A-1 predicts non-calcified coronary burden over time. The primary outcome of this study was non-calcified coronary burden by coronary computed tomography angiography. To assess non-calcified coronary burden, participants underwent coronary computed tomography angiography using the same scanner (320-detector row Aquilion ONE ViSION, Toshiba, Japan). For ApoA-1 quantification, fasting blood draw was performed the same day as the coronary computed tomography angiography. The 400MHz proton Vantera Clinical Analyzer was used to quantify Plasma apolipoprotein A-1. The study determined that low levels of apolipoprotein A-1 are associated with increased coronary artery burden and that this relationship persists over time. The data are available through dbGaP and the dataset includes all variables reported in the manuscript.

  Study phs003231

• NHLBI TOPMed: Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH)

  During Visit One, the PUSH Study will perform echocardiography on 600 children and adolescent with patients with sickle cell disease (SCD) and 100 control children and adolescents at three Field Centers, namely Howard University, Children's National Medical Center and University of Michigan. Patients or their parents will be approached and asked to give informed consent. If they appear to have a difficult reading, reading of the consent will be offered. Patients or their parents not appearing to comprehend the consent will not be eligible. As a part of this visit, each participant or parent will sign informed consent, complete a Participant Contact Information Form, complete a Medical History Form, undergo physical examination with completion of a Physical Examination Form and have blood drawn. Each participant must have echocardiography performed with measurement of Tricuspid Regurgitant Jet Velocity (TRV). In addition, attempts will be made 1) to perform a six-minute walk test, 2) to collect information from a recent (within six months) Transcranial Doppler Study (TCD) or to perform TCD, and 3) to perform pulmonary function tests. Study personnel will review all forms for completeness and conduct phlebotomy. Blood will be shipped to the Central Lab. Results of all procedures and tests will be transmitted to the Data Manager at Howard University. Sequencing was only done on sickle cell participants.

  Study phs001682

• The Bangladesh Environmental Enteric Dysfunction (BEED) Study

  Environmental enteric dysfunction (EED), a sub-acute inflammatory condition of the small intestinal mucosa of unclear etiology, has been associated with a variety of environmental exposures and host factors and is implicated in growth faltering. Linear growth faltering usually occurs within the first two years of life and in most of the cases is irreversible demanding early diagnosis for treatment to be successful. The objectives of 'The Bangladesh Environmental Enteric Dysfunction Study (BEED)' are to investigate role of EED in malnutrition, examine the biology of EED to identify common biological pathways for potential interventions, to validate a system for histological scoring for EED and test the effectiveness of nutritional interventions in improving the growth parameters in children with stunting and or EED. In Bangladesh, participants are recruited from two age groups; a child cohort and a malnourished an adult cohort. In addition, two control groups are recruited for comparison consisting of a) children that are undergoing endoscopy as a part of their clinical care at the University of Virginia Health system (UVAHS) and b) an adult well-nourished control group recruited from the Gastroenterology Outpatient Department of Dhaka Medical College and Hospital in Bangladesh. The description of the study design and procedures of the study can be obtained from Mahfuz M, Das S, Mazumder RN, et al., 2017, PMID: 28801442.

  Study phs001891

• Single cell sequencing reveals the origin and the order of mutation acquisition in T-cell acute lymphoblastic leukemia.

  Next-generation sequencing has provided a detailed overview of the various genomic lesions implicated in the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL). Typically, 10 to 20 genomic lesions are found in T-ALL cells at diagnosis. However, it is currently unclear in which order these mutations are acquired and in which progenitor cells this is initiated. To address these questions, we used targeted single-cell sequencing of total bone marrow cells and CD34+CD38- multipotent progenitor cells for 4 T-ALL cases. Hierarchical clustering detected a dominant leukemia clone at diagnosis, accompanied by a few subclones harboring only a fraction of the mutations. We developed a graph-based algorithm to determine the order of mutation acquisition. Two of the four patients had an early event in a known oncogene (MED12, STAT5B) amongst various pre-leukemic events. Intermediate events included loss of 9p21 (CDKN2A/B) and acquisition of fusion genes, while NOTCH1 mutations were typically late events. Analysis of CD34+CD38- cells and myeloid progenitors revealed that in half of the cases somatic mutations were detectable in multipotent progenitor cells. We demonstrate that targeted single cell sequencing can elucidate the order of mutation acquisition in T-ALL and that T-ALL development can start in a multipotent progenitor cell.

