15038 results for "cancer studies using rna-seq"

in 55.82 milliseconds.

• Whole genome characterisation of lung cancer organoids and tissue

  Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here we describe a method to establish long-term expanding human airway organoids from broncho-alveolar biopsies or lavage material. The pseudostratified airway organoid epithelium consists of basal cells, functional multi-ciliated cells, mucus-producing goblet cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoid culture conditions also allow gene editing as well as the derivation of various types of lung cancer organoids. Respiratory syncytial virus (RSV) infection recapitulated central disease features and dramatically increases organoid cell motility, found to be driven by the non-structural viral NS2 protein. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.

  Study EGAS00001002899

• Spatial and temporal diversity in genomic instability processes define early stage lung cancer evolution.

  Deciphering the complexity of non-small cell lung cancer (NSCLC) evolutionary histories may elucidate the basis for its dismal outcome. We performed multi-region sequencing on 25 regions from seven early-stage NSCLCs. Spatial dissection revealed branched tumor evolution, with driver mutations occurring before and after subclonal diversification. Intra-tumor heterogeneity in DNA copy number alterations, translocations and endogenous APOBEC mutational processes, demonstrates that NSCLC may follow multiple distinct evolutionary trajectories simultaneously. In smokers, despite maintained carcinogen exposure, temporal dissection reveals a proportional decrease in smoking-related mutations during tumor progression, accompanied by an increase in APOBEC-related mutations. We observed genome-doubling events early in tumor development of ex-smokers, suggesting prolonged latency periods before clinical detection. Multi-region sequencing demonstrates the relentless and heterogeneous nature of genomic instability processes in early-stage NSCLCs.

  Study EGAS00001000840

• Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci

  Multiple regulatory elements distant to their targets on the linear genome can influence the expression of a single gene through chromatin looping. Chromosome conformation capture implemented in Hi-C allows for genome-wide agnostic characterization of chromatin contacts. However, detection of functional enhancer-promoter interactions is precluded by its effective resolution that is determined by both restriction fragmentation and sensitivity of the experiment. Here we have developed a capture Hi-C (cHi-C) approach to allow an agnostic characterisation of these physical interactions on a genome-wide scale. Single nucleotide polymorphisms associated with complex diseases often reside within regulatory elements and exert effects through long-range regulation of gene expression. Applying this cHi-C approach to 14 colorectal cancer risk loci has allowed us to identify key long-range chromatin interactions in cis and trans involving these loci.

  Study EGAS00001001085

• The genomic and radiomic complexity of multifocal prostate cancer

  Multiparametric magnetic resonance imaging (mpMRI) and molecular prognostic tests are emerging to guide screening and prostate cancer (PCa) diagnosis, however their efficacy and cross validation requires further assessment in the context of intraprostatic heterogeneity and patient prognosis. To evaluate the molecular features that make prostate tumors visible to mpMRI, we established an mpMRI-blind multicore collection and performed low pass whole genome, exome, transcriptome and methylation profiling of 14 lesions and 23 representative cores from 6 PCa patients. Our results show that diagnosis based on mpMRI does not capture the genomic complexity of tumors, and reveal that commercial prognostic signature results based on single-biopsy assessments are insufficient to define risk of progression. Altogether, our study supports the use of a multi-biopsy assessment in both mpMRI visible and non-visible areas in order to provide a truly personalised diagnosis

  Study EGAS00001002767

• cfDNA and CDX/PDX methylation profiling in Small Cell Lung Cancer

  This study contains methyl-binding domain sequencing and shallow whole genome sequencing from circulating free DNA (cfDNA) for 79 patients with small cell lung cancer (SCLC) and 78 non-cancer controls. We also sequence genomic DNA (both methyl-binding domain sequencing and shallow whole genome sequencing) from 30 circulating-tumour-cell derived explant models (CDXs, from 23 unique patients with SCLC), 20 patient derived explant models (PDXs, from 10 unique patients with SCLC) and 13 lung tissue samples.

  Dataset EGAD00001008673

• Offspring Sex Impacts DNA Methylation and Gene Expression in Placentae from Women with Diabetes during Pregnancy

  Exposure to diabetes in utero is known to increase the offspring's likelihood of developing metabolic disease in adulthood, but the mechanisms involved are unknown. It has been proposed that early exposure to hyperglycemia and elevated insulin levels may lead to malprogramming of the fetus leading to the subsequent development of diabetes and obesity. Epigenetic modifications of the genome including DNA methylation, provide a plausible mechanism that allows for permanent propagation of gene activity states from one generation of cells to the next. The placenta, a fetal tissue easily accessible for study, is a complex organ that is essential in regulating fetal growth. The changes in placental nutrient transport associated with diabetes during pregnancy (DDP) have significant effects on the developing fetus, indicating that the placenta plays a critical role in fetal programming. The aim of our study was to investigate whether exposure to DDP alters genome-wide DNA methylation in the placenta obtained from term pregnancies resulting in differentially methylated loci of metabolically relevant genes and downstream changes in RNA and protein expression.

  Study phs001535

• Tissue and Fluid Analysis in Ocular Inflammatory Disease

  Granulomas are found in multiple infectious and non-infectious human diseases, yet the pathogenic drivers of granulomatous disease are still poorly understood. To enrich for pathologic inflammatory cells, we leveraged the intrinsic immunologic isolation of the eye by examining granulomatous uveitis, a form of ocular inflammation. We performed single-cell RNA-sequencing to obtain an unbiased gene expression survey of ocular immune cells in the anterior chamber of four live human donors with granulomatous uveitis. We paired this with antigen-receptor sequence analysis to identify clonally expanded lymphocytes. Each individual had robust clonal expansion arising from a single T or B cell lineage, suggesting distinct pathogenic processes in each patient. This variability in clonal expansion was mirrored by individualized combinations of TH1, TH1/TH17, and Tregs in ocular CD4 T cells. In contrast, ocular CD8 T cells were more transcriptionally similar across donors. Finally, clonally expanded, activated B cells displayed evidence of plasmablast differentiation and class-switching within the ocular microenvironment. Collectively, our study identified conserved and individualized features of granulomatous inflammation, illuminating parallel pathophysiologic mechanisms.

  Study phs002449

• The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR)

  The Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR) Registry and Repository, supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), was established in 2000 to provide a resource for the scientific community to explore genetic and non-genetic factors affecting rheumatoid arthritis (RA) occurrence and outcomes in African Americans. The long term objective is a database and a repository of 1,100 RA and 550 matched healthy African-American subjects. This CLEAR Registry and Repository has two arms: a longitudinal arm for subjects with early RA (enrollment from 2000 to 2005) and a cross-sectional arm for subjects with any disease duration (enrollment from 2006 to 2012). CLEAR has two components: a database and a repository. The database contains extensive demographic, socioeconomic, clinical and radiographic (radiographs of hands and feet) information and bone mineral density data from DEXA scans. The repository contains genomic DNA, plasma and serum on most of the participants. Participants in CLEAR II had RNA isolated from peripheral blood cells.

