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• Pre-diagnostic saliva microbiota of Finnish children with autoimmune diseases

  Pre-diagnostic saliva microbiota samples of Finnish children (aged 11/12 years). This is a case-control study, where case refers to the children who developed Type 1 DM or IBD later in life and control refers to the children who were free from these diseases. The aim of the study was to find biomarkers in saliva microbiota that may help us predict DM or IBD before the onset of these diseases.

  Study EGAS00001006949

• Inhibiton of the GABPB1L-containing GABP tetramer is sufficient to reverse replicative immortality in TERT promoter mutant glioblastoma cells.

  Over 50 types of cancer acquire TERT promoter mutations. These single point mutations reactivate telomerase, allowing for indefinite maintenance of telomere length and enabling cellular immortalization. The transcription factor binding site created by the point mutations specifically recruit the ETS factor GABP, a multimeric transcription factor composed of the GABPα and GABPβ subunits. GABP can form two functionally independent transcription factor species – a dimer or a tetramer – depending on which of the structurally distinct GABPβ isoforms is incorporated into the complex. In this study, we show that genetic disruption of GABPβ1L, a tetramer forming isoform of GABPβ that is dispensable in normal development, results in TERT silencing in a TERT promoter mutation dependent manner. Failure to activate TERT expression by GABPβ1L culminates in telomere dysfunction, DNA damage, and mitotic cell death exclusively in TERT promoter mutant cells. Furthermore, exogenous expression of TERT is sufficient to prevent telomere degradation and loss of cell viability in GABPβ1L-reduced lines bearing the mutant TERT promoter. Orthotopic injection of tetramer-deficient mutant TERT promoter GBM cells rendered lower tumor burden and prolonged the overall survival of the tumor-bearing mice. These results highlight the potentially widespread role of GABPB1L in enabling replicative immortality of TERT promoter cancers.

  Study EGAS00001002582

• Circulating cell-free DNA methylation profiles as noninvasive multiple sclerosis biomarkers: A proof-of-concept study

  In chronic neurodegenerative diseases such as multiple sclerosis (MS), there is a critical unmet need for cost-effective non-invasive blood biomarkers to concurrently classify disease subtypes, monitor disability severity, and predict long-term progression. In this proof-of-concept study, we performed low-coverage whole-genome bisulfite sequencing (WGBS) on 75 plasma cell-free DNA (cfDNA) samples collected from a well-characterized real-world prospective clinic cohort with longitudinal disability outcome measurements. We assessed the clinical utility of cfDNA methylation profile for differentiating MS patients from non-MS controls, classifying MS subtypes, estimating disability severity, and predicting disease trajectories.

  Study EGAS50000001277

• Searching for variants associated with endometriosis

  We explored regulatory mechanism of a SNP on chromosome 9p21 associated with endometriosis by leveraging “allele-specific” functional genomic approaches. By re-sequencing 1.29 Mb of 9p21 region and scrutinizing DNase-seq data from the ENCODE project, we prioritized rs17761446 as a candidate functional variant that was in perfect linkage disequilibrium with the original GWAS SNP (rs10965235) and located on DNase I hypersensitive site. Chromosome conformation capture followed by high-throughput sequencing revealed that the protective G allele of rs17761446 exerted stronger chromatin interaction with ANRIL promoter. We demonstrated that the protective allele exhibited preferential binding affinities to TCF7L2 and EP300 by bioinformatics and chromatin immunoprecipitation (ChIP) analyses. ChIP assays for histone H3 lysine 27 acetylation and RNA polymerase II reinforced the enhancer activity of the SNP site. The allele specific expression analysis for eutopic endometrial tissues and endometrial carcinoma cell lines showed that rs17761446 was a cis-regulatory variant where G allele was associated with increased ANRIL expression.

  Study EGAS00001001741

• Final results and ctDNA analyses from the randomized phase 3 IMpassion031 trial evaluating peri-operative atezolizumab for early-stage triple-negative breast cancer

  In IMpassion031, adding atezolizumab to neoadjuvant chemotherapy significantly improved pathologic complete response (pCR) rate (primary endpoint) for stage II/III triple-negative breast cancer (TNBC). Patients with stage II/III TNBC were randomized 1:1 to neoadjuvant chemotherapy plus peri-operative atezolizumab or pre-operative placebo. Descriptive secondary endpoints included event-free, disease-free, and overall survival. Long-term outcomes favored the atezolizumab group (event-free survival HR 0.76, 95% CI: 0.47–1.21). Among patients without pCR, 14/70 (20%) atezolizumab-treated and 33/99 (33%) placebo-treated patients received additional adjuvant therapy, frequently capecitabine. In exploratory analyses, pCR was prognostic for long-term outcome. Patients with baseline ctDNA-negative status (6%) had excellent long-term outcomes. Most patients (87%) had cleared ctDNA at surgery. ctDNA-positive status at surgery identified a subset of non-pCR patients with poorest prognosis. Long-term safety was consistent with primary results. Adding atezolizumab to chemotherapy for stage II/III TNBC is associated with more favorable long-term outcomes. ctDNA dynamics provide prognostic value beyond pCR. ClinicalTrials.gov identifier: NCT03197935

  Study EGAS50000000974

• POT1_splice_site_mutant_analysis

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

  Study EGAS00001000571

• non-malignant plasma cfRNA

  Dataset contains mRNA capture sequencing data from plasma of 125 different human donors: 88 patients with a non-malignant disease and 37 cancer-free controls. Samples were sequenced on a NovaSeq X and sequencing data is provided in FASTQ format.

  Dataset EGAD50000001806

• FFPE, buffycoat and cell free DNA from N. German esophagus cancer patients - 2021

  We recruited 28 patients and sequenced samples from their FFPE tissue, full blood buffy coat and plasma cell free DNA from diagnosis and other, longitudinal time points. The cell free DNA was sequenced ultra-deeply. The IDT PanCancer panel was used for targeted enrichment. Aims: detection of primary tumor mutations in cell free DNA, overlap and difference in mutation profiles between primary tumor, metastases and cell free DNA.

  Study EGAS00001006813

• Data access to Small RNA-Seq of MicroRNA's in Tear EV's of Ushers Syndrome patients

  Via this DAC you can get access to Small RNA-Seq dataset of MicroRNA's in Tear EV's of Ushers Syndrome patients. The study involved genetically confirmed USH1B patients and their healthy relatives, with additional fibroblast samples from Spanish collaborators, to ensure a robust comparison of small non-coding RNAs (sncRNAs). Tear and blood samples were collected using non-invasive methods, and extracellular vesicles (EVs) were isolated from both tears and hiPSC-derived retinal pigment epithelium (RPE) cells. RNA was extracted from these EVs and assessed for quality before preparing libraries using the TruSeq Small RNA Library Preparation Kit. Sequencing was performed on the Illumina NextSeq 2000 platform, generating data for comparative analysis of sncRNA profiles between patients and controls.

  Dac EGAC50000000711

• NHLBI TOPMed - NHGRI CCDG: Pakistan Risk of Myocardial Infarction Study (PROMIS)

  The Pakistan Risk of Myocardial Infarction (PROMIS) study is a retrospective multicenter case-control cohort study of individuals with and without coronary heart disease from Pakistan. Multiple biological samples have been collected from the participants including DNA, plasma, serum, and whole blood. The goal of the study is to recruit 20,000 cases and 20,000 controls of Pakistani descent. Eligible cases were individuals aged 30-80 who presented to the emergency department of a participating recruitment center in Pakistan with clinical symptoms consistent with a myocardial infarction (MI), ECG changes consistent with MI, elevated troponin levels consistent with MI, and no prior history of cardiovascular disease. Controls were individuals of Pakistani descent who did not have a self-reported history of cardiovascular disease. This site hosts data generated via NHLBI's TOPMed program and NHGRI's Common Disease Genomics (CCDG) program. Both whole exome and whole genome data are presented here, namely 4,211 whole genomes from TOPMed, 3,859 whole genomes from NHLBI supplemental funds, 1,136 whole genomes and 16,855 whole exomes from CCDG. Please note that there is additional legacy whole exome data (7,298 subjects) also generated via NHGRI funds as part of the MIGen Exome Sequencing project that can be found in dbGaP at phs000917.

  Study phs001569

• Acute Respiratory Distress Network (ARDSNet) Studies 10 and 12 Statins for Acutely Injured Lungs from Sepsis (SAILS) (ARDSNet-SAILS-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Biospecimens Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-SAILS include Plasma, DNA, and Urine. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives The SAILS trial was intended to assess the efficacy and safety of oral rosuvastatin in participants with sepsis-induced Acute Lung Injury (ALI) and test the hypothesis that rosuvastatin therapy would improve the clinical outcomes of critically ill participants with sepsis-associated acute respiratory distress syndrome (ARDS). Background In ARDS, inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in participants with sepsis. Participants There were 745 participants. Design Participants were randomly assigned in permuted blocks to receive either enteral rosuvastatin or placebo. A 40 mg loading dose of the study drug was administered within four hours after randomization. Subsequently, maintenance doses of 20 mg were administered daily until the third day after discharge from the intensive care unit, study day 28, hospital discharge, or death, whichever came first. The primary outcome measure was mortality before hospital discharge home or until study day 60 if the participant was still in a health care facility. Secondary outcome measures included the number of ventilator-free days to day 28, organ-failure-free days to day 14, and ICU-free days to day 28. Conclusions The study was stopped because of futility after 745 of an estimated 1000 participants had been enrolled. There was no significant difference between study groups in 60 day in-hospital mortality or in mean ventilator-free days. The rosuvastatin group had fewer days free of hepatic or renal failure. Thus, rosuvastatin therapy did not improve clinical outcomes in participants with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction.

  Study phs003736

• Analysis_of_genomic_integrity_of_disease_corrected_human_induced_pluripotent_stem_cells_by_exome_sequencing

  Induced pluripotent stem (iPS) cells hold great promise for autologous cell transplantation. In order to apply this therapy to monogenic disorder, disease-causing mutations must be corrected prior to transplantation. We generated iPS cells from patients with alpha-1 antitrypsin deficiency, which is caused by homozygous non-synonymous mutation in the SERPINA1 gene. In vitro differentiation of patient-derived iPS cells to hepatocytes showed recapitulation of the disease phenotype. We corrected the mutations by gene targeting using zinc finger nuclease (ZFN) and piggyBac transposon technologies. Our mutation correction is highly accurate. There is no exogenous sequence left behind at the targeted site. The corrected iPS cell-derived hepatocytes were indistinguishable from healthy hepatocyte, suggesting that the corrected gene was fully functional. The genomic integrity was also analyzed by CGH and SNP array, showing no genomic alterations. These are important points to ensure clinical safety as well as functional restoration of the corrected gene. One remaining question is if these corrected iPS cells are clinically safe at the single base-pair level. Recent publications suggested that cancer-related mutations are significantly accumulated during iPS cell propagation. We aim to assess the clinical safety of the corrected iPS cells by using exome sequencing. Outcome from this project would bring iPS cell technology one step closer to clinical applications.

  Study EGAS00001000055

• Discrepancies in Tumour Mutation Burden (TMB) reporting from sequential Endobronchial ultrasound trans bronchial needle aspiration (EBUS TBNA) samples within single lymph node stations

  Introduction: Tumour Mutation Burden (TMB) is a potential biomarker for immune therapies. Identifying factors that may affect TMB prediction is key to its utility as biomarker for treatment options. Here we investigated parameters that might affect TMB using cytology smears obtained from endobronchial ultrasound transbronchial needle aspiration (EBUS TBNA)-sampled malignant lymph nodes, which are often the only diagnostic samples collected in patients with advanced lung cancer. Methods: Individual Diff-Quik cytology smears were prepared for each needle pass from the same enlarged malignant mediastinal lymph nodes. DNA extracted from smears of each pass underwent sequencing using a large gene panel sequencing (TSO500, Illumina). TMB was estimated for each individual needle pass using the TSO500 Local App v. 2.0 (Illumina). Results: Twenty patients had two or more Diff-Quik smears (total 45 smears) which passed sequencing quality control. Average TMB for all smears was 8.7 ± 5.0 mutations per megabase (Mb). Sixteen of the 20 patients had paired samples with minimal differences in TMB score (average difference 1.3 ± 0.85). Paired samples from 13 patients had concordant TMB in terms of scores being below or above a threshold of 10 mutations/Mb. Samples from seven patients had discrepant TMB, with four cases in particular exhibiting an average difference of 11.3 ± 2.7 mutations/Mb. Factors affecting TMB calling involved tumour content of the samples, the amount of DNA used in sequencing as well as bone fide intra tumour heterogeneity between paired samples. Conclusions: TMB assessment is feasible from EBUS-TBNA derived Diff-Quik slides from a single needle pass. Repeated samples of one or more lymph nodes have minimal variation in TMB in most cases (80%), suggesting accuracy of the test overall. To enhance accuracy of the result, care should be taken in relation to the tumour content of the cytology smear. Further, clinicians should be aware that even slight differences in lymph node site selection could give rise to variable genomics and discrepant TMB due to tumour heterogeneity. Therefore, it would be reasonable for multi-lymph node site analysis of TMB to be performed using EBUS TBNA aspirates from different easily accessible lymph nodes. Further investigations need to determine whether these samples should be combined as one sample or tested separately.