  Study EGAS00001002830

• Hyperhaploid Multiple Myeloma

  Hyperhaploid multiple myeloma is a rare numerical aberration group defined by a range of 24-34 chromosomes which is associated with a poor prognosis. Hyperhaploid samples were sequenced by either exome or targeted panel sequencing. Samples had a median of 13 monosomies (range 12-14), which in general were those not associated with trisomies in hyperdiploid samples. The chromosomes traditionally trisomic in hyperdiploid myeloma were disomic in hyperhaploid myeloma with retention of heterodisomy. We examined the hyperhaploid samples for frequently mutated genes and found that 9/9 (100%) hyperhaploid samples had a mutation in TP53, exceeding the overall rate of mutation in newly diagnosed patients (5.5%), indicating an oncogenic dependency in this group. All samples with TP53 mutation also had monosomy of chromosome 17, indicating bi-allelic inactivation of TP53. As such, this high risk group is part of Double-Hit myeloma. DNA was obtained from either CD138+ cells from the bone marrow of multiple myeloma patients (tumor) or from stem cell harvests from the same patient (control). 100 ng of DNA was fragmented, end-repaired, and adapters ligated using the HyperPlus kit (KAPA Biosystems). After PCR amplification the libraries were hybridized with probes against either the entire exome (MedExome, Nimblegen) or a targeted panel of 140 genes using SeqCap reagents (Nimblegen). Hybridized libraries underwent further amplification before being sequenced on a NextSeq500 (Illumina) using 75 bp paired end reads.

  Study EGAS00001003203

• Detection of mutational patterns in cell free DNA (cfDNA) of colorectal cancer by custom amplicon sequencing

  Monitoring the mutational patterns of solid tumors during cancer therapy is a major challenge in oncology. Analysis of mutations in cell free (cf) DNA offers a non-invasive approach to detect mutations that may be prognostic for disease survival or predictive for primary or secondary drug resistance. A main challenge for the application of cfDNA as a diagnostic tool is the diverse mutational landscape of cancer. Here, we developed a flexible end-to-end experimental and bioinformatics workflow to analyze mutations in cfDNA using custom amplicon sequencing. Our approach relies on open software tools to select primers suitable for multiplex PCR using minimal cfDNA as input. In addition, we developed a robust linear model to identify specific genetic alterations from sequencing data of cfDNA. We used our method to design a custom amplicon panel suitable for detection of hotspot mutations relevant for colorectal cancer and analyzed mutations in serial cfDNA samples from 34 patients with advanced colorectal cancer. Our data demonstrates that recurrent and patient-specific mutational patterns can be reliably detected for the majority of patients. Furthermore, we show that the allele frequency of mutations in cfDNA correlates well with disease progression. Finally, we demonstrate that monitoring of cfDNA can outperform the predictive power of currently used tumor markers and reveal mechanisms of resistance to anti-EGFR antibody treatment.

  Study EGAS00001003382

• Identifying genetic consequences of Epstein-Barr Virus transformation by comparing an individual’s genomic DNA with that of its lymphoblastoid cell line.

  A detailed analysis of whole genomes can be now achieved with next generation sequencing. Epstein Barr Virus (EBV) transformation is a widely used strategy in clinical research to obtain an unlimited source of a subject’s DNA. Although the mechanism of transformation and immortalization by EBV is relatively well known at the transcriptional and proteomic level, the genetic consequences of EBV transformation are less well understood. A detailed analysis of the genetic alterations introduced by EBV transformation is highly relevant, as it will inform on the usefulness and limitations of this approach. We used whole genome sequencing to assess the genomic signature of a low-passage lymphoblastoid cell line (LCL). Specifically, we sequenced the full genome (40X) of an individual using DNA purified from fresh whole blood as well as DNA from his LCL. A total of 217.33 Gb of sequence were generated from the cell line and 238.95 Gb from the normal genomic DNA. We determined with high confidence that 99.2% of the genomes were identical, with no reproducible changes in structural variation (chromosomal rearrangements and copy number variations) or insertion/deletion polymorphisms (indels). Our results suggest that, at this level of resolution, the LCL is genetically indistinguishable from its genomic counterpart and therefore their use in clinical research is not likely to introduce a significant bias.