  Study phs001360

• Transcriptomics sequencing analysis of pre-invasive lung adenocarcinoma in never-smokers

  The prevalence of lung adenocarcinoma (LUAD) has increased sharply in East Asia. Early diagnosis leads to better survival rates, but this requires an improved understanding of the molecular changes during early tumorigenesis, particularly in non-smokers. We performed whole exome-sequencing and RNA-sequencing for samples from 94 East Asian patients with precancerous lesions (25 with atypical adenomatous hyperplasia [AAH]; 69 with adenocarcinoma in situ [AIS]) and 73 patients with early invasive lesions (minimally invasive adenocarcinoma [MIA]). Cellular analysis revealed that the activities of endothelial and stromal cells could categorize tumors into molecular subtypes within pathology-defined lesion types. These subtypes were linked with the advanced radiology-defined lesion type and coordinated with immune cell infiltration throughout the progression of LUAD. Characterization of these lesion types identified positively selected mutation patterns, and suggested that angiogenesis of the late-stage AIS type potentially contributes to tissue invasion of the MIA type. Our findings offer a novel resource that may help to improve early diagnosis and patient prognosis, and also suggest possible approaches for early disease interception.

  Study EGAS50000000439

• Whole exome sequencing of pre-invasive lung adenocarcinoma in non-smokers

  The prevalence of lung adenocarcinoma (LUAD) has increased sharply in East Asia. Early diagnosis leads to better survival rates, but this requires an improved understanding of the molecular changes during early tumorigenesis, particularly in non-smokers. We performed whole exome-sequencing and RNA-sequencing for samples from 94 East Asian patients with precancerous lesions (25 with atypical adenomatous hyperplasia [AAH]; 69 with adenocarcinoma in situ [AIS]) and 73 patients with early invasive lesions (minimally invasive adenocarcinoma [MIA]). Cellular analysis revealed that the activities of endothelial and stromal cells could categorize tumors into molecular subtypes within pathology-defined lesion types. These subtypes were linked with the advanced radiology-defined lesion type and coordinated with immune cell infiltration throughout the progression of LUAD. Characterization of these lesion types identified positively selected mutation patterns, and suggested that angiogenesis of the late-stage AIS type potentially contributes to tissue invasion of the MIA type. Our findings offer a novel resource that may help to improve early diagnosis and patient prognosis, and also suggest possible approaches for early disease interception.

  Study EGAS50000000438

• Proteogenomics reveals two distinct biological pilocytic astrocytoma subgroups

  Pilocytic astrocytoma (PA) is the most common pediatric brain tumor and driven by aberrant MAPK signaling, typically mediated by BRAF alterations. While five-year overall survival rates exceed 95%, tumor recurrence constitutes a major clinical challenge in incompletely resected tumors despite chemotherapeutic or radiation based therapies. Therefore, we used proteogenomics to discern the biological heterogeneity of PA to improve classification of this tumor entity and identify novel therapeutic targets. Our proteogenomics approach integrates RNA sequencing and LC/MS-based proteomic profiling data from a cohort of 58 confirmed, primary PA samples. An integrative genomics approach was conducted to discern the biological heterogeneity of PA and to identify aberrant pathway activation in these biological subgroups. In summary, Pilocytic astrocytomas segregate into two groups where younger patients are significantly associated with Group 1. Importantly, we validate the two distinct biological subgroups in two non-overlapping cohorts. The biological heterogeneity seen here may improve biological classification and reveal novel therapeutic targets specifically useful for non-resectable tumors with high risk of recurrent or progressive disease.

  Study EGAS00001006402

• Genomic landscape of oral cancers (Illumina RNA-Seq)

  Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCC) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCC, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. By contrast, in HPV-negative OSCC, T>C substitutions in the sequence context 5’-ATN-3’ correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCC. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1 and NFKBIA. Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon and nuclear factor-B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr. 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCC, in contrast to their gains in HPV-negative OSCC. High-ranking variant allele fractions implicated ZNF750, PIK3CA and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