  Study EGAS00001007484

• Whole transcriptome profiling of liquid biopsies from tumour xenografted mouse models: validation cohort

  While cell-free DNA (cfDNA) in liquid biopsies is widely being used and investigated, free circulating RNA (extracellular RNA, exRNA) has the potential to improve therapy response monitoring and cancer detection due to its dynamic nature. A fundamental open question hampering the initiation of large-scale liquid biopsy collections for tumour exRNA analysis is that it remains unclear in which blood subcompartment tumour-derived exRNAs primarily reside. We set out to develop a host-xenograft deconvolution framework, exRNAxeno, with cDNA mapping strategies to either a combined human-mouse reference genome or both species genomes in parallel, that can be applied to exRNA sequencing data from liquid biopsies of human xenograft mouse models, enabling to distinguish (human) tumoural RNA from (murine) host RNA, and as such to specifically analyse tumour-derived exRNA. Subsequently, the preferred exRNAxeno combination pipeline was applied to total exRNA sequencing data from blood platelets and three plasma fractions from a breast cancer patient-derived and neuroblastoma cell line-derived xenograft mouse model. We show that tumoural exRNA concentrations are not determined by plasma platelet levels, while host exRNA concentrations increase with platelet content. Furthermore, a large variability in exRNA levels and gene content across individual mice is observed. In general, the tumoural gene detectability in plasma is correlated with the RNA expression levels in the tumour tissue or cancer cell line. Our results unravel new aspects of tumour-derived exRNA biology in xenograft mouse models.

  Study EGAS00001006582

• Fragmentomics analyses of urinary cell-free DNA permit multi-urologic cancer detection and reduction in tissue biopsies for prostate cancer

  This study demonstrated the close association between urinary cell-free DNA (cfDNA) methylation status and the fragmentation patterns in healthy controls and patients with various diseases. Fragmentomics-based methylation analysis (FRAGMA) enables accurate estimation of methylation levels in urinary cfDNA, which is proved by paired bisulfite sequencing and non-bisulfite sequencing data. FRAGMA showed high accuracy in deducing tissue-of-origin of urinary cfDNA in transplantation patients and pregnant women. Moreover, FRAGMA showed great potential in the detection and classification of multiple cancers from the urinary system, including bladder, kidney, and prostate cancer. This study demonstrated that FRAGMA could be applied to improve current diagnostic strategies based on urine samples.

  Study EGAS50000001431

• Distribution of data using Live Distribution

  Live Distribution Welcome to the documentation for using the Live Distribution feature for distributing data files securely through the EGA platform. This guide will walk you through the process of downloading encrypted files and decrypting them using Crypt4GH. Please follow the steps below to ensure a smooth experience. Before Downloading Create an EGA user. Make sure that you have the permissions to download the dataset of interest. In case you don’t have access, request access to the dataset. Add your Crypt4GH-compatible public key to your EGA account. Please allow a few hours for your public key to be synced with your profile. Afterwards, you will be able to connect to your EGA outbox using the SFTP protocol. Download Graphical User Interface (GUI) You can use any GUI that supports SFTP connections, such as FileZilla, an open-source FTP client. For Filezilla as your GUI, follow these steps to download files: Open FileZilla and access Site Manager (File > Site Manager). Create a new connection with the following settings (Figure 1): Protocol: SFTP - SSH File Transfer Protocol Host: __EGA_OUTBOX_DOMAIN__ Logon Type: Key file User: your EGA username Key file: path/to/your/private_key Figure 1: Process of establishing a new connection to __EGA_OUTBOX_DOMAIN__ using a key file as the logon method in FileZilla. The figure showcases the FileZilla version 3.52.2 operating on IOS v11.2.3. By following the depicted steps, users can create a secure and efficient connection to the EGA outbox, ensuring seamless data transfers. Click Connect to access your Outbox. This folder serves as your storage space within the EGA cloud, containing files accessible for download in a secure way. Browse the remote directory on the right side of the FileZilla screen. Select the files you wish to download, right-click, and choose Download (Figure 2). Figure 2: Step-by-step process of manually downñoad files from __EGA_OUTBOX_DOMAIN__ using FileZilla, with FileZilla version 3.52.2 operating on IOS v11.2.3. The figure demonstrates how users can downñoad data from the EGA outbox to their local storage by following the depicted steps SFTP command line You can also use the SFTP command line to securely download files from the EGA Outbox. Using SFTP command line client in Linux/Unix Open a terminal window Enter the following command to connect: sftp username@hostname Enter your EGA password To see a list of available sftp commands type help sftp> put – Upload file sftp> get – Download file sftp> cd path – Change remote directory to ‘path’ sftp> pwd – Display remote working directory sftp> lcd path – Change the local directory to ‘path’ sftp> lpwd – Display local working directory sftp> ls – Display the contents of the remote working directory sftp> lls – Display the contents of the local working directory Type get command to download files. For example: get encrypted_file.c4gh Use the bye command to close the connection (SFTP session). Convenient SSH settings Include the following settings in your SSH config file, located in ~/.ssh/config Host __EGA_OUTBOX_DOMAIN__ EGA-outbox hostname __EGA_OUTBOX_DOMAIN__ User username IdentityFile path/to/the/private/key Replace username and path/to/the/private/key with the appropriate settings, and you will be able to connect to the __EGA_OUTBOX_DOMAIN__ simply using sftp EGA-outbox. How to decrypt Files archived at the EGA are encrypted based on Crypt4GH. Hence, to decrypt the files you need to install Crypt4GH. You can install a python implementation of it, with pip install crypt4gh or directly from the Github repository pip install git+https://github.com/EGA-archive/crypt4gh.git After installing Crypt4GH, decrypt files using the following command: crypt4gh decrypt --sk /path/private/key < encrypted_file.c4gh > decrypted_filename The command reads the encrypted file from stdin (with <) and output the decrypted version to stdout (with >). Replace encrypted_file.c4gh and decrypted_filename with the appropriate filenames but make sure to not use the same filename for both reading and writing because your SHELL would then truncate both files before you even read or write. Frequently Asked Questions What username should I use to log in to my outbox? The authentication process for logging in to the EGA website, as well as accessing your inbox and outbox, requires the use of your username, not your email address. Therefore, if you registered a username different from your email address when creating your EGA account, you must use that username to log in. If you have forgotten your registered username, please, contact our Helpdesk team for assistance. I see that some files in my dataset have 'unavailable' as extension. What should I do? Within your Outbox, you'll find a list of all the datasets available for download. Occasionally, certain files may be marked as "unavailable". These unavailable files can be identified by the "unavailable" extension added to their filenames (e.g. filename.fastq.gz.unavailable.c4gh). If you encounter an unavailable file that you need, please reach out to our Helpdesk. We'll promptly work on making the file accessible for download as soon as possible. Specific to using keys Can I access one EGA account from different devices? Yes, you can access your account from different devices by linking several public keys to your EGA account. Each device can generate a unique public-private key pair, and the corresponding public keys can be linked to the same account. This way, you can use different public keys on different devices and still have access to the same account and data. I have several keys and I don't remember which one is which When generating SSH keys, it's a good practice to add a comment using the -C flag. This will allow you to add a descriptive tag to your key, making it easier to identify later on. Here's an example command that generates an SSH key with a comment: ssh-keygen -t ed25519 -C work-pass In this example, we're generating an ed25519 SSH key with the comment work-pass. Once you have multiple keys with different comments, you can use the comments to easily identify each key. To view the comments for your existing SSH keys, you can use the following command: ssh-keygen -l -f /path/to/key This will display the key fingerprint and the associated comment. By checking the comments, you should be able to identify which key is which. What if I can't find my SSH keys for uploading files with a key file, and how can I use new keys? If you can't find your SSH keys, don't worry - you can make new ones. To do this, open your terminal or command prompt and type a command to make a new SSH key. You can pick a name for the key, and choose a password to keep it safe. After making the key, you can add the new key to your account or server where you want to upload files using the key file. This usually involves copying and pasting the key's "public" (e.g. file.pub) part to the right place. If you lose track of the key again, just make a new one and add it again. Keep in mind that SSH keys belong to you and your computer, so if you switch computers or accounts, you'll need to make new keys. I don't want to type the passphrase every time I use the key. What can I do? You can use an ssh-agent to avoid typing the passphrase every time you use the key. An ssh-agent is a program that stores your private keys in memory and provides them to ssh when needed. You can add your key to the ssh-agent using the command ssh-add followed by the path to your key file.Here's an example of the steps to follow: Open a terminal window.Start the ssh-agent by typing the command eval $(ssh-agent).Add your key to the ssh-agent by typing the command ssh-add [key filepath]. For instance, if your key file is located in the home directory with the name mykey, the command will look like this: ssh-add ~/mykey After adding your, key to the ssh-agent, you should be able to use ssh without having to enter your passphrase every time. Can I use my password for authentication (without my private key)? If you prefer to use your username and password for authentication instead of your private key, you can still do so. When using a Graphical User Interface (GUI) such as FileZilla, you can select Ask for password as your Logon Type (Figure 3). This option will prompt you to enter your password when you click Connect, instead of using your private key. Figure 3: This option will prompt you to enter your password when you click "Connect", instead of using your private key. Figure 3: Process of establishing a new connection to __EGA_OUTBOX_DOMAIN__ using your password as the logon method in FileZilla. The figure showcases the FileZilla version 3.52.2 operating on IOS v11.2.3. By following the depicted steps, users can create a secure and efficient connection to the inbox, ensuring seamless data transfers. It's worth noting that using a password for authentication can be less secure than using an SSH key, as passwords can be more easily compromised through various means. However, if you choose to use your password for authentication, selecting "Ask for password" as your Logon Type is a good way to do so securely via a GUI. Why is it better to use my key and not my password? SSH keys for authentication is generally considered to be more secure and convenient than using passwords. SSH keys are more difficult to crack than passwords, and they can be restricted to specific users and machines, giving you more control over access. Once you set up your SSH keys, you can use them to authenticate quickly and easily, without having to enter a password every time. This makes automation of tasks, such as uploading encrypted files, much simpler. Additionally, SSH keys provide better logging, allowing you to keep track of who is accessing your systems and when. All in all, using SSH keys is a good practice for improving security and convenience in your authentication process.

  Documentation access/download/files/live-outbox

• Cell-free DNA cleavages analysis (human)

  Cell-free DNA cleavages analysis (human)

  Study EGAS00001006701

• Amplicon sequencing of melanoma samples

  The types of biomarkers for skin tumors have been 1) biochemical markers in blood, urine, and body fluid, 2) histopathological markers, 3) genetic examination of tumor tissue, 4) tumor-susceptibility assessed by germ_x0002_line genetic examination. Biomarkers in a blood are frequently used in the treatment of cutaneous malignancies, but are not suitable for early detection of malignancies. Research on circulating tumor cells, cell free DNA, exosomes has been promoted in recent years, but clinical application is halfway. Based on these circumstances, the purpose of this study is to search for biomarkers for diagnosis, therapeutic effect, and follow-up of skin tumors, and to verify their usefulness.

  Study JGAS000351

• Reference Exome Data for a Northern Brazilian population

  Whole exome sequencing (WES) is a popular technology widely used in the diagnosis of rare genetic diseases and provides useful variant data for analysis of complex diseases. However, there is not always adequate population-specific reference data available to assist clinical geneticists in assigning a diagnostic variant to a specific clinical condition. Here we provide a catalogue of variants called after sequencing the exomes of 45 babies from the State of Rio Grande do Nord in Brazil. Sequence data were processed using an ‘intersect-then-combine’ (ITC) approach, using GATK and SAMtools to call variants. A total of 612,761 variants were identified in at least one individual in this Brazilian Cohort, including 559,448 single nucleotide variants (SNVs) and 53,313 insertion/deletions. Of these, 58,111 overlapped with nonsynonymous (nsSNVs) or splice site (ssSNVs) SNVs in dbNSFP. As an aid to clinical diagnosis of rare diseases, we used the American College of Medicine Genetics and Genomics (ACMG) guidelines to assign pathogenic/likely pathogenic status to 439 (0.755%) of the 58,111 nsSNVs and ssSNVs. Our data set provides a useful reference point for diagnosis of rare diseases in Brazil.