  Study EGAS00001000323

• Structural variant analysis of homologous recombination-deficient genomes

  Homologous recombination (HR) deficiency causes DNA breaks and cytogenetic aberrations. Paradoxically, the types of DNA rearrangements specifically associated with HR-deficient cancers only minimally impact chromosomal structure. Addressing this, we combined a genome graph analysis of short-read whole genome sequencing (WGS) profiles across thousands of tumors with deep linked-read (LR) WGS of 46 BRCA1 or BRCA2 mutant breast cancers to discover a distinct class of HR deficiency-enriched rearrangements called reciprocal pairs. LR WGS showed that reciprocal pairs with identical rearrangement orientations gave rise to one of two distinct chromosomal outcomes, distinguishable only with long molecule data. While one (cis) outcome corresponded to the copy and pasting of a small segment to a distant site, a second (trans) outcome was a quasi-balanced translocation or multi-megabase inversion with substantial (10kb) duplications at each junction. The full spectrum of reciprocal pair outcomes could be explained by an HR-independent replication restart repair mechanism. LR WGS additionally identified single-strand annealing (SSA) as a BRCA2-deficiency specific repair pathway in human cancers. Replication restart- and SSA-associated SVs improved BRCA1- vs. BRCA2- deficiency classification and identified metastatic cancer cases with favorable chemotherapy responses. Our data reveal classes of BRCA1- and BRCA2-deficiency specific rearrangements as drivers of cytogenetic aberrations in HR deficient cells.

  Study EGAS00001007186

• A neoadjuvant, phase II trial demonstrates efficacy and tolerability of Talimogene laherparepvec in cutaneous basal cell carcinoma (NeoBCC trial)

  We present a single arm, phase II neoadjuvant trial with the oncolytic virus Talimogene laherparepvec (T-VEC) in 18 patients with difficult-to-resect basal cell carcinomas. Six cycles of T-VEC were applied intralesionally. The primary endpoint of the study, defined as the proportion of the patients, who after six cycles of T-VEC (13 weeks) at the time point of surgery, become resectable with primary wound closure without the need for plastic reconstructive surgery like skin flaps or skin grafts, was achieved (9/18 patients; 50.0%). Secondary endpoints also included the relapse free survival rate (100%), overall survival (100%) and biological read outs in the tumor samples. T-VEC led to a significant increase of cytotoxic T cells, B cells and myeloid cells, and a decrease of Tregs within the tumor microenvironment. We observed a potent induction of antitumoral and antiviral T cell clones, as well as a strong humoral immune response. The objective response rate was 55.6% and the complete pathological response rate was 33.3%. Only mild adverse events occurred. Together, neoadjuvant T-VEC represents a viable treatment option for patients with difficult-to-resect BCCs (EudraCT Number 2018-002165-19).

  Study EGAS50000000252

• A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells

  Molecular heterogeneity of tumors, epigenetic changes and a diverse range of molecular mechanisms are main contributors to drug resistance, which represents one of the great challenges in cancer treatment. A deeper understanding of the molecular biology of cancer has resulted in better targeted therapies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has to some extent also been observed in colorectal cancer (CRC) patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block resistance. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant CRC cells as a well-define model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both well-known and novel responses. We primarily observe widespread upregulation of tyrosine kinases (RTKs) and and metabolic pathways. This points to by which the treated cells switch energy sources as a defensive response entering a quiescent like state, while activating signalling to re-activate the MAPK pathway.