  Study EGAS00001003237

• How to encrypt files with EGACryptor

  File preparation Due to the processes used at the EGA for file archival the use of non-alphanumeric characters in a filename will cause issues in archival. By convention whitespaces in filenames are to be avoided and should be replaced with the underscore character (_). Before encrypting your files please make sure that any files that will be uploaded to EGA do not use special characters such as # ? ( ) [ ] / \ = + < > : ; " ' , * ^ | &  Crypt4gh EGACryptor Files encrypted with EGACryptor must be uploaded via FTP EGACryptor The EGACryptor v.2.0.0 is a JAVA-based application which enables submitters to produce EGA compliant encrypted files along with files for the encrypted and unencrypted md5sum for each file to be submitted. The application will generate an output folder that will by default mirror the directory structure containing the original files. This output folder can subsequently be uploaded to the EGA FTP staging area via an FTP or Aspera client. Download EgaCryptor Download EgaCryptor Using the EgaCryptor Using the EgaCryptor Encrypting single file Encrypting multiple files Encrypting all files in folder Points to note Troubleshooting Troubleshooting Download EGACryptor The required jar files can be obtained by downloading EgaCrytptor jar file After the file has been downloaded, extraction of the zipped archive is required. The EGACryptor has been built to work with Java Runtime Environments from version 6 and above and with the OpenJDK Environment. Please refer to the relevant resources for installation guidance. Installing the latest version of the OpenJDK will include the JCE files. If your installation of Java JRE is less than 1.8.0_151 will require the manual installation of the JCE Policy Files. You can verify the version of the Java SE Runtime Environment (JRE) installed by using the command: $ java -version If you need to install the JCE please follow the instructions below: Installing the JCE policy files (due to licensing terms and conditions the required policy files must be downloaded direct from the ORACLE website) : Download the unlimited strength JCE policy files (JRE 6 / JRE 7/ JRE 8) Uncompress and extract the downloaded file. This will create a subdirectory called JCE. This directory contains the following files: README.txt, COPYRIGHT.html, local_policy.jar and US_export_policy.jar Install the two policy JAR files by replacing the existing ones in your java home directory. Install the two policy JAR files by replacing the existing ones in your directory. The standard place for JCE jurisdiction policy JAR files is: /lib/security [Unix] or \lib\security [Win32] Notes: refers to the directory where the Java SE Runtime Environment (JRE) was installed. Additional performance enhancements that have been included in the EGACryptor V2.0.0: The ability to parallelise the processing of datasets through the use of the resources on a system. Multicore systems will allow the user to specify n-1 cores for an n-core system. The use of this feature on clusters may speed up the processing of datasets that have large file numbers but consult your local cluster guide to ensure that there are not monopolising resources that are needed by other system users. The default for this process remains single threaded. 3 levels of system usage can be specified. Full usage within the limits detailed above. A limited mode that will ensure that 50% of the system resources are available for other tasks. Maximum mode is limited to 75% of system resources, this allows encryption to be prioritised but allows for the system to be usable for light alternate tasks. Finally there is a throttling mode that allows you to specify the exact number of computational threads to be used. the EGACryptor is able to ingest a structured directory and will output a directory with the same structure containing the encrypted files along with the md5checksums for the plain and encrypted files. The entire output directory can then be uploaded to the EGA for archival. as with the input path, it is now possible to specify the output path. the options have been updated inline with the upgraded functionality. The tool can only be used via the command line. The EGACryptor is designed to perform a single task, encrypting your data, for upload of these files please refer to our uploading guide Using the EgaCryptor Below are the three ways on how the EGACryptor tool can be used: Encrypting a single file : java -jar ../EGA-Cryptor_2_0_0.jar -i example1.bam Encrypting multiple files : java -jar ../EGA-Cryptor_2_0_0.jar -i "example1.bam,example2.bam" Encrypting all the files within a folder java -jar ../EGA-Cryptor_2_0_0.jar -i path/to/target/directory By default the EGACryptor v2 will create a new output directory containing all encrypted files and the relevant checksums within the target directory. If a specific directory is desired this can be specified by using the -o flag. This can be achieved in a similar manner to the following example: java -jar ../EGA-Cryptor_2_0_0.jar -i /path/to/target/directory -o /path/to/output/directory The tool will output three files per input file: file.gpg ( encrypted file ) file.md5( file md5 sum value file ) file.gpg.md5 ( encrypted file md5 sum value file ) All output files must then be uploaded to your submission account using Aspera or FTP. Further documentation on how to upload files: FTP and Aspera. Points to note Remember to provide the path to EgaCryptor.jar and run the command from within the directory the file/s are located. ECryptor writes files to the source directory of your local file system, as a result you must have write-access permissions for the source directory. Troubleshooting If in doubt about the function of the EGACryptor it is recommended to first consult the built-in documentation. This can be accessessed by using the -h flag as stated in the following table. Built-in Commands Table: list of the command line options built into EGA-Cryptor v2.0.0. Command line Option Action --------------------- ----------- -f Set this option to allow application to create maximum threads to utilise full capacity of cores/processors available on machine -h Use this option to view the bult-in help menu * -i File(s) to encrypt. Provide file/folder path or comma separated file path if multiple files in double quotes -l Set this option to allow application to create maximum threads equals to 50% capacity of cores/processors available on machine -m Set this option to allow application to create maximum threads equals to 75% capacity of cores/processors available on machine -o Path of the output file. This is optional. If not provided then output files will be generated in the same path as that of source file (default: output- files) -t Set this option if user wants to control application to create maximum threads as specified. Application will calculate no. of cores/processors available on machine & will create threads accordingly Encryption Errors UnixFileSystem.createFileExclusively (Native Method) The error is thrown by UNIX ("UnixFileSystem.createFileExclusively(Native Method)"). It appears that the user does not have write-access to the file system where the file to be uploaded is located. EGACryptor always writes MD5 checksums into files before uploading them to the server, and these files are created in the same location where the uploaded file itself resides.Solution: address your directory permission issue and re-run the command. Install JCE Unlimited Strength Jurisdiction Policy files The JCE policy unlimited strength jurisdiction files should be installed according to your current java version If you are still facing difficulty with the EGACryptor v.2 after having consulted the documentation please contact the EGA Helpdesk.

  Documentation submission/data/file-preparation/egacryptor

• Circulating tumor DNA dynamics reveal KRAS G12C mutation heterogeneity and response to treatment with the KRAS G12C inhibitor divarasib in solid tumors

  Purpose: To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study. Experimental design: Plasma samples were collected for serial ctDNA profiling at baseline (Cycle 1 Day 1 prior to treatment) and multiple on-treatment time points (Cycle 1 Day 15 and Cycle 3 Day 1). Results: KRAS G12C ctDNA was detectable from plasma samples in 72.9% (43/59) and 92.6% (50/54) of patients with non-small cell lung cancer and colorectal cancer, respectively, the majority of whom were eligible for study participation based on a local test detecting the KRAS G12C mutation in tumor tissue. Baseline ctDNA tumor fraction was associated with tumor type, disease burden, and metastatic sites. A decline in ctDNA level was observed as early as Cycle 1 Day 15. Serial assessment showed a decline in ctDNA tumor fraction associated with response and progression-free survival. Except for a few cases of KRAS G12C sub-clonality, on-treatment changes in KRAS G12C variant allele frequency mirrored changes in the overall ctDNA tumor fraction. Conclusion: Across tumor types, the KRAS G12C mutation likely represents a truncal mutation in the majority of patients. Rapid and deep decline in ctDNA tumor fraction was observed in patients responding to divarasib treatment. Early on-treatment dynamics of ctDNA were associated with patient outcomes and tumor response to divarasib treatment.

  Study EGAS50000000315

• 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

• A higher ctDNA fraction decreases survival in regorafenib-treated metastatic colorectal cancer patients

  The predictive effect of circulating tumor DNA (ctDNA) in colorectal cancer (CRC) treatment is still highly discussed. The primary objective of this study was to investigate a possible prognostic/predictive value of ctDNA under regorafenib treatment. This prospective multicenter translational biomarker phase II pilot study enrolled 30 metastatic CRC patients (67% men, 33% women) treated with regorafenib. ctDNA was assessed in plasma before treatment start and at defined time points during administration. Measurement of tumor fraction as well as mutation and copy number analysis of CRC driver genes were performed by next generation sequencing approaches. Multivariate analyses for survival and treatment efficacy were adjusted to age, gender and ECOG. Disease control rate was 30%. Median tumor fraction at baseline was 18.5% (0-49.9). Mutations in CRC driver genes or genes involved in angiogenesis were identified in 25 patients (83.3%). KRAS mutations were detected in 13 out of 14 KRAS positive tumors, in three patients without KRAS mutation in the respective tumor acquired mutations as a consequence of prior anti-EGFR treatment were detected. In a subset of patients, novel occurring mutations or focal amplifications were detected. A tumor fraction of 5% and higher at baseline was significantly associated with a decreased OS (p=0.022; HHR 3.110 (95%CI: 1.2-8.2). ctDNA is detectable in a high proportion of mCRC patients. Higher ctDNA levels are associated with survival among regorafenib treatment. Moreover, our data highlight the benefit of a combined evaluation of mutations and somatic copy number alterations (SCNA) in advanced cancer patients.

  Study EGAS00001004491

• Colorectal cancer study

  Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and non-matrix proteins. Although most MMPs are secreted as inactive proenzymes and they are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C&gt;T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11’s protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.