  Study EGAS00001004112

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

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

  Study phs003074

• Germline genome-wide association studies in women receiving neoadjuvant chemotherapy with or without bevacizumab on NSABP B-40

  Neoadjuvant chemotherapy (NAC) for breast cancer is widely employed. We performed genome-wide association studies (GWAS) to determine if germline genetic variability was associated with benefits, in terms of pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS), in patients entered on the NSABP B-40 NAC (National Surgical Adjuvant Breast and Bowel Project, B-40, Neoadjuvant Chemotherapy) trial where some patients were randomized to receive bevacizumab, in addition to chemotherapy.

  Study phs001365

• Plasma mutation profile of precursor lesions and colorectal cancer using the Oncomine Colon cfDNA Assay

  Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Early detection of precursor lesions or early-stage cancer could hamper cancer development or improve survival rates. Liquid biopsy, which detects tumor biomarkers, such as mutations, in blood, is a promising avenue for cancer screening. To assess the presence of genetic variants in plasma cell-free tumor DNA from patients with precursor lesions and colorectal cancer using the commercial Oncomine Colon cfDNA Assay. Cell-free DNA (cfDNA) samples from the blood plasma of 52 Brazilian patients were analyzed. Eight patients did not have any significant lesions (five normal colonoscopies and three hyperplastic polyps), 24 exhibited precursor lesions (13 nonadvanced adenomas, ten advanced adenomas, and one sessile serrated lesion), and 20 patients with cancer (CRC). The mutation profile of 14 CRC-associated genes were determined by next-generation sequencing (NGS) using the Oncomine Colon cfDNA Assay in the Ion Torrent PGM/S5 sequencer.

  Dataset EGAD50000000679

• Molecular biomarkers in progression from refractory celiac disease to the lethal cancer variety enteropathy associated T cell lymphoma (EATL)

  Enteropathy associated T cell lymphoma (EATL) is frequently preceded by a state of refractoriness to the gluten-free diet, called “refractory celiac disease” or RCD. We aim to study which mutations and copy number aberrations are already manifest in RCD and to identify differences between RCD patients that do, and do not, develop EATL. We have applied whole exome sequencing to detect mutations and copy number aberration predictive for progression from RCD to EATL.

  Study EGAS00001006669

• RNA sequencing in blood samples of cluster headache patients

  Cluster headache is a relatively rare headache disorder, typically characterized by multiple daily, short-lasting attacks of excruciating, unilateral (peri-)orbital or temporal pain associated with autonomic symptoms and restlessness. To better understand the pathophysiology of cluster headache, we used RNA sequencing to identify differentially expressed genes and pathways in whole blood of patients with episodic (n = 19) or chronic (n = 20) cluster headache in comparison with headache-free controls (n = 20). Blood samples were subjected to globin reduction before sequencing.

  Study EGAS00001001918

• The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer (CIN3+)

  We analysed DNA methylation at &gt;850,000 CpG sites across the genome using the Illumina EPIC array in a total of 1,254 cervical liquid-based cytology samples from cases of screen-detected histologically verified CIN1-3+ (98% hrHPV-positive) and population-based control women free from any cervical disease (100% hrHPV-positive). We developed the WID-CIN-test which is a DNA methylation signature consisting of 5,000 CpG sites.

  Study EGAS00001005078

• Whole exome sequencing identifies clinically relevant mutational signatures in resected hepatocellular carcinoma

  We conducted a multicentre pilot study on patients with localized HCC following complete radiological response to surgical resection. Patients received 250 mg oral gefitinib once daily as adjuvant therapy, up to a maximum of 6 months. The clinical endpoints included recurrence-free survival (RFS) and overall survival (OS), and correlative genetic analyses were conducted from whole exome sequencing data (n=33). All statistical analyses were carried out on an intention-to-treat basis. The study is registered with ClinicalTrials.gov (NCT00282100).

  Study EGAS00001004371

• HG_Retroduplications_in_Neurodevelopmental_Disorders

  Mobile genetic Elements (MEs) are pieces of DNA which, through an RNA intermediate, can generate new copies of themselves elsewhere in the host genome. Additionally, MEs can facilitate the duplication of non-ME transcripts, typically genes, through the mechanism of retroduplication. In humans, several disorders have been directly attributed to ME-derived mutagenesis but not to retroduplication events. We propose to whole genome sequence the 7 individuals with putative de novo gene retroduplications in order to identify the site of insertion. This sequencing will serve two primary purposes: 1.) Identify the first documented case of a de novo retrogene insertion event causing a disease in humans 2.) provide additional whole genome sequencing of undiagnosed probands recruited into the DDD 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 EGAS00001002907

• Bisulfite sequencing of cell-free DNA in NMOSD patients

  Cell-free DNA was extracted from plasma and analyzed by bisulfite sequencing in Neuromyelitis Optica Spectrum Disorders(NMOSD) patients and healthy controls(HC). we aimed to investigate the primary source of cell-free DNA production.

  Study JGAS000515

• High-Risk Breast Cancer GWAS

  The GWAS includes High Risk Women from the following epidemiological studies of breast cancer, comprising a total of 3,719 cases and 3,642 controls (cases/controls: MEC, 0/200; ABCFR, 326/418; FCCC, 56/3; BCFR-UT, 66/32; CNIO-BC, 87/92; GESBC, 65/0; LIFE, 164/0; MARIE, 41/105; MAYO, 208/210; MNYR, 293/409; MSKCC, 310/0; NC-BCFR, 234/233; OFBCR, 553/560; POSH, 377/0; HBOC, 47/47; BBCS, 612/1333; UPENN, 280/0 This study was funded by a grant CA165038 to Christopher Haiman (University of Southern California) and John Hopper (University of Melbourne) from the National Cancer Institute, National Institute of Health. The contributing studies: Multiethnic Cohort (MEC). This study was supported by grant UM1 CA164973 from the National Cancer Institute, National Institute of Health. Ontario Familial Breast Cancer Registry, the Ontario site of the Breast Cancer Family Registry Cohort (OFBCR). This study was supported by grant UM1 CA164920 from the National Cancer Institute. Utah Breast Cancer Family Registry (BCFR-UT). This study was supported by grant UM1 CA164920 from the National Cancer Institute. New York site of the Breast Cancer Family Registry (MNYR). This study was supported by grant UM1 CA164920 from the National Cancer Institute. Northern California site of the Breast Cancer Family Registry (NC-BCFR). This study was supported by grant UM1 CA164920 from the National Cancer Institute. Australian Breast Cancer Family Registry (ABCFR). This study was supported by grant UM1 CA164920 from the National Cancer Institute. Breast Cancer Study (CNIO-BC). This study has been partially funded by The Spanish Network on Rare Diseases (CIBERER) and the Spanish National Genotyping Center (CEGEN). Genetic Epidemiologic Study of Breast Cancer (GESBC). The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and German Cancer Research Center (DKFZ). Mammary Carcinoma Risk Factor Study (MARIE). This study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH). Funding for the POSH study was provided by Cancer Research UK (grant refs A7572, A11699, C22524), the Breast Cancer Campaign (grant number: 2013MayPR044) and from 2003-2006 by a grant from The Wessex Cancer Trust. Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH). Funding for the POSH study was provided by Cancer Research UK (grant refs A7572, A11699, C22524), the Breast Cancer Campaign (grant number: 2013MayPR044) and from 2003-2006 by a grant from The Wessex Cancer Trust. Hereditary Breast and ovarian Cancer: Genetic and Molecular Studies (HBOC). This study was supported by National Cancer Institute grant CA58860 and The Lon V Smith Foundation: LVSF-44528. Mayo Clinic inherited breast and ovarian cancer study (MAYO). This study was supported by the Breast Cancer Research Foundation, NIH grants CA192393, CA176785, and an NIH CA116201 Specialized Program of Research Excellence (SPORE) in Breast Cancer. British Breast Cancer Study (BBCS); Mammographic oestrogens and growth factor study (MOG). The BBCS and the MOG study are funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledge NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). Genotyping of non-BRCA1/2 mutation carriers (UPENN). The study is supported by the Basser Research Center at the University of Pennsylvania, Rooney Family Foundation, NIH grants CA176785 and CA192393, the Breast Cancer Research Foundation, the Susan G. Komen Foundation for the Cure and Macdonald Family Foundation. Clinical Significance of Germline BRCA Mutations (MSKCC). The study is supported by the Robert and Kate Niehaus Clinical Cancer Genetics Research Initiative, The Breast Cancer Research Foundation, and the Cancer Center Support Grant from the National Institute of Health, National Cancer Institute 5P30 CA08748-40. Women&#39;s Learning the Influence of Family and Environment (LIFE). This study was supported by grants CA17054 and CA74847 from the National Cancer Institute, National Institutes of Health, No. 4PB-0092 from the California Breast Cancer Research Program of the University of California. Philadelphia site of the Breast Cancer Family Registry at Fox Chase Cancer Center (FCCC). This study is supported by NIH grant CA164920.

  Study phs000929

• Whole genome sequencing data of paediatric KMT2A-rearranged acute lymphoblastic leukemia

  Whole genome sequencing data from infant (<1 y) paediatric (< 18 y) KMT2A-rearranged acute lymphoblastic leukemias. Dataset includes fastq and BAM files from diagnostic and remission (control) samples of 3 patients. Dataset consists of two experiments depending on library preparation method; "Experiment 1" is made using normal WGS library preparation (pcr+), and "Experiment 2" is made using pcr-free library preparation method.

  Dataset EGAD50000001568

• prostate cancer plasma cfRNA

  Dataset contains mRNA capture sequencing data from plasma of 180 different human donors: 132 prostate cancer patients (PRAD) and 48 cancer-free controls. Samples were sequenced on a NovaSeq X and sequencing data is provided in FASTQ format.

  Dataset EGAD50000001805

• Effects of nucleases on cell-free extrachromosomal circular DNA

  Effects of nucleases on cell-free extrachromosomal circular DNA

  Study EGAS00001005873

• De Novo Characterization of Cell-Free DNA Fragmentation Hotspots in Plasma Whole-Genome Sequencing

  The raw sequencing data deposited here are low-coverage (~1X) whole-genome sequencing (WGS) of plasma cell-free DNA (cfDNA). The purpose is to validate the performance of early-stage cancer diagnosis in the Zhou et al. 2020 BioRxiv paper, mainly for two types of cancer: early-stage liver cancer and breast cancer. The cases and controls are matched with age, gender, smoking history, and alcohol usage. We developed a computational method to identify the cfDNA fragmentation hotspots from pooled low-coverage cfDNA WGS data. We found the cfDNA fragmentation hotspots are highly enriched in regulatory regions, such as open chromatin regions. The signals from these regions can help the diagnosis of early-stage cancers and their tissues-of-origin.

  Study phs003062

• C3 SNPs and outcome after lung transplantation

  Background: Development of chronic rejection is still a severe problem and causes high mortality rates after lung transplantation (LTx). Complement activation is important in the development of acute rejection (AR) and bronchiolitis obliterans syndrome, with C3 as a key complement factor. Methods: Since a single nucleotide polymorphism (SNP) in the C3 gene (rs2230199) is associated with long-term outcome after solid organ transplantation, we investigated this SNP in relation to LTx. In addition, we looked at local production of C3 by analyzing bronchoalveolar lavage fluid (BALF) of LTx patients using isoelectric focusing (IEF). Results: We demonstrated the presence of C3 in BALF and showed that this is produced by the donor lung based on the genotype of SNP rs2230199. We also analyzed donor and patient SNP configurations and observed a significant association between the SNP configuration in patients and episodes of AR during 4-years follow-up. Survival analysis showed a lower AR-free survival in homozygous C3 slow patients (p=0.005). Furthermore, we found a significant association between the SNP configuration in donors and BOS development. Patients receiving a graft from a donor with at least one C3 fast variant for rs2230199 had an inferior BOS-free survival (p=0.044). Conclusions: In conclusion, our data indicate local C3 production by donor lung cells. In addition, a single C3 SNP present in recipients affects short-term outcome after LTx, while this SNP in donors has an opposite effect on long-term outcome after LTx. These results could contribute to an improved risk stratification after transplantation.