  Study EGAS00001002654

• Carbamazepine-induced hypersensitivity reactions in Europeans

  An antiepileptic drug carbamazepine is well tolerated by the majority of patients, but can cause severe and potentialy fatal hypersensitivity reactions in a small number of individuals. The aim of this study was to identify genetic predictors of hypersensitivity reactions to carbamazepine. We undertook a genome-wide association study (GWAS) in 22 patients of European ancestry with carbamazepine-induced hypersensitivity syndrome (HSS) and compared our data with genotypes from a healthy population within the WTCCC. We performed imputation of classical HLA alleles according to a recently described method (Science. 2010 Dec 10;330(6010):1551-7. Epub 2010 Nov 4). GWAS statistical analysis was performed using logistic regression with an additive model of inheritance.

  Study EGAS00000000037

• RNA-Sequencing of cervical cancers

  Question: Can we identify cervical cancer patients who are at risk for distant metastatic (DM) recurrence following treatment with radiotherapy, concurrent weekly cisplatin and brachytherapy (RTCT). Findings: An immune-based 55 gene risk score was developed using a cohort of 81 patients treated with RTCT that was strongly predictive of DM and cause-specific survival (CSS). The risk score was validated in two independent patient cohorts. A high immune metastatic risk score was associated with a high tumor mutational burden and a ‘cold’, immune-excluded tumor microenvironment at diagnosis. Meaning: The immune gene expression risk score may help to identify patients at risk of DM and potential targets for mitigating this risk.

  Study EGAS50000000087

• Alcohol Dependence: Sequencing from Multiplex Families

  Two multiplex for alcohol dependence family studies were initiated based on the gender of a pair of probands. Ascertainment of a pair of AD probands was used to increase the density of alcohol dependence within the family. Identification of male (Cognitive and Personality Factors in Relatives of Alcoholics Family Study) and female (Biological Risk Factors in Female Alcoholics Family Study) alcohol dependent probands was accomplished by identifying an alcohol dependent proband while in treatment in a substance abuse treatment facility in Pittsburgh and surrounding communities who provided contact information for a sibling whom he/she thought might be interested in participating. The studies had identical ascertainment requirements. DNA was banked for all willing participants.

  Study phs001775

• Genomic Landscape of High-Grade Neuroendocrine Neoplasms

  This project is a multi-omics study of high grade (grade 3) neuroendocrine neoplasms across diverse organs. Genomic analysis using low-pass whole genome sequencing for copy number analysis, whole exome sequencing and whole transcriptomic sequencing using RNAseq were performed. As high grade neuroendocrine neoplasms are highly lethal with a median survival of approximately 7 months, new insights are urgently needed for better prognosis, diagnosis and management. This study focuses on gene and pathway discoveries in this cancer, and includes samples from a diverse set of organs, including the lungs, gastroenteropancreatic tract, breast, prostate, head and neck and bladder. This study was made possible by a generous donation from The Helen B. Rodde Fund.

  Study phs002070

• Sweden-Schizophrenia Population-Based Case-Control Exome Sequencing

  Current findings of the genetic risk of schizophrenia and bipolar disorder emerging from genome wide association studies (GWAS) support a highly polygenic model displaying the full spectrum of causal alleles that includes the extremes of rare, penetrant alleles as well as common alleles of small effect. Lower frequency polymorphism, rare variants and private mutations have eluded measurement by GWAS studies and thus association with disease. In order to create a comprehensive catalogue of low frequency or rare coding variation in individuals with psychiatric disease and to build a foundation for future genetic studies of schizophrenia and bipolar disorder, we have obtained whole exome DNA sequence from a population-based schizophrenia and bipolar disorder Swedish case-control cohort.

  Study phs000473

• Next-generation molecular analysis of surgical margins in oral squamous cell carcinoma for assessment of microscopic residual disease and personalized postoperative treatment decision

  Background : Patients operated for an early oral squamous cell carcinoma (OSCC) with clear margins have a 5-year local relapse rate of around 15%. Assessing the microscopic residual disease (MRD) remains a challenge. In a phase II prospective trial, we evaluated the tetranucleotide microsatellite instability markers in the surgical margins in T1-T2 OSCC resected with pathologically clear margins. Goal : Detect MRD in surgical margins and adapt the postoperative decision-making Details : Whole exome sequencing (WES) on early oral squamous cell carcinoma (OSCC) with clear margins, and on resection margins, 86 patients with a median follow-up of 58 months (range 30.4-83 months)

  Study EGAS50000000823