  Study EGAS00001006489

• PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO-trial

  Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype but published data on trials specific for ILC are so far lacking. Translational research revealed that a subset of ILCs may be immune-related and more sensitive to DNA-damaging agents such as platinum. In murine ILC models, synergy between immune checkpoint blockade and platinum has been observed. Here, we tested this concept in the phase II, GELATO-trial (NCT03147040), in which patients with metastatic ILC were treated with weekly carboplatin (AUC 1.5) as immune induction treatment for 12 weeks and atezolizumab (PD-L1 blockade; every three weeks) from the third week onwards until disease progression. Four out of 23 evaluable patients had a partial response (17%, 95%CI 5-39%) and two patients had stable disease for at least 24 weeks, resulting in a clinical benefit rate of 26% (95%CI 10-48%). Out of these six patients, four patients had triple-negative ILC (TN-ILC). In serial biopsies of metastatic lesions, we observed higher CD8 T-cell infiltration, expression of immune checkpoints, and exhausted T cells upon carboplatin/PD-L1 blockade. This is the first report of a clinical trial specifically for ILC and we demonstrate promising anti-tumor activity of atezolizumab with carboplatin as immune induction, in particular for TN-ILC. While activity of carboplatin/PD-L1 blockade in classical ER+ ILC was limited, our translational data yield important insights for the design of highly needed clinical trials in ILC.

  Study EGAS00001006902

• Disorders/Differences of Sex Development (DSD) Study Performed at UCLA in Collaboration with the DSD-Translational Research Network (DSD-TRN), with the Support of the Gabriella Miller Kids First Pediatric Research Program

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. Whole Genome Sequence (WGS) and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Disorders/Differences of Sex Development (DSD) are congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical. DSD are chronic medical conditions collectively affecting &#126;1&#37; of the population, frequently requiring life-long care by multiple specialists, and carrying a significant public health burden. Some are associated with life-threatening events, such as adrenal crises in Congenital Adrenal Hyperplasia (CAH). DSD are also associated with increased infertility, cancer, gender dysphoria risks, psychosocial distress and pervasive challenges to health-related quality of life (HRQoL) for patients and families. DSD are broadly classified into three categories: sex chromosome DSD, 46,XY DSD and 46,XX DSD, and further classified according to the type of gonad found in the patient (ovary, testis, ovotestis). We were able to increase significantly the diagnostic success for DSD using Whole Exome Sequencing (WES), with the identification of disease-causing and likely pathogenic variants in a third of a cohort of 46,XY patients. We have therefore proposed a shift in the diagnostic approach to DSD to use next-gen sequencing as a first-line clinical test, which could lead to faster and more accurate diagnosis, and orient further clinical management, limiting unnecessary, costly, and often invasive endocrine testing and imaging. However many remain unexplained (over half of the XY cases, a significant minority of XX cases, including most ovotesticular DSD, and most syndromic cases). In addition, the very large phenotypic variability in cases with known variants in the same gene is unexplained. We here propose to use Whole-Genome Sequencing (WGS), which dramatically improves upon exome sequencing, covering both coding and non-coding parts of the genome more uniformly, as an approach to not only improve diagnostic yield, but also to identify novel genes and regulatory elements involved in DSD.

  Study phs001178

• Mutational dynamics of triple negative breast cancer over neoadjuvant chemotherapy treatment reveal frequent whole genome duplication events

  Background Triple-negative breast cancer (TNBC) is associated with poor survival rate and high genomic instability, generating complex tumour genomes. However, the processes generating this complexity are poorly studied over time. Here, we study the temporal dynamics of TNBC somatic mutations, revealing major transitions in tumour genome evolution, from diagnostic biopsies, through treatment, to cancer remission or recurrence. Methods Deep whole exome sequencing and CUTseq, a reduced representation whole genome sequencing approach, were performed in parallel, to comprehensively identify short nucleotide variants (SNVs), copy number alterations (CNAs) and aneuploidies genome-wide. We profiled (N=74) tumour samples from 22 patients across the course of disease, including spatially diverse samples from many tumours, allowing us to observe the gain and loss of candidate driver variants over time. Results As expected, tumour infiltrating lymphocyte (TIL) levels and residual cancer burden (RCB) score were negatively correlated, with good responses to neoadjuvant chemotherapy (NACT) seen in pre-treatment samples with high infiltration. In general, SNV mutational burden remained stable across disease progression and RCB classes. Recurrent SNVs across the cohort implicated several known TNBC driver genes in disease progression and response to treatment, with TP53, MICA, CYP2D6, BRCA1 and BRCA2 frequently altered. However, the presence of candidate driver SNVs in these genes often varied throughout a patient’s treatment, including the loss of those seen in a given driver gene in pre-treatment samples, but gain of novel variants in the same gene at later time points. Dramatic structural dynamics were seen in all tumours, including abundant CNA including chromosome arm aneuploidies seen in pre-treatment samples, followed by frequent loss of these alterations post-treatment, and their re-emergence at recurrence. Whole genome duplication (WGD) events appear to drive these dynamics, with a higher frequency of pre-treatment WGD seen in patients with the best response to NACT. Conclusions Comprehensive longitudinal profiling demonstrates the complex interplay of SNVs and copy number alterations during TNBC progression, leading to diverse evolutionary trajectories and patient outcomes. Complex mutational patterns emerge as important features during progression, with WGD events emerging as potential candidate biomarkers of response at both tumour establishment and recurrence.

  Study EGAS00001008261

• Dataset of methylation data from whole blood DNA

  This dataset includes raw data (.idat) for the Illumina Human450k beadchip and methylation levels (.txt files). Methylation level were treated for normalization and background substraction. We removed probes with at least one of the following characteristics: (1) weak signal (p &gt; 0.01) (2128 CpG sites), (2) SNP-enriched sites (4100 sites), (3) out of a CpG context (not on a CG) (3149 sites), or (4) located on sex chromosomes (11,129 sites). A total of 465,071 CpG sites were analyzed initially. Signal was then normalized, first by scaling to the internal controls using the methylumi R package, then by applying the method of subset-quantile within array normalization (SWAN) implemented in the minfi R package.

  Dataset EGAD00010001593

• Summary Statistics GWAS SSNS

  Column 1 rsid: SNP identifier;Column 2 chromosome: name of chromosome on which the SNP is located;Column 3: position: base pair position on the chromosome;Column 4 minor_test_allele: the base that constitutes the minor allele;Column 5 major_allele: the base that constitutes the major allele;Column 6 maf: the frequency of the minor allele, indicated as a fraction of 1;Column 7 allele_freq_cases: the minor allele frequency in cases;Column 8 allele_freq_controls: the minor allele frequency in controls;Column 9 regression_pvalue: the p-value for the difference in allele frequency between cases and controls;Column 10 odds_ratio: the odds ratio, as calculated using logistic regression under an additive model with adjustment for the first ten principal components of ancestry

  Dataset EGAD00010002316

• Evidence for Enhancer Activity in Intron 1 of TNFRSF1A Using CRISPR/Cas9 in Human Induced Pluripotent Stem Cell-derived Macrophages

  Use of CRISPR/Cas9 technology to study the TNFRSF1A gene, which plays a key role in autoimmune diseases such as ankylosing spondylitis, multiple sclerosis, and inflammatory bowel disease. By editing a specific regulatory element within the TNFRSF1A locus, we have identified the role of an enhancer element that is not well understood.