  Study EGAS00001003843

• Evolutionary origin and methylation status of human intronic CpG islands that are not present in mouse

  Imprinting of the human RB1 gene is due to the presence of a differentially methylated CpG island (CGI) in intron 2, which is part of a retrogene derived from the PPP1R26 gene on chromosome 9. The murine Rb1 gene does not have this retrogene and is not imprinted. We have investigated whether the RB1/Rb1 locus is unique with respect to these differences. For this we have compared the CGIs from human and mouse by in silico analyses and found out that there are at least 2033 human intronic CGIs that are not present in the mouse. Among these CGIs, 104 show sequences similarities elsewhere in the human genome, which suggests that they arose by retrotransposition. We could narrow down the time points when most of these CGIs appeared during evolution. Their methylation status was analysed in two monocyte methylome datasets from whole genome bisulfite sequencing and in 18 published methylomes. Five CGIs appear to be differentially methylated, which suggests that they are subject of genomic imprinting. They are located in introns of the following genes: RB1, ASRGL1, PARP11, PDXDC1 and MYO1D. Four of these CGIs are parts of retrogenes. Our study supports the notion that imprinting builds on host defence mechanisms by which the genome protects itself against retrotransposed and foreign DNA and that the epigenetic fate of the retrotransposed DNA depends on selective forces at the integration site.

  Study EGAS00001000719

• Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer

  Mutations in the TERT promoter are the single most common non-coding mutation in cancer and represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, G228A and G250A, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants in the TERT promoter are unknown. We identified duplications of wildtype sequence within the core promoter region of TERT in 7 different cancer types that have strikingly similar features including size, insertion position, and inclusion of one of the native ETS motifs. Each duplication activates the TERT promoter to a similar level as G228A and G250A and is critically dependent on the insertion site. The GABP tetramer binds to the TERT duplicated promoter sequence by virtue of the native ETS motif and its duplicated version with precise spacing, and it is necessary for the transcriptional activation by all duplications tested. Spatiotemporal analysis in a multifocal glioblastoma shows the duplication is clonal and its activation of TERT is readily detectable at the single cell level and in bulk tumor tissue. We conclude that recurrent TERT promoter duplications of the native ETS sequence are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.

  Study EGAS00001006118

• RNA-Seq Data From Early Stage Triple Negative Breast Cancer Tumors Treated With TVEC and Chemotherapy (MCC18621)

  This study is a phase 1/phase 2 trial testing the combination of talimogene laherparepvec (TVEC) and neoadjuvant chemotherapy for the treatment of stage II-III triple negative breast cancer. The trial demonstrated that the addition of TVEC to neoadjuvant chemotherapy was feasible, and resulted in a pathological complete response (pCR) rate of 45.9%, residual cancer burden (RCB) 0-1 rate of 65%, and event free survival of 89%. The macrodissected formalin-fixed paraffin-embedded (FFPE) samples were from 50 patients treated across two phases at different timepoints (pre-treatment, 6th week of treatment, and surgical resection). RNA-Seq data is provided along with clinical classifiers.

  Study phs003199

• Rare SNPs in receptor tyrosine kinases are negative outcome predictors in multiple myeloma

  Multiple myeloma (MM) is a plasma cell disorder that is characterized by a great genetic heterogeneity. Recent next generation sequencing studies revealed an accumulation of tumor-associated mutations in receptor tyrosine kinases (RTKs) which may also contribute to the activation of survival pathways in MM. To investigate the clinical role of RTK-mutations in MM, we deep-sequenced the coding DNA-sequence of EGFR, EPHA2, ERBB3, IGF1R, NTRK1 and NTRK2 which were previously found to be mutated in MM, in 75 uniformly treated MM patients of the "Deutsche Studiengruppe Multiples Myelom". Subsequently, we correlated the detected mutations with common cytogenetic alterations and clinical parameters. We identified 11 novel non-synonymous SNVs or rare patient-specific SNPs, not listed in the SNP databases 1000 genomes and dbSNP, in 10 primary MM cases. The mutations predominantly affected the tyrosine-kinase and ligand-binding domains and no correlation with cytogenetic parameters was found. Interestingly, however, patients with RTK-mutations, specifically those with rare patient-specific SNPs, showed a significant lower overall, event-free and progression-free survival. This indicates that RTK SNVs and rare patient-specific RTK SNPs are of prognostic relevance and suggests that MM patients with RTK-mutations could potentially profit from treatment with RTK-inhibitors.

  Study EGAS00001001665

• Whole exome sequencing of SU- DIPG-XIII from different sites

  Whole exome sequencing of diffuse intrinsic pontine glioma (DIPG) cells isolated from the pons and from a sub-ventricular zone site of spread within the frontal lobe from the same individual (SU- DIPG-XIII)

  Dataset EGAD00001003563

• Similarity and diversity of the tumor microenvironment in multiple metastases: critical implications for overall and progression-free survival of high-grade serous ovarian cancer.

  The tumor microenvironment is pivotal in influencing cancer progression and metastasis. Different cells co-exist with high spatial diversity within a patient, yet their combinatorial effects are poorly understood. We investigate the similarity of the tumor microenvironment of 192 local metastatic lesions in 61 ovarian cancer patients. An ecologically inspired measure of microenvironmental diversity derived from multiple metastasis sites is correlated with clinicopathological characteristics and prognostic outcome. We demonstrate a high accuracy of our automated analysis across multiple sites. A low level of similarity in microenvironmental composition is observed between ovary tumor and corresponding local metastases (stromal ratio r = 0.30, lymphocyte ratio r = 0.37). We identify a new measure of microenvironmental diversity derived from Shannon entropy that is highly predictive of poor overall (p = 0.002, HR = 3.18, 95% CI = 1.51-6.68) and progression-free survival (p = 0.0036, HR = 2.83, 95% CI = 1.41-5.7), independent of and stronger than clinical variables, subtype stratifications based on single cell types alone and number of sites. Although stromal influence in ovary tumors is known to have significant clinical implications, our findings reveal an even stronger impact orchestrated by diverse cell types. Quantitative histology-based measures can further enable objective selection of patients who are in urgent need of new therapeutic strategies such as combinatorial treatments targeting heterogeneous tumor microenvironment.

  Study EGAS00001002065

• Characterization of CNS Metastases

  Metastatic disease to the central nervous system (CNS) is devastating, with a poor prognosis. There are limited treatment options for patients with CNS metastases, and in particular with leptomeningeal carcinomatosis (LMD). In this study, we evaluated the molecular and cellular features of parenchymal brain metastases and LMD. We used single-cell RNA and cell-free DNA profiling of CSF from patients with LMD receiving immunotherapy to demonstrate shifts in the liquid LMD tumor microenvironment. We also characterize the tumor microenvironment of parenchymal brain metastases using single cell sequencing, before and after treatment with immunotherapy.

  Study phs002416

• Normative Aging Study (NAS)

  The Normative Aging Study (NAS) is a longitudinal study established by the United States Department of Veterans Affairs in 1963. Participants were male residents and free of chronic disease at the time of recruitment. Participants were invited to undergo an in-person examination every 3-5 years. Participants provided information on medical history, lifestyle and demographic factors and underwent a physical examination and laboratory tests, at each visit. Participants provided written informed consent at each visit, and the VA Boston Healthcare System Institutional Review Board approved the study.

  Study phs000853

• Whole-Genome Sequencing of a Healthy Aging Cohort.

  Studies of long-lived individuals have revealed few genetic mechanisms for protection against age-associated disease. Therefore, we pursued genome sequencing of a related phenotype-healthy aging-to understand the genetics of disease-free aging without medical intervention. In contrast with studies of exceptional longevity, usually focused on centenarians, healthy aging is not associated with known longevity variants, but is associated with reduced genetic susceptibility to Alzheimer and coronary artery disease. Additionally, healthy aging is not associated with a decreased rate of rare pathogenic variants, potentially indicating the presence of disease-resistance factors. In keeping with this possibility, we identify suggestive common and rare variant genetic associations implying that protection against cognitive decline is a genetic component of healthy aging. These findings, based on a relatively small cohort, require independent replication. Overall, our results suggest healthy aging is an overlapping but distinct phenotype from exceptional longevity that may be enriched with disease-protective genetic factors.

  Study EGAS00001002306

• Genomic Analyses of Germline and Somatic Variation in High-Grade Serous Ovarian Cancer

  The goal of this study was to identify and characterize germline and somatic genetic variation in women with high grade serous ovarian cancers treated at a single cancer center and their associations with relapse-free and overall survival. We conducted paired tumor/normal targeted next-generation sequencing of 577 genes in pathways of DNA repair, response to DNA damage, cell-cycle regulation, programmed cell death, MAPK, and P13K/AKT/MTOR signaling in 114 tumors from 71 women. In addition, we investigated single copy number alterations (SCNAs) and loss of heterozygosity in a subset of 61 tumors. We validated our results with data from ovarian tumors in TCGA. Our results were similar to other studies of high-grade serous carcinomas. As an example, we found that approximately one third of the tumors harbored loss of function variants in homologous recombination genes and that &gt;90% had TP53 somatic mutations. Through GISTIC analysis of the OncoScan data on tumor DNA from 61 cases, we identified several regions of high copy number alterations including including NOTCH3 and PIK3R2 that were significantly associated with an increase in cancer recurrence and a reduction in overall survival. We identified few changes in mutation profiles where we had multiple tissues, either from multiple surgeries or from the primary site to metastatic sites within the same surgery. However, we did not investigate copy number alterations in multiple tissues from the same individuals, and so it may be that copy number alterations are more important. Data available through dbGAP will be the BAM files and the phenotypic data on the tumor samples, the age, race, ethnicity of the participants and their outcomes, and the Oncoscan OSCHP files.

  Study phs003198

• Activating AKT1 and PIK3CA mutations in metastatic castration-resistant prostate cancer

  This dataset contains all available targeted exon sequencing bam files from our study, "Activating AKT1 and PIK3CA mutations in metastatic castration-resistant prostate cancer". Patient identifiers are denoted by the first segment of the sample aliases (e.g. "P1"), and additional information is appended to reflect which serial sample is referenced (1st, 2nd, 3rd, etc.), and whether the sample represents cell-free DNA ("cfdna") or paired white-blood cell control ("WBC"). All samples were sequenced using Illumina technology.

  Dataset EGAD00001006122

• Study of Women's Health Across the Nation (SWAN) Repository

  The Study of Womens Health Across the Nation (SWAN) is an active multi-site, multi-disciplinary, longitudinal study of women&#39;s health. Initially funded in 1994 by the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR), and the Office of Research on Women&#39;s Health (ORWH), the overall goal of SWAN is to describe the natural history of the menopausal transition and the post menopause including biological, behavioral, and psychosocial characteristics. SWAN focuses on the impact of menopause on age-related chronic diseases, such as diabetes, cardiovascular disease, depression, bone loss and osteoporosis, as well as physical and cognitive functioning. SWAN has seven clinical study sites located in six states, two in California, and one each in Chicago, Boston, Detroit area, northern New Jersey and Pittsburgh. The SWAN cohort was recruited from these areas and consists of 3,302 African American, Caucasian, Chinese American, Hispanic and Japanese American women. SWAN participants were enrolled in 1996-1997 and have been seen annually or bi-annually for clinic visits, which include interviews, measurements, and the collection of blood and urine samples. SWAN participants have now been seen for the baseline and 15 follow-up visits.

  Study phs001470

• Integrated Genomic Analysis of Periampullary Tumors at The Human Genome Sequencing Center, Baylor College of Medicine (HGSC-BCM)

  Adenocarcinomas arising in the complex environment of the ampulla of Vater constitute a histopathological heterogenous group, presumably originating from the different epithelial cellular constituents present at the site: pancreas, bile duct, and intestinal duodenum. These tumors have been described in many different ways: intra-ampullary, periampullary, intra-ampullary papillary-tubular neoplasm, ampullary-ductal, periampullary-duodenal, and ampullary-not otherwise specified. These varied classifications reflect the difficulty in classifying these tumors into specific groups. Only the tumors clearly localized in the bile duct or duodenum are identified as distal cholangiocarcinomas (CAC) or duodenal adenocarcinomas (DUOAC). The current classification is based on macroscopic features that may distinguish the epithelium of origin, microscopic features, clinicopathological criteria, histopathology and expression of differential markers. This classification is subjective and prone to inter-observer variability and significantly impacts on treatment selection and therapeutic development. In order to define subtypes of periampullary cancer with clinical relevance, we performed whole exome sequencing and copy number analysis of 160 cancers arising in the periampullary region, 62 of these clearly arising from either the bile duct (n = 44), or the duodenum (n = 18) and 98 periampullary cancers (AMPAC) where the epithelium of origin could not be clearly defined.