  Study EGAS50000000703

• Mutation screening in a large series of Japanese hearing loss patients using massively parallel DNA sequencing analysis.

  In the present study, mutation screening in a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of each deafness causative genes. Massively parallel DNA sequencing of 63 or 68 target genes were performed in 2969 unrelated Japanese HL patients to identify genomic variations responsible for HL.

  Study JGAS000490

• TS and WGS data

  The dataset contains the targeted sequencing (TS) and the whole genome low pass (WGS) BAM files of the study. For the TS: Samples: TS_XXX There are normal and tumor DNA samples. Each DNA strand has been sequenced independently (PoolA and PoolB). A TruSeq Custom Amplicon panel of 20 genes frequently mutated in ILC and/or ER-positive BC in general was designed using DesignStudio from Illumina: AKT1, ARID1A, CDH1, ERBB2, ERBB3, ESR1, FOXA1, GATA3, IGF1R, JAK2, MAP2K4, MAP3K1, NF1, PIK3CA, PTEN, RB1, RUNX1, STAT3, TBX3, and, TP53. For the WGS: Samples: WGS_XXX There are normal and tumor DNA samples. Samples were sequenced to an average target coverage of 0.5X.

  Dataset EGAD00001006393

• Chracterising cellur pathways underlying CD3/CD28 activation of human CD4+ cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Sorted Tcons were activated using a titration of anti-CD3 and anti-CD28 in combination as well as individually. As a control we cultured cells in the same conditions but without the stimuli. In total, we defined seven conditions from four individuals for sequencing. 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/ .

  Dataset EGAD00001006612

• Chracterising cellur pathways underlying CD3/CD28 activation of human CD4+ cells

  We devised an approach to disentangle the TCR and CD28 pathways upon stimulation in naive and memory primary human CD4+ T cells (Tcons) in response to defined stimulatory signals. Sorted Tcons were activated using a titration of anti-CD3 and anti-CD28 in combination as well as individually. As a control we cultured cells in the same conditions but without the stimuli. In total, we defined seven conditions from four individuals for sequencing. 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/.

  Dataset EGAD00001006610

• Targeted sequencing of healthy individuals, aged individuals and AML patients

  Targeted sequencing using BD Rhapsody with 462 mRNA and 97 antibodies of healthy young and aged adult as well as AML bone marrow mononuclear cells from iliac crest aspirations. Please note raw and integrated gene expression data, cell type annotation, metadata and dimensionality reduction are available as Seurat v3 objects through figshare. Access link is https://figshare.com/s/0fda29b169c719223ee3.

  Dataset EGAD00001008188

• Single cell sequencing of human normal luminal cells

  The dataset includes 12 paired FASTQ files (6 samples) with single cell transcriptome sequencing data of normal breast luminal cells from ducts and TDLUs derived from reduction mammoplasties from three patients. Chromium Single Cell 3’ Reagent Kit v2 or v3 (10x Genomics) were used for processing of cells, whereafter sequencing was performed using the Illumina® NextSeq500/550 High Output Kit v2. Cell Ranger was used for generating FASTQ files and files from different lanes were concatenated prior to uploading the data to EGA. "R1" files include the feature barcodes and UMIs, while "R2" files include the reads.

  Dataset EGAD00001008499

• Genetic architecture of autism spectrum disorder in India

  The dataset consists of whole exome sequencing data (fastq format) of 100 non-syndromic autism spectrum disorder patients from India. Whole exome sequencing data is generated using Agilent SureSelect v6 capture kit and Illumina HiSeq sequencing platform. Paired end fastq files are available.

  Dataset EGAD00001008621

• Summary Statistics GWAS SSNS

  Column 1 “rsid”: SNP identifier Column 2 “chromosome”: name of chromosome on which the SNP is located Column 3: “position”: base pair position on the chromosome Column 4 “minor_test_allele”: the base that constitutes the minor allele Column 5 “major_allele”: the base that constitutes the major allele Column 6 “maf”: the frequency of the minor allele, indicated as a fraction of 1 Column 7 “allele_freq_cases”: the minor allele frequency in cases Column 8 “allele_freq_controls”: the minor allele frequency in controls Column 9 “regression_pvalue”: the p-value for the difference in allele frequency between cases and controls Column 10 “odds_ratio”: the odds ratio, as calculated using logistic regression under an additive model with adjustment for the first ten principal components of ancestry

  Dataset EGAD00001008782

• A new subgroup of hepatocellular adenomas with sonic hedgehog pathway activation

  Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients’ risk factors for HCA, disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients with HCA. Related Publication: Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation Nault, Jean-CharlesLaurent, Christophe et al. Gastroenterology , Volume 152 , Issue 4 , 880 - 894.e6 http://dx.doi.org/10.1053/j.gastro.2016.11.042

  Dataset EGAD00001003092

• Immune Response Targeted Panel + B/TCR Profiling + AbSeq + Sample Tag Multiplexing

  Multiomics data for a cohort of 20 COVID-19 patients (10 patients mild, 3 patients moderate, 4 patients severe, 3 patients critical) obtained from peripheral blood mononuclear cells (PBMCs) from longitudinally sampled at hospital admission, discharge, and 1 month thereafter. The data has been obtained a multiwell-based single-cell technology (BD Rhapsody) that includes the targeted expression of BD Immune Response Targeted Panel, the TCR/BCR profiling and a set of 52 surface proteins. The samples of the different patients at different collection times were labelled using a cell hashing strategy with the BD Single-Cell Multiplexing Kit (6 samples for each run).

  Dataset EGAD00001011319

• Type 1 Diabetes Genetics Consortium (T1DGC): ImmunoChip Study

  The Type 1 Diabetes Genetics Consortium (T1DGC) was formed to address issues of limited sample size and consistency of phenotyping that had limited genetic investigations on risk of type 1 diabetes (T1D). The T1DGC first collected affected sib pair (ASP) families from four geographic networks (Asia-Pacific, Europe, North America, United Kingdom). In addition, T1D cases and controls were ascertained from existing and de novo collections. The T1DGC assembled 2,601 T1D ASP families and 69 Parent-T1D offspring trios, T1D cases from the UK Genetic Resource Investigating Diabetes (UKGRID, N=6,670), and controls from the British 1958 Birth Cohort (B58BC, N=6,523), the UK National Blood Services collection (NBS, N=2,893) and the NIHR Cambridge Biomedical Research Centre BioResource (CBR, N=2,846). All samples included in this series have reported or self-declared European ancestry. All DNA samples were collected after approval from relevant institutional research ethics committees. Genotyping was performed using a custom Illumina Infinium high-density genotyping array, ImmunoChip (Illumina, Inc; CA) according to manufacturer&#39;s protocols. The ImmunoChip was designed to densely genotype, using 1000 Genomes and any other available disease specific resequencing data, immune-mediated disease loci identified by common variant GWAS. The ImmunoChip Consortium selected 186 distinct loci containing markers meeting genome wide significance criteria (P&lt;5x10-8) from twelve such diseases (autoimmune thyroid disease, ankylosing spondylitis, Crohn&#39;s disease, celiac disease, IgA deficiency, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, T1D and ulcerative colitis). All 1000 Genomes Project pilot phase CEU population variants (Sept 2009 release) within 0.1cM (HapMap3 CEU) recombination blocks around each GWAS region lead marker were submitted for array design. No filtering on correlated variants (linkage disequilibrium) was applied. Additional content included regional resequencing data (submitted by several groups) as well as a small proportion of investigator-specific undisclosed content including intermediate GWAS results. After data cleaning and quality control, a total of 154,939 single nucleotide polymorphisms (SNPs) from 186 loci on ImmunoChip were scored. Case-control and family data were analyzed independently and combined by meta-analysis.

  Study phs000911

• Acute Respiratory Distress Syndrome Clinical Network: Fluid and Catheter Treatment Trial (ARDSNet FACTT-BioLINCC)

  Data Access NOTE: Please refer to the &#8220;Authorized Access&#8221; 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-FACTT include plasma, DNA, and serum. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: This study evaluated the benefits and risks of Pulmonary Artery Catheters (PACs) in patients with established acute lung injury in a trial comparing hemodynamic management guided by a PAC with hemodynamic management guided by a central venous catheter (CVC) using an explicit management protocol.Background: Optimal fluid management in patients with acute lung injury is unknown. Diuresis or fluid restriction may improve lung function but could jeopardize extrapulmonary organ perfusion.Participants: This randomized study compared a conservative and a liberal strategy of fluid management using explicit protocols applied for seven days in 1000 patients with acute lung injury. The primary end point was death at 60 days. Secondary end points included the number of ventilator-free days and organ-failure-free days and measures of lung physiology. Design: Participants were randomly assigned to a strategy involving either conservative or liberal use of fluids with concealed allocation in permuted blocks of eight with the use of an automated system. Participants were simultaneously and randomly assigned to receive either a pulmonary-artery catheter or a central venous catheter in a two-by-two factorial design.Conclusions: There was no significant difference in the primary outcome of 60-day mortality; however, the conservative strategy of fluid management was associated with improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing non-pulmonary organ failures. These results support the use of a conservative strategy of fluid management in patients with acute lung injury. (NEJM June 15, 2006; Vol 354, No. 24, pp 2564-75; NEJM May 25, 2006; Vol 354, No. 21, pp 2213-24)

  Study phs004165

• Netherlands Cancer Institute (NKI-AVL) general DAC

  Data is available under reasonable request. All data requests will be reviewed by the NKI IRB and must be supported by the Principal Investigator of the study. The researcher will need to sign a data access agreement with the NKI after approval. Go to https://ega.nki.nl to fill out the form to request access.

  Dac EGAC50000000055

• DELFI low-coverage WGS of plasma cfDNA

  The dataset "DELFI low-coverage WGS of plasma cfDNA" includes paired FASTQ files produced by WGS of 689 plasma cfDNA samples from 153 patients with colorectal cancer. WGS (100bp PE) was performed on a NovaSeq 6000 with a target depth of coverage of 8x.

  Dataset EGAD50000000630

• eSENSES control samples

  This dataset comprises BAM files from 18 control samples analyzed with the eSENSES targeted NGS panel. Spanning approximately 2 Mb, the panel features around 15,000 evenly distributed genome-wide SNPs, over 500 focal SNPs targeting key breast cancer driver regions, and more than 2,000 exons from 81 commonly altered genes.

  Dataset EGAD50000001167

• DNA sequencing of sgRNAs enriched from the CRISPR-Cas9 screened HCC organoids

  There are 12 samples. The project aims to find enriched or depleted sgRNAs to identify functional genes in HCC progression and lenvatinib resistance

  Study EGAS50000001130

• Pediatric B-cell precursor acute lymphoblastic leukemia Micro-C sequencing

  This dataset included 35 childhood B-cell precursor (BCP) acute lymphoblastic leukemia Micro-C samples. All samples were subjected to Illumina pair-end sequencing.

  Study EGAS50000000764

• Angiosarcoma_follow_up_study

  A bespoke targeted pulldown experiment will be performed on patients with Angiosarcoma. the resulting products will be sequenced to determine the prevalence of previously found mutations in these patients.

  Study EGAS00001000405

• The integrated genomic and immune landscapes of lethal metastatic breast cancer.

  We report on the extensive molecular profiling of multiple individual metastases from 10 warm autopsies of patients with lethal multi-therapy resistant breast cancers.

  Study EGAS00001002703

• MPN_mutation_order_followup

  To evaluate the presence of mutations in frequently mutated genes in MPN by performing targeted resequencing of a selected gene panel comprising of 111 genes across 40 samples with MPN.

  Study EGAS00001000663

• EBV_AID_project

  Whole genome sequencing of EBV-transformed B cells in order to determine whether EBV induction of activation-induced cytidine deaminase (AID) produces genome-wide mutations and/or chromosomal rearrangements.

  Study EGAS00001000955

• Prognostic_factors_in_prostate_cancer__deep_sequencing_pilot_project_TAPG

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

  Study EGAS00001000879

• Angiosarcoma_follow_up_2_validation_study

  A bespoke targeted pulldown experiment will be performed on patients with Angiosarcoma. the resulting products will be sequenced to determine the prevalence of previously found mutations in these patients.

  Study EGAS00001000518

• The polarity and specificity of antiviral T lymphocyte responses determine susceptibility to SARS-CoV-2 infection in cancer patients and healthy individuals.

  The goal of this study was to identify immune correlates of clinical protection against SARS-CoV-2 infection.

  Study EGAS00001005985

• The_Little_Princess_Knowledge_Bank_

  We propose to build a genetic knowledge bank of Wilms tumour that integrates clinical outcome data with a genetic, epigenetic, and transcriptomic survey of 1,000 Wilms tumours.

  Study EGAS00001004237

• Somatic_Genetics_of_lesions_from_a_POT1_patient

  In this project we will use exome sequencing to identify somatic mutations in lesions from a patient with a germline mutation in the protection of telomeres 1 gene (POT1).

  Study EGAS00001001343

• Bone_Cancer___Rare_Types_Whole_Genome

  We propose to definitively characterise the somatic genetics of a selection of rare bone cancers through generation of comprehensive catalogues of somatic mutations by high coverage genome sequencing.