  Study phs000895

• Mutational Patterns in Metastatic Cutaneous Squamous Cell Carcinoma

  Cutaneous squamous cell carcinoma (cSCC) from the head and neck typically metastasizes to the lymph nodes of the neck and parotid glands. When a primary is not identified, they are difficult to distinguish from metastases of mucosal origin and primary salivary gland SCC. Ultraviolet radiation causes a mutation pattern that predominantly features cytosine to thymine transitions at dipyrimidine sites and has been associated with cSCC. In this study, we used whole genome sequencing data from 15 cSCC metastases and show that a UV signature mutation is pervasive across the cohort and distinct from mucosal SCC. The mutational burden was exceptionally high and concentrated in some regions of the genome, especially insulator elements (mean 162 mutations / Mb). We therefore evaluated the likely impact of UV-induced mutations on the dipyrimidine rich binding site of the main human insulator protein, CCCTC-binding factor (CTCF), and the possible implications on CTCF function and the spatial organization of the genome. Our findings suggest that mutation signature analysis may be useful in determining the origin of metastases in the neck and the parotid gland. Furthermore, UV-induced DNA damage to insulator binding sites may play a role in the carcinogenesis and progression of cSCC.

  Study EGAS00001003370

• The biology of cell-free DNA fragmentation and the roles ofDNASE1, DNASE1L3 and DFFB

  The biology of cell-free DNA fragmentation and the roles of DNASE1, DNASE1L3 and DFFB

  Study EGAS00001003514

• META-PRISM

  A pan-cancer cohort of 1031 patients resistant to systemic therapies or with no approved therapeutic options. It includes whole-exome sequencing of 571 tumor and matched-normal samples, and transcriptome sequencing of 947 tumor samples. Biopsies were taken at entry into precision medicine trials, often after diagnosed resistance. Comprehensive clinical information is available for all patients and include patient age at biospy, tumor primary site and histological subtype, biopsy site, treatments received prior to biopsy, blood assessment results at biopsy, metastatic sites at biopsy, and survival time from the biopsy date.

  Dataset EGAD00001009684

• Aligned Low pass whole genbome sequencing of cell free and tumour DNA from 5 patients with high grade serous ovarian cancer. Samples have been aligned to hg19 and bam files uploaded

  This is the aligned bam files of 5 patients, with sequential sampltes from patients comprising cfDNA and FFPE extracted tumour DNA

  Dataset EGAD50000001632

• Analysis of cell type contributions to cell free DNA in health and disease.

  This study looks at cell type contributions to cell free DNA in health and disease.

  Study EGAS50000000178

• Tumor Fraction Guided Cell-Free DNA Profiling in Metastatic Cancer Patients

  Cell-free DNA (cfDNA) profiling is increasingly used to guide cancer care, yet mutations are not always identified. The ability to detect somatic mutations in plasma depends on both assay sensitivity and the fraction of circulating DNA in plasma that is tumor-derived (i.e cfDNA tumor fraction). We hypothesized that cfDNA tumor fraction could inform the interpretation of negative cfDNA results and guide the choice of subsequent assays of greater genomic breadth or depth. Plasma samples collected from 118 metastatic cancer patients were analyzed with cf-IMPACT, a modified version of the FDA-authorized MSK-IMPACT tumor test that can detect genomic alterations in 410 cancer-associated genes. Shallow whole genome sequencing (sWGS) was also performed in the same samples to estimate cfDNA tumor fraction based on genome-wide copy number alterations using z-score statistics. The results show that cfDNA tumor fraction can inform the interpretation of negative cfDNA results and guide the selection of subsequent sequencing platforms that are most likely to identify clinically-relevant genomic alterations.

  Study phs002290

• Childhood Cancer Data Initiative (CCDI): Pediatric In Vivo Testing Program – Sarcomas and other Solid Tumors

  The primary goal of this project involves the comprehensive molecular profiling of patient-derived xenograft (PDX) mouse tumor models. Molecular profiling of each PDX model will include whole exome sequencing (WES), RNAseq, MethylEPIC arrays, CytoSNP array, and DNA fingerprint for quality control. Limited clinical demographic data (e.g. diagnosis, disease site, disease status) will be obtained. This data can be utilized to validate PDX models with matched patient tumors and can be used to guide model selection for downstream preclinical drug testing.

  Study phs003161

• Genome-wide NanoRCS sequencing of cfDNA and ctDNA from liquid biopsies of healthy individuals and cancer patients

  Levels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant molecules, extremely sensitive sequencing methods are required. We developed a new technique, NanoRCS, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule for genome-wide sequencing, and applied this to plasma of healthy individuals, Esophageal cancer patients and Granulosa cell tumor patients and ascites of Ovarian cancer patients. We also sequenced these samples on Illumina Novaseq, to compare the two techniques.

  Study EGAS50000000154

• Large Cancer Fingerprint Screening for Detection of Minimal Residual Disease.

  We describe an approach for large cancer fingerprint screening and its application to cell-free DNA from patients with cancer. Our approach involves tracking somatic mutations identified from patients' tumor biopsies, in the cell-free DNA from a blood draw.

  Study phs001977

• About

  About What's the EGA? The European Genome-phenome Archive (EGA) is a global network for permanent archiving and sharing of personally identifiable genetic, phenotypic, and clinical data generated for the purposes of biomedical research projects or in the context of research-focused healthcare systems. Jointly managed by the European Bioinformatics Institute (EMBL-EBI) in Cambridge (UK) and the Centre for Genomic Regulation (CRG) in Barcelona, we aim to advance biomedical research and promote personalised medicine worldwide by enabling discovery of and access to human genomic and health research data. The EGA contains data collected from individuals whose consent agreements authorise data release for specific research use to bona fide researchers. We ensure strict security measures to control access to the data and maintain patient confidentiality. With expertise in data management and technical infrastructure, we promote FAIR data reuse and enable researchers to share their data securely. By leveraging public funding and our strategic partnerships, the EGA provides a free service for permanent data storage, data discovery, and secure data access. In addition, we foster a federated network to provide transnational access to human research data in compliance with legal frameworks. For additional information about the EGA, please contact: Helen Parkinson and Mallory Freeberg EMBL European Bioinformatics Institute Arcadi Navarro, Roderic Guigó, and Jordi Rambla Center for Genomic Regulation History The European Genome-phenome Archive was launched in 2008 at the European Bioinformatics Institute (EMBL-EBI), an outstation of the European Molecular Biology Laboratory (EMBL), to address an identified need for archiving and sharing the results of genome-wide association studies from the Wellcome Trust Case Control Consortium. With the signing of a memorandum of understanding in 2013 and a formal agreement in 2016, the EGA became a joint project of EMBL-EBI and the Centre for Genomic Regulation (CRG). The two institutes work together to support the EGA services, including supporting submissions, website, strategic leadership, and data infrastructure developments. In 2022, the Federated EGA was officially launched with the signature of the first five countries: Finland, Germany, Norway, Spain, and Sweden. With more than 20 additional nodes worldwide preparing to join, the Federated EGA aims to become the largest human omics data sharing initiative towards understanding human health and disease. EGA overview If you're a researcher you may need to deposit, manage, or access genomic data in a secure and regulated way. The European Genome-phenome Archive (EGA) is a platform that facilitates these processes, ensuring that sensitive data is stored and shared in accordance with legal and ethical regulations. Submission process To start a submission, you need to become an EGA submitter. For that, you’ll need to sign a Data Processing Agreement (DPA) with us, that defines the terms and conditions under which your data will be processed and shared within the EGA system. The access to each study is controlled by its Data Access Committee (DAC). The DAC is responsible for managing data access requests and ensuring that the release of data is in accordance with the General Data Protection Regulation (GDPR). Please, note that once your data is released, all public metadata related to your study and dataset(s) will be searchable on the EGA website. However, the files are only accessible under controlled access, which means that a DAC has to agree to a previous data access request. Request process It is possible to submit an access request to data stored at the EGA. The DAC assigned to the study will assess the request and, if approved, grant access to the data. Requesters must provide sufficient justification for your request and comply with the intended data usage in order to get access to it. Each dataset is covered by a Data Access Agreement (DAA) that defines the terms and conditions of use for the specified dataset/s. The DAA is created and provided by the DAC, and must be signed by the individual requesting access to the given dataset/s. Download process Once the request for access is approved, the data and metadata can be downloaded. The EGA offers various download options to fit the needs: it is possible to preview files without downloading them, download specific files of interest, or even download terabytes of data. Overall, the EGA provides a secure and regulated environment for depositing, managing, and accessing human data. Regardless of the role - submitter, DAC member, or requester - the EGA provides assistance for each while ensuring that sensitive data is managed in an ethical and responsible manner. More information on how EGA handles data is available in the EGA dataflow.

  Documentation about/ega

• 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

• Systemic Inflammation and Lymphocyte Activation Precede Rheumatoid Arthritis

  The Allen Institute for Immunology-University of California, San Diego-University of Colorado Transition to Rheumatoid Arthritis (ALTRA) project is a prospective longitudinal cohort study to understand the pre-clinical development of rheumatoid arthritis (RA). We performed cross-sectional and longitudinal multi-omics analyses of peripheral immunity in the anti-citrullinated protein autoantibody-positive (ACPA+) at-risk for RA period. We provide FASTQ files from (1) single-cell RNA sequencing (scRNA-seq) of ACPA+ at-risk (n=45), ACPA+ early RA (n=11), and site-matched ACPA- controls (n=38); (2) scRNA-seq of longitudinal samples from ACPA+ at-risk who developed clinically active RA during our study (n=16 participants, n=75 samples) and ACPA- controls (n=29 subjects, n=89 samples); (3) trimodal TEA-seq of a subset of ACPA+ at-risk (n=7) and ACPA- controls (n=5). Using these data, we characterize pathogenesis prior to clinical RA diagnosis and suggest the at-risk state exhibits substantial immune alterations that could potentially be targeted for early intervention to delay or prevent autoimmunity.

  Study phs003944

• An essential role for MYB in driving oncogenic EVI1 expression in enhancer-rearranged leukemias

  In acute myeloid leukemia (AML) with inv(3)(q21;q26) or t(3;3)(q21;q26), a translocated GATA2 enhancer drives oncogenic expression of EVI1. We generated an EVI1-GFP AML model and applied an unbiased CRISPR/Cas9 enhancer scan to uncover sequence motifs essential for EVI1 transcription. Using this approach, we pinpoint a single regulatory element in the translocated GATA2 enhancer that is critically required for aberrant EVI1 expression while being dispensable for GATA2 expression from its endogenous locus. This element contains a DNA binding motif for the transcription factor MYB that heavily occupies this site specifically at the translocated allele. MYB knockout as well as peptidomimetic blockade of p300-dependent MYB function resulted in downregulation of EVI1 but not of GATA2. Targeting MYB or mutating its DNA-binding motif within the GATA2 enhancer resulted in myeloid differentiation and cell death, suggesting that interference with MYB-driven EVI1 transcription provides a potential entry point for therapy of inv(3)/t(3;3) AMLs.

  Study EGAS00001004839

• Genomic analysis and evolutionary modeling of breast and larynx cancer, based on specimens from Polish population

  We explore the genomic characteristics of the original dataset of breast and larynx cancer specimens of several cell types from the collection of the Department of Applied Radiology of the Maria Sklodowska-Curie National Research Institute of Oncology, Krakow (Poland) Branch and Institute of Human Genetics Polish Academy of Sciences. DNA from paired tissue samples from primary tumor locations and concurrent metastasis to regional lymph nodes was sequenced and matched to controls. A range of genomic analyses was carried out, such as estimation of variant allele frequencies (VAF) and copy number variation (CNV). They show that subsets of variants from primary tumors are present in metastatic lymph nodes and that the CNV pattern is similar, but not identical to that known in the literature. In addition to that, we fit the VAF data to theoretical site frequency spectra predicted by multiple models found in the literature. Analysis suggests existence of secondary advantageous subclones arising on the clonal background as well as of a number of neutral or slightly deleterious passenger mutations.

  Study EGAS00001006456

• Methylation sequencing of CSF-derived cell free DNA

  We sequenced and enzymatically converted cell free DNA from 268 samples from 157 patients with brain tumors and 58 control CSF patients.

  Study EGAS50000001365

• Sequencing of cell-free DNA from breast cancer patients

  To assess the utility of high coverage whole genome sequencing analysis of cell-free DNA to detect tumour-specific genomic changes

  Study EGAS00001004960

• dbGaP Collection: Open Translational Science in Schizophrenia (OPTICS)

  Schizophrenia is a chronic, severe, disabling brain disorder that affects approximately 1% of the population worldwide. Epidemiologic studies have clearly demonstrated that genetics play a strong role in etiology, but the inheritance is very complex. Innovative analytic approaches and creative ways of combining disparate data sets will be necessary for making breakthroughs in identifying causal pathways and ultimately new drug targets. This dbGaP Collection consists of all genetic studies of schizophrenia available in dbGaP that have been consented for general research use. The goal is to facilitate identification of datasets with related scientific content in order to expedite the application process and ascertainment of datasets of interest for increased scientific discovery. The Open Translational Science in Schizophrenia (OPTICS) Project, was launched by Janssen Research &amp; Development, LLC, part of the Janssen Pharmaceutical Companies of Johnson &amp; Johnson, with a group of leading research organizations including the National Institutes of Health, Yale University School of Medicine, Rutgers University and the Harvard T.H. Chan School of Public Health, to create a new forum for collaborative analysis of Janssen&#39;s schizophrenia clinical trial data and other publicly available data about schizophrenia with the goal of creating new models for conducting research. The OPTICS project is one part of a larger effort at Janssen and other Johnson &amp; Johnson research companies to share clinical trials data to enhance public health and advance science and medicine. Qualified investigators and physicians may apply for access to anonymized clinical trials data from Janssen, for more information please visit https://sites.google.com/site/opticsschizophrenia/.

  Study phs000887

• Analysis of mechanisms of CD19- relapse following novel low affinity CD19 Chimeric Antigen Receptor (CAR) T-cells (CD19 CAR T-cells) in a Phase I clinical study in paediatric ALL: CARPALL

  Phase I clinical study (CARPALL, NCT02443831) utilizing a novel low affinity CD19CAR CAR in patients age &lt;25 with high risk CD19+ ALL. Seventeen patients were enrolled and 14 received an infusion of CAR T cells. Among those achieving complete remission, 6 subsequently relapsed, 5 with CD19- disease, 1 with CD19+ disease. Whole exome sequencing of bone marrow DNA from patients with CD19- relapse showed mutations in the CD19 gene predicted to result in loss of surface expression in 4/5 patients. These mutations were not detectable prior to CAR T cell therapy. With a median follow-up of 14 months, 5/14 patients (36%) are alive and disease-free. Overall survival was 84% at 6 months and 63% at 12 months and by the criteria used in the ELIANA study, event-free survival was 67% and 46%. Using more stringent criteria where an event is defined as molecular relapse, molecular EFS was 55% and 29 %. The median duration of remission in responding patients was 7.4 months.

  Study EGAS00001003733

• Epigenetic dynamics of monocyte to macrophage differentiation

  Monocyte to macrophage differentiation involves major biochemical and structural changes in non-dividing cells. In order to elucidate the role of gene regulatory changes during this process, we used high-throughput sequencing to analyze the complete transcriptome and epigenome of human monocytes that were isolated by elutriation and differentiated in vitro by addition of MCSF in serum-free medium. We also investigated the effect of loading the macrophages with modified LDL. We found that many mRNAs and miRNAs were significantly up- or downregulated during differentiation. While there was no correlation between gene expression and DNA methylation changes at transcription start sites, we identified a large number of intra- and intergenic regions that rapidly lost DNA methylation, became nucleosome-free and gained histone marks indicative of active enhancers. Loading of macrophages with modified LDL caused gene expression changes, but no chromatin changes. In summary, our results demonstrate that monocyte to macrophage differentiation is associated with rapid, highly targeted epigenetic changes, whereas lipid uptake mainly affects regulatory circuits of soluble factors.

  Study EGAS00001001595

• Modifier Genes in 21-hydroxylase Deficiency

  CAH is a genetic steroidogenesis disorder. The most common form, 21OHD, leads to cortisol deficiency and, in turn, an excess of androgen, a hormone that promotes the development and maintenance of male sex characteristics. As a result of this androgen excess, prepubescent males and newborn, prepubescent, and grown females exhibit mature masculine characteristics. The symptoms and severity of 21OHD vary among individuals with the disease and in adults versus children. The reasons for these differences are not yet known. Current therapy for 21OHD consists of administration of glucocorticoids to replace cortisol and suppress excessive pituitary function. With more information about what genes or factors contribute to the severity of 21OHD, researchers may be able to better treat children and adults with the disease. This study will examine participants&#39; DNA to determine what other genes may affect the severity of 21OHD and may make the disease milder in adults than in children This is a 3-day inpatient study. Once eligibility is confirmed through physical exam and blood analysis, eligible participants are admitted to the study site in the morning on the first study day. A blood sample is taken and participants receive one 10-mg pill of hydrocortisone. Heart rates and blood pressures are taken every 4 hours throughout the day. In the morning of Day 2, a blood sample will be obtained and a 24 hour urine collection will begin. On the morning of Day 3, another blood sample is obtained. Participants then receive intravenous cosyntropin, a synthetic form of a hormone that the body makes. About 1 hour after this, participants provide a final blood sample. Participants receive a pill of hydrocortisone prior to the end of the study.

  Study phs001313

• Whole exome sequencing of an invasive diffuse intrinsic pontine glioma sampled from different sites

  The lateral ventricle subventricular zone (SVZ) is a frequent site of high-grade glioma (HGG) spread and tumor invasion of the SVZ is a predictor of a worse clinical prognosis. A range of HGG types invade the stem cell niche of the SVZ, including both adult glioblastoma and pediatric high-grade gliomas such as diffuse intrinsic pontine glioma (DIPG). The cellular and molecular mechanisms mediating this frequent invasion of the SVZ are poorly understood. Here we demonstrate that neural precursor cell (NPC):glioma cell communication underpins the propensity of glioma to colonize the SVZ. SVZ NPCs secrete chemoattractant signals toward which glioma cells home. Biochemical and proteomic analyses of factors secreted by SVZ NPCs revealed a discrete list of candidate proteins. Necessity and sufficiency testing implicated the neurite outgrowth-promoting factor pleiotrophin, along with three required binding partners (secreted protein acidic and rich in cysteine (SPARC), SPARC-like protein 1, and heat shock protein 90B), as key mediators of this chemoattractant effect. Pleiotrophin protein expression is strongly enriched in the SVZ, and knockdown of pleiotrophin expression starkly reduced glioma invasion of the SVZ in the adult murine brain. Pleiotrophin, in complex with the three binding partners, activated the Rho/ROCK pathway in DIPG cells, and inhibition of ROCK resulted in decreased DIPG invasion toward SVZ neural precursor cell-secreted factors. These findings demonstrate a pathogenic role for neural precursor cell – glioma interactions and potential therapeutic targets to limit glioma invasion.

  Study EGAS00001002326

• Copy number profiling of putative cancer stem from pleural effusion aspirates from breast cancer patients

  A common symptom during late stage breast cancer disease is pleural effusion, which is related to poor prognosis. In pleural effusions malignant cells can be detected, which indicates a metastatic spread from the primary tumor site. Beside the usefulness for investigation of the metastatic process, it has been a source to isolate cells with putative cancer stem cell (CSC) properties. For this study, pleural effusion aspirate from 25 metastatic breast cancer patients were processed to establish in vitro culture. Patient-derived aspirates were cultured under sphere forming conditions and isolated primary cultures were sorted for cancer stem cell populations ALDH1+ and CD44+CD24-/low and sphere forming efficiency of CSC and non-CSC subpopulation was determined. Unsorted cells had a higher potential to form spheres compared to CSC subpopulations. Subsequently, DNA was isolated from pleural effusions before and after cell sorting, to compare their copy number profiles generated by low-coverage whole genome sequencing to DNA from FFPE primary tumors or bone metastasis. Unbalanced profiles could be detected in four pleural samples before sorting, in two ALDH1+ sorted samples, in one CD44+CD24-/low and in all control samples. Additionally, spheroid culture from one pleural sample could be passaged on and was characterized. Therefore, pleural effusions are an appropriate media for enrichment of putative CSC. However, low-coverage sequencing is difficult due to low quantities of abnormal cells compared to normal cells.

  Study EGAS00001002343

• Cardiovascular disease biomarkers derived from circulating cell-free DNA methylation

  Acute coronary syndrome (ACS) remains a major cause of worldwide mortality. The syndrome occurs when blood flow to the heart muscle is decreased or blocked, causing muscle tissues to die or malfunction. There are three main types of ACS: Non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, and unstable angina. The treatment depends on the type of ACS, and this is decided by a combination of clinical findings, such as electrocardiogram and plasma biomarkers. Circulating cell-free DNA (ccfDNA) is proposed as an additional marker for ACS since the damaged tissues can release DNA to the bloodstream. We used ccfDNA methylation profiles for differentiating between the ACS types and provided computational tools to repeat similar analysis for other diseases. We leveraged cell type specificity of DNA methylation to deconvolute the ccfDNA cell types of origin and to find methylation-based biomarkers that stratify patients. We identified hundreds of methylation markers associated with ACS types and validated them in an independent cohort. Many such markers were associated with genes involved in cardiovascular conditions and inflammation. ccfDNA methylation showed promise as a non-invasive diagnostic for acute coronary events. These methods are not limited to acute events, and may be used for chronic cardiovascular diseases as well.

  Study EGAS00001007263

• Lung Multi-site Targeted Sequence Capture

  DNA extracted from multiple biopsies taken from different areas of primary lung tumours will be subjected to targeted re-sequencing and analysed in order to assess intra-tumour heterogeneity with respect to mutations in a selection of cancer related genes.

  Dataset EGAD00001001017

• Latency and interval therapy affect the evolution in metastatic colorectal cancer

  The cohort of 15 patients included ten patients with available tissue from the primary tumor and ≥1 metastatic site, four patients with pairs of metastases only, and one patient with an anastomotic recurrence five years after initial resection of the primary tumor

  Dataset EGAD00001005226

• Methylation and nucleosome occupancy studies on cell-free DNA using enzymatic cytosine conversion

  Raw sequencing data (PE, fastq.gz) from NovaSeq 6000 sequencing runs of: 1. Blood-derived cell-free DNA from six healthy controls, enzymatic cytosine conversion (between 1 and 3 replicates each) 2. Urine-derived cell-free DNA from three healthy controls, enzymatic cytosine conversion (between 1 and 3 replicates each) 3. Blood-derived cell-free DNA from six patients with acute or chronic kidney disease with/without other relevant organ dysfunction, enzymatic cytosine conversion (between 1 and 3 replicates each) 4. Urine-derived cell-free DNA from three patients with acute kidney disease, enzymatic cytosine conversion (between 1 and 3 replicates each) 5. Blood-derived cell-free DNA from three healthy controls, bisulfite cytosine conversion (single datasets) 6. Conventional whole-genome sequencing on genomic DNA of two healthy kidney donors for two of the studied patients (single datasets).

  Dataset EGAD00001006072

• Identification of hypermutation and defective mismatch repair in ctDNA from metastatic prostate cancer

  DNA mismatch repair defects (MMRd) and tumor hypermutation are rare and under-characterized in metastatic prostate cancer. Furthermore, since hypermutated MMRd prostate cancers can respond to immune checkpoint inhibitors, there is an urgent need for practical detection tools. We analyzed cell-free DNA targeted sequencing data from 434 metastatic prostate cancer patients with circulating tumor DNA (ctDNA) purity above 2%. Samples with somatic hypermutation were subjected to 150x whole exome sequencing. These data allowed us to interrogate the salient genomic properties of this rare prostate cancer subtype and correlate findings with patient clinical outcomes.

  Study EGAS00001003899

• Cergentis FFPE-TLC sequencing of colorectal carcinoma

  In this study, formalin-fixed paraffin-embedded targeted locus capture (FFPE-TLC) sequencing is used as a novel technology for targeted detection of tumor-specific genomic structural variants (SVs) in the primary tumor of 29 colorectal cancer patients with metastatic disease. The tumor region was macrodissected and sequenced for 29 patients, and the "normal" region of the same slide was macrodissected and sequenced for 8 of these patients. SVs were found in the common fragile site (CFS)-associated genes MACROD2, PRKN, FHIT and WWOX as well as SVs caused by three LINE transposable elements. Tumor-specificity of selected SVs was independently verified by droplet digital PCR of tumor tissue DNA and their applicability as plasma circulating tumor DNA biomarkers was demonstrated. This dataset contains the hg19 reference alignment of the FFPE-TLC sequences for all 29 colorectal cancers and 8 adjacent normals.

  Dataset EGAD50000000618

• Methylation Profiles of Cell-Free DNA Using Nanopore Sequencing

  Epigenetic characterization of cell-free DNA (cfDNA) is an emerging approach for detecting and characterizing diseases such as cancer. We developed a strategy using nanopore-based single-molecule sequencing to measure cfDNA methylomes. This approach generated up to hundreds of millions of reads for a single cfDNA sample from cancer patients, an order of magnitude improvement over existing nanopore sequencing methods. We developed a single-molecule classifier to determine whether individual reads originated from a tumor or immune cells. Leveraging methylomes of matched tumors and immune cells, we characterized cfDNA methylomes of cancer patients for longitudinal monitoring during treatment.Control subjects consist of healthy individuals without a positive diagnosis of cancer. cfDNA was obtained through purification of plasma from blood draws. Genomic DNA (gDNA) was derived from extraction of primary tumor tissue or from leukocytes from blood draws.