  Study EGAS00001000501

• Whole genome sequencing of matched esophageal tumor-normal samples

  The dataset includes whole genome sequencing (WGS) data on ten matched esophageal tumor-normal pairs. WGS was performed by the cancer sequencing service of CG with an average read coverage of approximately 50-fold. Illumina HiSeq2000 instrument was used to perform the sequencing.

  Dataset EGAD00001004832

• CYPTAM - PacBio SMRT sequencing

  Dataset contains CYP2D6 sequencing data of 566 individuals who used tamoxifen as adjuvant breast cancer therapy. Phenotype data consists of the ratio between the metabolites endoxifen and desmethyltamoxifen (Metabolic ratio (MR)) as a proxy for CYP2D6 enzyme activity. Each sample is linked to one bam-file containing the CYP2D6 sequence.

  Dataset EGAD00001005972

• Whole genome sequencing data of high-grade serous ovarian cancer samples (set 0)

  Whole genome sequencing data of 5 High-grade serous carcinoma (HGSC) patients (6 samples) sequenced with BGI.

  Dataset EGAD00001009738

• Bulk RNAseq

  Bulk tumor RNAseq FASTQ files from 124 samples from patients with hormone sensitive or castration resistant prostate cancer.

  Dataset EGAD00001008760

• WGS data of colorectal cancer patients

  36 samples from individuals with colorectal tumors, whole genome sequencing

  Dataset EGAD00001007746

• Single Cell Genome Sequence for DLP+ library A110660A

  Single Cell Genome Sequence for triple negative breast cancer patient-derived xenograft SA610 passage 3 on DLP+ library A110660A

  Dataset EGAD00001009430

• Matched Pair Cell Line Tumour RNAseq

  In this study we will sequence the transcriptome of Verified Matched Pair Cancer Cell line tumour samples. This will be married up to whole exome and whole genome sequencing data to establish a full catalog of the variations and mutations found.

  Dataset EGAD00001000630

• 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

• Single Cell Genome Sequence for DLP+ library A96187A

  Single Cell Genome Sequence for triple negative breast cancer patient-derived xenograft SA501 passage 11, patient-derived xenograft SA609 passage 7 on DLP+ library A96187A

  Dataset EGAD00001009464

• Single Cell Genome Sequence for DLP+ library A98181A

  Single Cell Genome Sequence for triple negative breast cancer patient-derived xenograft SA919 passage 7, patient-derived xenograft SA1050A passage 1 on DLP+ library A98181A

  Dataset EGAD00001009479

• Somatic pseudogenes acquired during cancer development – RNAseq

  Insertion of processed pseudogenes is known to occur in the germline but has not previously been observed in somatic cells. Formation of pseudogenes could represent a new class of mutation in cancers and a new source of potential driver events.

  Dataset EGAD00001000639

• Single Cell Genome Sequence for DLP+ library A96109A

  Single Cell Genome Sequence for triple negative breast cancer patient-derived xenograft SA501 passage 2 on DLP+ library A96109A

  Dataset EGAD00001009452

• 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

• Exome sequencing files for "A single mutant clone populates the pancreatic ductal system to generate coexisting neoplastic lesions"

  Files from whole exome sequencing of eight tumors from eight pancreatic cancer patients along with matched PanIN precursor lesion(s) and a matched normal tissue.

  Dataset EGAD00001004044

• WES data of colorectal cancer patients

  35 samples from individuals with colorectal tumors, exome sequencing

  Dataset EGAD00001007745

• Whole genome sequencing data of high-grade serous ovarian cancer samples (set 8a)

  Whole genome sequencing data of 26 high-grade serous carcinoma (HGSC) patients (87 samples) sequenced with MGISEQ-2000 and HiSeq X Ten.

  Dataset EGAD00001011304

• sWGS data of Pap test smears and tumor tissues

  Shallow whole-genome sequencing data divided into three groups: - sWGS data from Pap smears of patients with confirmed high grade serous ovarian cancer - sWGS data from matched tumor tissue (at diagnosis) from the same patients - sWGS data from Pap tests smears of healthy women

  Dataset EGAD00001010141

• Organoid Derivation Project: TGS (2023-06-22)

  Sequencing of tissue samples and their derived organoids from oesophageal, pancreatic and colorectal cancer patients. . This dataset contains all the data available for this study on 2023-06-22.

  Dataset EGAD00001011089

• RNA Sequencing of Pulmonary Arterial Endothelial Cells in Pulmonary Hypertensive Patients and Controls

  The transcriptome of pulmonary arterial endothelial cells from healthy lungs and from lungs of patients with idiopathic pulmonary arterial hypertension have been analyzed and specific differences in disease-relevant pathways were identified. The genes identified as altered in these patients have direct effects on pulmonary arterial endothelial cell function. This finding may underlie the inability of the pulmonary vasculature to respond to and repair the damage observed in pulmonary hypertension.

  Study phs000998

• Airway Epithelial Cell Culture RNA Expression

  This study seeks to characterize airway epithelial mRNA and miRNA expression under a variety of experimental conditions. Samples are available from primary human cell cultures as well as cell lines grown under a variety of experimental conditions as documented in the phenotype and conditions associated with each individual sample. For some experiments, cells on plastic were exposed to cigarette smoke condensate to evaluate the effects of smoking. FOSL1 is a target gene for regulation by MIR34A family microRNAs.

  Study phs002472

• RNA Sequencing of Control and Myotonic Dystrophy Type 1 Cells During Myogenic Differentiation

  Immortalized control, patient-derived and CRISPR/Cas9-edited patient-derived myoblasts (known in the literature as C25, DM11, and DM11_1E6 cells, respectively) were grown confluent and were fused to myotubes in differentiation medium. Samples were collected at day -2 before initiation of differentiation (i.e. proliferation stage), at day 1 and at day 5 of differentiation in lysis buffer and stored at -70 degrees until all samples were collected.

  Study EGAS50000001152

• RNA-Sequencing and Somatic Mutation Status of Adrenocortical Tumors: Novel Pathogenetic Insights

  To investigate the relationship between transcriptome profile and genetic background in a large series of adrenocortical tumors and to identify new potential pathogenetic mechanisms, we performed transcriptome profiling by high-throughput sequencing. We collected snap-frozen tissue from patients with adrenocortical tumors (n = 59) with known genetic background: 26 adenomas with Cushing syndrome, 17 adenomas with mild autonomous cortisol secretion, 9 endocrine-inactive adenomas, 7 adrenocortical carcinomas. Additionally, we sequenced 4 control samples.

  Study EGAS00001004533

• Genome-wide genotyping data and exome sequencing of 100 European-descent and 100 African-descent Belgians used in the EGAS00001001895 study

  We recruited 100 healthy, male donors of self-reported European descent (EUB) and 100 of self-reported African descent (AFB) (Ghent, Belgium). For each participant, peripheral blood mononuclear cells (PBMCs) were isolated from whole blood on Ficoll-Paque density gradients. Monocytes were then positively selected with magnetic CD14 microbeads and exposed for 6 hours to different ligands activating TLR4 (LPS), TLR1/2 (Pam3CSK4), TLR7/8 (R848) and to a human seasonal influenza A virus (IAV). High-quality RNA was obtained from unstimulated and stimulated monocytes for 970 of the 1000 samples (200 x 5 conditions), and was sequenced on an Illumina HiSeq2000. On average, 34 million 101-bp single-end reads were obtained per sample.