  Study phs002950

• Metadata Public API

  Metadata Rest Endpoints Common Aspects Functionality Identifiers Requests and Responses Request Response Querying Querying by Object Cross-Querying by Object Common Aspects Functionality The Metadata REST API allows EGA users to request metadata from the EGA. Using this api you will be able to obtain the publicly available information from EGA study, sample, experiment, run, analysis, policy, dac and dataset. The API also allows for objects to be cross-referenced in order to obtain for example all the datasets linked to a dac. Identifiers EGA objects can be identified by their unique accession. These are ID's displayed everywhere, shared among all EGA locations and specific for each data type (More information on the list below) EGA Accession ID EGA Object description EGAS EGA Study Accession ID EGAC EGA DAC Accession ID EGAP EGA Policy Accession ID EGAN EGA Sample Accession ID EGAR EGA Run Accession ID EGAX EGA Experiment ID EGAZ EGA Analysis Accession ID EGAD EGA Dataset Accession ID EGAB EGA Submission ID EGAF EGA File Unique Accession ID Server Request and Response Request All the endpoints implement these two HTTP methods, GET and HEAD. Moreover, there is an authentication layer that allows to disclose the private information about each object if the user runs the endpoint with their token and has permissions to the related dataset. HTTP Method Description GET Returns the objects and their public information (including private information if the user has permissions) HEAD Returns the count of objects to be returned Response API responses are diverse but they always return a status call. Below you have a summary on what these codes mean and some tips that can help you troubleshooting them: HTTP Status Code Description Resolution 200 OK No error handling necessary 206 Partial Content Expected status code when paginating the results. No error handling necessary 400 BAD REQUEST Request incorrectly formulated 401 UNAUTHORISED/FORBIDDEN You do not have permissions over the object you are trying to access. / The authorised user is not permitted to make the given request. 404 NOT FOUND The object/resource you are trying to access does not exist. 500 INTERNAL SERVER ERROR This is a server-side error, try later. If the issue persists, contact the Heldpesk. Querying Querying by Object In the below documentation, worked examples can be found on how to use the API, to query about each unique EGA object. https://metadata.ega-archive.org/analyses/{id} https://metadata.ega-archive.org/dacs/{id} https://metadata.ega-archive.org/datasets/{id} https://metadata.ega-archive.org/runs/{id} https://metadata.ega-archive.org/samples/{id} https://metadata.ega-archive.org/studies/{id} Worked example for the EGA data access committee(DAC) EGAC00001000514 https://metadata.ega-archive.org/dacs/EGAC00001000514 Points to notice Please, be advised that all EGA objects can be queried by using the same endpoint. For example: https://metadata.ega-archive.org/datasets Returns all the datasets registered at the EGA. https://metadata.ega-archive.org/datasets?limit=5&offset=15 Returns 5 results skipping the initial 15 results. Cross-Querying by Object The EGA REST API Metadata also allows for the crossquerying of public metadata. For example, should I want to query the datasets included in the ICGC DAC: https://metadata.ega-archive.org/dacs/EGAC00001000010/datasets Below, you can find worked examples on how to perform the call to the API. https://metadata.ega-archive.org/datasets/EGAD00001000645/analyses https://metadata.ega-archive.org/datasetsEGAD00001000645/files https://metadata.ega-archive.org/datasets/EGAD00001000620/runs https://metadata.ega-archive.org/datasets/EGAD00001000620/samples https://metadata.ega-archive.org/samples/EGAN00001092114/datasets https://metadata.ega-archive.org/files/EGAF00000056146/dacs https://metadata.ega-archive.org/files/EGAF00000056146/datasets https://metadata.ega-archive.org/files/EGAF00000056146/studies There are more endpoints included in this category. Please, find all the possibilities (green tick) in the table below. Table The table displays in a ordered fashion the objects that can be crossreferenced using the metadata API. BY Analysis Dac Dataset Experiment Policy Run Sample Study File Analysis ✔ ✔ Dac ✔ ✔ Dataset ✔ ✔ ✔ ✔ Experiment ✔ ✔ ✔ ✔ Policy ✔ Run ✔ ✔ ✔ Sample ✔ ✔* ✔ Study ✔ ✔ ✔ ✔ ✔ ✔* File ✔ *: These cross queries do not include data from Array-File submissions. Check out the SPEC

  Documentation discovery/metadata/public-metadata-api

• Targeted sequencing of cell free DNA samples from oligometastatic colorectal cancer patients

  In order to discover specific mutations that correlate with prognosis, target sequencing was performed using cell-free DNA samples from oligometastatic colorectal cancer patients.

  Study JGAS000196

• Ongoing Replication Stress Tolerance and Clonal T Cell Responses Distinguish Liver and Lung Recurrence and Patient Outcomes in Pancreatic Ductal Adenocarcinoma

  Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) survive longer when disease spreads to the lung but not to the liver. We generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease progression results in lung metastasis without liver metastases (lung cohort). Lung cohort patients generally survived longer than liver cohort patients, independent of tumor subtype. We developed a pORG gene signature that distinguishes primary tumors in the liver and lung cohorts. We identified ongoing replication stress (RS) response pathways in high pORG/liver cohort tumors, while low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid PDAC is associated with tolerance to ongoing RS, limited tumor immunity, and less favorable outcomes; whereas low RS, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes. As expected, we found high frequencies of KRAS, TP53, CDKN2A, and SMAD4 gene alterations in our tumor samples. High pORG activity (GSVA scores) in our primary tumors appear to be positively correlated with alteration frequencies in both TP53 and CDKN2A. We did not see a correlation with alterations in KRAS as almost all the tumor samples have KRAS alterations. From a de-identified dataset of 1,873 patients diagnosed with and/or treated for PDAC at our institution between 2004 and 2020, we identified 422 patients for which we had specimens with sequencing data (N=374) and/or specific evidence of disease metastasis site(s) from the OHSU cancer registry or disease-relevant computed tomography (CT) scans to allow cohort classification. Note that our study includes RNA-Seq, DNA-Seq panel, and TCR-Seq (T-cell Receptor Sequencing) data, but that this dbGaP submission just includes the patients/samples with RNA-Seq and/or DNA-Seq panel data. Therefore, this submission includes 290 samples from 278 patients. TCR sequence data is available on the Adaptive Biotechnologies platform. Clinical course timepoints, patient demographics, stage, grade, nodal involvement, resection margins, and angiolymphatic invasion were provided as deidentified data by the OHSU cancer registry with quality control data verification in a subset by pathologists (BB and TM). We reviewed all available computed tomography (CT) scans for all patients with primary tumor resection dates recorded by the cancer registrar, with tumor samples analyzed by RNA-seq, DNA-seq, or TCR-seq, and/or with additional information indicating metastatic spread (e.g., metastatic samples received for related studies). We abstracted the site of all lesions proven to be metastatic by biopsy and/or that clearly increased in size during progression or decreased in size during treatment as long as a radiologist described the lesion as &#8220;likely&#8221;, &#8220;suspicious for&#8221;, &#8220;concerning for&#8221;, or &#8220;favor&#8221; metastasis. Clinical imaging was reviewed by a radiologist (AG) to validate patient assignments to the liver, lung, and neither liver nor lung (other recurrence site) cohorts. Time to recurrence was calculated from the earliest of either the recurrence date provided by the OHSU cancer registry, or the date of earliest lesion abstracted from CT reports. The subject attributes reported in this submission were up to date at the time of our data freeze, which occurred July 2021.

  Study phs003597

• 36 mouse plasma cell-free DNA cases

  36 mouse plasma cell-free DNA cases

  Dataset EGAD00001008810

• Automated system for scoring hematoxylin and eosin-stained ovarian cancer sections by identifying single cells uncovered that stromal cell ratio is a significant predictor for overall survival and progression-free survival.

  Concerted efforts in genomic studies have revealed profound insights in prognostic ovarian cancer subtypes. On the other hand, abundant histology slides have been generated to date, yet their uses remain very limited and largely qualitative. Our goal is to develop automated histology analysis as an alternative subtyping technology for ovarian cancer that is cost-efficient and do not rely on DNA quality. We develop an automated system for scoring hematoxylin and eosin-stained (H&amp;E) primary tumour sections of 91 late-stage ovarian cancer to identify single cells including cancer and stromal cells. We demonstrated high accuracy of our system based on expert pathologists’ scores (cancer=97.1%, stromal=89.1%) as well as compared to immunohistochemistry scoring (correlation=0.87). Quantitative stromal cell ratio is significantly associated with poor overall survival after controlling for clinical parameters including debulking status and age (multivariate analysis p=0.0021, HR=2.54, CI=1.40-4.60) and progression-free survival (multivariate analysis p=0.022, HR=1.75, CI=1.09–2.82). We demonstrate how automated image analysis enables objective quantification of microenvironmental composition of ovarian tumours. Our analysis reveals a strong effect of the tumour microenvironment on ovarian cancer progression and highlights the potential of therapeutic interventions that target the stromal compartment or cancer-stroma signalling in the stroma-high, late-stage ovarian cancer subset.

  Study EGAS00001001694

• Genomic sequencing of Pediatric Rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood accounting for approximately 350 newly diagnosed cases yearly in the United States. With the development of multimodal chemotherapy regimens, relapse-free survival rates have improved to 70-80% in patients with localized disease albeit with significant toxicity. Unfortunately, despite aggressive treatment, patients with metastatic or recurrent disease continue to suffer from high mortality. Further characterization of the genetic events underlying this tumor type is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. In a collaborative effort between the National Cancer Institute, the Children's Oncology Group, and the Broad Institute, we use a combination of whole-genome and whole-exome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs.

  Study phs000720

• Long-read sequencing for cell-free DNA analysis (human)

  In this study, we compared the two long-read sequencing platforms, namely the single-molecule real-time sequencing by Pacific Biosciences and nanopore sequencing by Oxford Nanopore Technologies, for the analysis of cell-free DNA from plasma. Cell-free DNA from plasma samples of 31 pregnant women at different trimesters, 6 hepatitis B carriers, and 8 patients with hepatocellular carcinoma were sequenced with the two platforms.

  Study EGAS00001006328

• Characterization of Cell Free Plasma Methyl-DNA From Xenografted Tumors to Guide the Selection of Diagnostic Markers for Early-Stage Cancers

  Circulating cell-free methyl-DNA (mcfDNA) contains promising cancer markers but its low abundance and possibly diverse origin pose challenges toward the accurate diagnosis of early stage cancers. By whole-genome bisulfite sequencing (WGBS) of cell-free DNA (cfDNA) from about 0.5 mL plasma of mice xenografted with human tumors, we obtained and aligned the reads to the human genome, filtered out the mouse and carrier bacterial sequences, and confirmed the tumor origin of methyl-cfDNA (mctDNA) by methylation-sensitive restriction enzyme digestion prior to species-specific PCR. We estimated that human tumor-specific reads (ctDNA) or mctDNA comprised about 0.29 or 0.01%, respectively of the xenograft mouse cfDNA, and about 0.029 or 0.001% of the cfDNA of human early stage cancer patients. Similar WGBS of early stage (0-II, node- and metastasis-free) breast, lung or colorectal cancer samples identified hundreds of specific DMRs (differentially methylated regions) compared to healthy controls. Their association with tumourigenesis was supported by stage-dependent methylation, tumor suppressor or oncogene clusters, and genes also identified in the xenograft samples. Using 20 three-cancer-common and 17 colorectal cancer-specific DMRs in combination (top 0.0018% of the WGBS methylation clusters) was sufficient to distinguish the stage I colorectal cancers from breast and lung cancers and healthy controls. Our data thus confirmed the tumor origin of mctDNA by sequence specificity, and provide a selection threshold for authentic tumor mctDNA markers toward precise diagnosis of early stage cancers solely by top DMRs in combination. Biological Materials were provided by the Ontario Tumour Bank, which is funded by the Ontario Institute for Cancer Research Reference for citation: Ling Liu, Jinghua Feng, Julian Polimeni, Manli Zhang, Hai Nguyen, Urmi Das, Xu Zhang, Harminder Singh, Xiao-Jian Yao, Etienne Leygue, Sam K.P. Kung, and Xie J. Characterization of cell free plasma methyl-DNA from xenografted tumours to guide the selection of diagnostic markers for early-stage cancers. Frontiers in Oncology, 2021 Feb. 5. DOI: 10.3389/fonc.2021.615821.

  Study EGAS00001006175

• Splicing signature analysis of RNU4-2, RNU5A-1 and RNU5B-1

  Pathogenic variants in the snRNA RNU4-2 were recently described as a frequent cause of neurodevelopmental disorders. In our study we further delineate the phenotype associated with RNU4-2 and we also identify pathogenic variants in RNU5A-A and RNU5B-1. Capture-based RNA-Seq were performed to compare splicing pattern between affected and control individuals. A strong signature based on alternative 5' splice site usage was found for RNU4-2 patients, and we suggest an either 5' or 3' signature depending on the variant's localiztion in U5 genes.

  Study EGAS50000000889

• Whole genome sequencing of matched primary and metastatic acral melanomas

  Next generation sequencing has enabled systematic discovery of mutational spectra in cancer samples. Here we used whole genome sequencing to characterise somatic mutations and structural variation in a primary acral melanoma and its lymph node metastasis. Our data show that the somatic mutational rates in this acral melanoma sample pair was more comparable to the rate reported in cancer genomes not associated with mutagenic exposure than in the genome of a melanoma cell line or the transcriptome of melanoma short-term cultures. Despite the perception that acral skin is sun-protected, the dominant mutational signature in these samples is compatible with damage due to ultraviolet light exposure. A nonsense mutation in ERCC5 discovered in both the primary and metastatic tumours, could also have contributed to the mutational signature through accumulation of unrepaired dipyrimidine lesions. However, evidence of transcription-coupled repair was suggested by the lower mutational rate in the transcribed regions and expressed genes. The primary and the metastasis are highly similar at the level of global gene copy number alterations, loss of heterozygosity and single nucleotide variation (SNV). Furthermore, the majority of the SNVs in the primary tumour were propagated in the metastasis and one non-synonymous coding SNV and one splice site mutation appeared to arise de novo in the metastatic lesion.

  Study EGAS00001000169

• Detection of ctDNA in Plasma of Patients with Clinically Localised Prostate Cancer is Associated with Rapid Disease Progression

  Purpose: DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown. Patients and Methods: We performed whole genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 hours and 6 weeks) surgery. In a separate cohort (n=189) we identified the presence of ctDNA TP53 mutations in pre-operative plasma in a retrospective cohort, and determined its association with biochemical- and metastasis-free survival. Results: Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2-4.8, p = 0.014)). Conclusions: CtDNA is uncommonly detected in localised prostate cancer but its presence portends more rapidly progressive disease.

  Study EGAS00001004636

• 5 human plasma cell-free DNA cases (BS-seq)

  5 human plasma cell-free DNA cases (BS-seq)

  Dataset EGAD00001008809

• untargeted whole genome sequencing - Evaluation and correction of GC biases in cell-free DNA at the fragment level

  These are aligned paired-end reads from Illumina NovaSeq 6000 whole-genome sequencing of 4 cfDNA samples extracted from blood plasma (plasma-Seq). Three samples from patients with breast cancer, prostate cancer, or colorectal cancer and one sample from a healthy individual were aligned to GRCh38 (GCA_000001405.15_GRCh38_no_alt_plus_hs38d1_analysis_set). The observed GC bias is different in each of these cfDNA samples which leads to different average GC content per sample. This bias is corrected using the GCparagon commandline tool.

  Dataset EGAD00001010100

• Error-corrected flow-based sequencing at whole genome scale and its application to circulating cell-free DNA profiling

  Differentiating sequencing errors from true variants is a central genomics challenge calling for error suppression strategies that balance costs when sparse material or ultra-rare variants require high-accuracy methods. For example, circulating cell-free DNA (ccfDNA) sequencing for cancer monitoring is limited by sparsity of circulating tumor DNA (ctDNA), abundance of genomic material in samples, library preparation error rates and sequencing errors. Whole-genome sequencing (WGS) can overcome the low abundance of ccfDNA by integrating signal across the mutation landscape, but higher cost limits adoption compared with targeted panels, where ccfDNA abundance limits maximal coverage depths. Here we applied deep (~120x) lower-cost WGS (Ultima Genomics) with analytic error correction for tumor-informed ctDNA detection within the part-per-million range. We further developed high-coverage duplex error-corrected WGS of ccfDNA, achieving 7.7x10-8 error rates, to assess disease burden in melanoma and urothelial cancer patients without matched tumor sequencing. Together, we show that deeply sequenced error-corrected WGS accurately calls somatic variants, demonstrating the feasibility of WGS for tumor-informed and tumor-agnostic ctDNA detection.

  Study EGAS50000000844

• Heat selection enables highly scalable methylome profiling in cell-free DNA for noninvasive monitoring of cancer patients

  Genome-wide analysis of cell-free DNA (cfDNA) methylation profile has been recognized as a promising approach for sensitive and specific detection of many cancers. However, scaling such genome-wide assays for clinical translation is impractical due to the high cost of whole genome bisulfite sequencing. We have shown that the small fraction of GC-rich genome is highly enriched in CpG sites and disproportionately harbors the majority of cancer-specific methylation signature. Here, we report on the simple but effective Heat enrichment of CpG-rich regions for Bisulfite Sequencing (Heatrich-BS) platform that allows for focused methylation profiling in these highly informative regions. Our novel method and bioinformatics algorithm enable accurate tumor burden estimation with high sensitivity and quantitative tracking of colorectal cancer patient’s response to treatment, at much reduced sequencing cost suitable for frequent monitoring. We also show, for the first time, tumor epigenetic subtyping from cfDNA using Heatrich-BS, which could enable patient stratification from non-invasive liquid biopsy. As such, Heatrich-BS holds great potential for highly scalable screening and regular monitoring of cancer using liquid biopsy.

  Study EGAS00001006198

• Multimodal plasma and urinary cell-free DNA profiling improves risk stratification in newly diagnosed prostate cancer

  Prostate cancer (PCa) is a heterogeneous disease, impeding early detection and risk stratification. Liquid biopsies (LBx) enable minimally invasive tumor profiling, but circulating tumor-derived DNA (ctDNA) detection remains difficult, particularly in early-stage PCa. We developed a multimodal LBx approach combining genomic and epigenomic cell-free DNA (cfDNA) features in plasma and urine from newly diagnosed PCa patients to improve early characterization of PCa and risk stratification of aggressive disease. Plasma and urine samples from 55 localized PCa (lPCa) patients, 18 advanced PCa (aPCa) patients, and 36 cancer-free controls were subjected to low-coverage whole-genome sequencing and methylated DNA immunoprecipitation sequencing to assess fragmentation, chromosomal instability, and methylation in cfDNA. This complementary approach yielded a 45% ctDNA detection rate in newly diagnosed PCa. Major differences were observed between aPCa and controls, reflecting increasing signals with tumor progression. Epigenomic cfDNA features differentiated lPCa from aPCa, and ctDNA was detected in 46% of PCa patients with prostate-specific antigen &lt;10 ng/ml, suggesting potential for risk stratification. This study highlights the value of multimodal LBx approaches for early characterization of primary PCa and identification of aggressive disease at initial diagnosis. Integration into clinical workflows could complement diagnostics and support personalized decision-making tailored to patients’ PCa risk profiles. 

  Study EGAS00001008195

• Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA.

  3784 whole genome sequencing bam files were generated from plasma cell-free DNA of healthy individuals and patients with cancer. Paired reads were mapped to hg19 human reference genome.

  Study EGAS00001006553

• Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer

  No consensus strategies exist for prognosticating metastatic castration-resistant prostate cancer (mCRPC). Circulating tumor DNA fraction (ctDNA%) is increasingly reported by commercial and laboratory tests but its utility for risk stratification is unclear. Here, we intersect ctDNA%, treatment outcomes, and clinical characteristics across 738 plasma samples from 491 male mCRPC patients from two randomized multicentre phase II trials and a prospective province-wide blood biobanking program. ctDNA% correlates with serum and radiographic metrics of disease burden and is highest in patients with liver metastases. ctDNA% strongly predicts overall survival, progression-free survival, and treatment response independent of therapeutic context and outperformed established prognostic clinical factors. Recognizing that ctDNA-based biomarker genotyping is limited by low ctDNA% in some patients, we leverage the relationship between clinical prognostic factors and ctDNA% to develop a clinically-interpretable machine learning tool that predicts whether a patient has sufficient ctDNA% for informative ctDNA genotyping (available online: https://www.ctDNA.org). Our results affirm ctDNA% as an actionable tool for patient risk stratification and provide a practical framework for optimized biomarker testing.

  Study EGAS50000000211

• Aberrant Oligoclonal Hematopoiesis in Remission AML and Relapse from Rare Cells Genomically Resembling Leukemic Blasts

  Acute myelogenous leukemia (AML) is a hematological malignancy that often responds well to initial treatment in which patients achieve a complete remission (CR). Nevertheless, most patients will relapse after achieving a CR, which is often fatal. This minimal residual disease (MRD) that remains after CR is likely the source of relapse and so improved measurement and characterization of these residual cells is critical. Employing droplet digital PCR (ddPCR), we were able to measure mutated alleles of many recurrently mutated genes in bone marrow samples acquired during CR from AML patients at levels as low as 0.002% variant allele frequency. Most of these gene mutations persisted in CR but at very variable and gene-dependent levels. Most AML cases involved residual aberrant oligoclonal hematopoiesis, and rare cell populations (as few as 1 in 15,000) were detected that were genomically similar to the AML blast populations at that dominated at diagnosis and were fully clonally represented at relapse. From a clinical perspective, the mutant allele frequency correlated closely with relapse-free and overall survival.

  Study phs001408

• Feasibility Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN) in resectable stage III melanoma patients

  OpACIN is a feasibility study including 20 patients with palpable stage III melanoma that were 1:1 randomized to receive ipilimumab 3mg/kg and nivolumab 1mg/kg, either 4 courses after surgery (adjuvant arm), or 2 courses prior to surgery and 2 courses post-surgery (neoadjuvant arm). WES and RNA-seq was performed on baseline biopsy material and correlated with outcome of the patients (relapse free survival). TCRseq from baseline tumor samples was used to analyse the top 100 tumor resident clones and analyse their change in PBMC comparing baseline versus week 6 of immunotherapy.

  Study EGAS00001003099

• Genetics of Mood Disorders: Aging and Emotion Regulation Brain Circuitry in Bipolar

  This single-site study is designed to investigate age-related changes in structure and function of a ventral prefrontal cortex (VPFC) neural system, that subserves emotion processing and regulation, during mid to later adulthood in individuals with bipolar disorder (BD), compared to healthy controls (HC). It is a 5-year study of age-related changes in mood, emotion regulation and related symptoms and behaviors using multimodality imaging measures [structural magnetic resonance imaging (MRI) of gray matter, diffusion tensor imaging (DTI) of white matter, and functional MRI measures of functional connectivity and of brain responses during implicit and explicit emotion regulation] comparing BD and HC groups ages 40-79 years, 50% female; a subgroup will be reassessed and rescanned after 2 years to study brain and associated behavioral changes over time. We will explore relationships between brain aging with risk factors implicated in progression. This will include genes, as well as adverse outcomes of progression such as suicide ideation and behavior. As there has been little study of effects of aging of the VPFC emotional circuitry in healthy individuals, findings could provide new insights into brain circuitry and emotional regulation in older adults. In addition to the importance of contributing to understanding BD, as BD is unique in having both elevated and depressive episodes, its study can provide a model for understanding progressive emotion dysregulation to both intervention and prevention that can be better targeted specifically for older individuals with BD. A de-identified blood sample will be sent to the Repository and Genomics Resource.

  Study phs001631

• WGS data of plasma cell free DNA

  Raw paired-end whole-genome sequencing data of plasma cell free DNA on the NovaSeq 6000.

  Dataset EGAD50000000257

• Differential methylation positions

  This dataset includes an analyzed DMP file that provide the information about differential methylation positions based on Illumina Infinium MethylationEPIC BeadChip. All samples (5 lung cancer cases vs. 5 benign lung disease controls) were obtained from bronchial washings at the site of the lesion under bronchoscopy manipulation. Of the five lung cancer cases, 3 are adenocarcinoma and 2 are squamous carcinoma.

  Dataset EGAD00001010147

• A phase II trial of the aurora kinase A inhibitor alisertib for patients with castration resistant and neuroendocrine prostate cancer: efficacy and biomarker evaluation

  Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop de novo or as a mechanism of treatment resistance. N-myc is capable of driving NEPC progression. Alisertib inhibits the interaction between N-myc and its stabilizing factor Aurora-A, inhibiting N-myc signaling, and suppressing tumor growth. In this single arm, multi-institutional open label phase 2 clinical trial of alisertib, sixty men were treated with alisertib 50mg twice daily for 7 days every 21-days. Eligibility included metastatic prostate cancer and at least one: small cell neuroendocrine morphology; &#8805;50% neuroendocrine marker expression; new liver metastases without PSA progression; elevated serum neuroendocrine markers. The primary endpoint was six-month radiographic progression free survival. Pre-treatment biopsies were evaluated by whole exome and RNA-seq.

  Study phs001666