  Dataset EGAD00001002714

• UMCU_Molpheno_Restricted

  This dataset contains Whole Genome Sequencing and, if available, RNA-sequencing and/or ATAC-sequencing data obtained from PBMCs derived from blood samples of 34 patients with intellectual disability and/or multiple congenital anomalies and their biological parents (58) included in the University Medical Center Utrecht (The Netherlands).

  Dataset EGAD00001004865

• Fastq files for the single cell RNAseq data of Follicular lymphoma study

  Fastq files for the single cell RNAseq data of Follicular lymphoma study. This dataset includes the paired single cell RNA sequencing data for 23 samples.

  Dataset EGAD00001008595

• Pre-activated anti-viral innate immunity in the upper airways controls early SARS-CoV-2 infection in children

  We investigated 10 female and 14 male SARS-CoV-2 positive children (age range: 0.8 to 18 years). Based on the WHO guidelines, 15 patients were classified as having mild COVID-19, while 7 children were classified as moderate COVID-19 cases. Two children were asymptomatic. 8 female and 10 male SARS-CoV-2 negative children were included as controls (age range: 4 to 16). 12 SARS-CoV-2 positive female and 9 male adults were included ( age range: 27 - 76) together with 13 female and 10 male SARS-CoV-2 negative adult controls (age: 24 - 77). 10 adult COVID-19 patients had mild disease, while 12 had moderate COVID-19. We performed single-cell RNA sequencing experiments.

  Dataset EGAD00001007969

• Massive parallel RNA sequencing of highly purified mesenchymal cells derived from bone marrow specimens of 10 healthy donors

  Highly purified mesenchymal cells (CD45-/7AAD-/CD235a-/CD31-/CD271+/CD105+) were prospectively FACS-isolated from bone marrow specimens of 10 healthy donors (HDs). This data set is used as a baseline control to observe the differences between gene expression profiles (GEPs) of pre-leukemia cases (45 low-risk myelodysplastic syndrome, 4 Shwachman-Diamond and 3 Diamond-Blackfan anemia patients) and gene expression patterns observed in a normal, healthy context. Through differential expression and gene set enrichment analysis we determined that inflammatory signaling pathways are significantly more active in mesenchymal cells of pre-leukemia cases compared to their healthy counterparts. Finally, we determined through statistical modelling of healthy donor's GEPs which pre-leukemia cases have significantly more active inflammatory signaling and demonstrated a strong relation to survival statistics.

  Dataset EGAD00001002659

• Targetable NOTCH1 rearrangements in reninoma - RNA

  Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assessed somatic changes in reninoma and found structural variants that generate canonical activating rearrangements of NOTCH1, whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observed excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma.

  Dataset EGAD00001010889

• Blood Transcriptome Profiling Links Immunity to Disease Severity in Myotonic Dystrophy Type 1 (DM1)

  Here, we explore the molecular signatures in RNA sequencing data from blood associated with disease severity as measured in Myotonic dystrophy type 1 (DM1) patients with less than 400 CTG-repeat length size in the DMPK gene in blood. These DM1 patients participated in the OPTIMISTIC study. This approach involved stratifying those within the OPTIMISTIC study into different patient groups with different degrees of disease severity (as measured by the muscle-impairment rating scale (MIRS)) and assessed at baseline. Patients were divided into groups with mild (MIRS 1–2) and severe (MIRS 3–5) neuromuscular symptoms with different DMPK repeat length characteristics. Therefore these .Bam files are baseline samples from this study.

  Dataset EGAD00001010010

• Organ maturation in preparation for birth (Peds RFA) to develop a tissue resource and a single-cell atlas of organ development and maturation for dissemination among the scientific and clinical community: RNA (2025-10-14)

  Knowledge about abnormal organ development is important to understand pathology and to develop novel treatment approaches for individuals with congenital and acquired disease. Most of our current understanding is based on examination of tissues from the embryo and early foetus, collected from women undergoing termination of pregnancy in the first trimester (third) of pregnancy. There is very little known about normal and abnormal organ development from a developmental perspective during the crucial last two-thirds of pregnancy when much remodelling of foetal tissues occurs. This study will generate a single-cell atlas of late-foetal lungs, blood, heart, bone and immune organs. . This dataset contains all the data available for this study on 2025-10-14.

  Dataset EGAD00001015737

• Pathways Study

  The Pathways Study (NCI R01 CA105274, PI: Kushi), is a prospective cohort study of a diverse population of recently diagnosed breast cancer survivors in KPNC. The aims are to examine the effect on recurrence and survival of 1) lifestyle factors such as diet, physical activity, and use of complementary and alternative therapies and 2) molecular factors such as biomarkers of inflammation and tumor DNA methylation profiles. Recruitment into the cohort was from January 2006 to May 2013. Baseline data collection was by in-person interview (on average two months post-diagnosis), with follow-up via mailed or phone questionnaires at 6, 24, and 72 months and outcomes and comorbidities at 12, 24, 48, 72, and 96 months post-enrollment. The Pathways Study is now funded through May 2021 as a cancer cohort infrastructure grant (U01 CA195565, MPI: Kushi/Ambrosone). The Pathways baseline interview consists of interviewer- and self-administered questionnaires. Interviewer-administered questionnaires collected information including demographics, family health history, pregnancy health history, menstrual history, history of breast care screening procedures, smoking history, hormone use, medication history, and vitamin and mineral use. Self-administered questionnaires collected information on diet, physical activity, CAM use, lymphedema, and psychosocial and quality of life measures.

  Study phs001534

• Transcriptome sequencing of human colon organoid after co-cultivation with Bifidobacterium longum

  The large intestine has a dense milieu of indigenous bacteria, generating a complex ecosystem with crosstalk between individual bacteria and host cells. In vitro host cell modeling and bacterial interactions at the anaerobic interphase have elucidated the crosstalk molecular basis. Although classical cell lines derived from patients with colorectal cancer including Caco-2 cells are used, whether they adequately mimic normal colonic epithelial physiology is unclear. To address this, we performed transcriptome profiling of Caco-2 and Monolayer cells derived from healthy Human Colonic Organoid (MHCO) cultured hemi-anaerobically. Coculture with the anaerobic gut bacteria, Bifidobacterium longum subsp. longum differentiated the probiotic effects of test cells from those of physiologically normal intestinal and colorectal cancer cells. We cataloged non- or overlapping gene signatures where gene profiles of Caco-2 cells represented absorptive cells in the small intestinal epithelium, and MHCO cells showed complete colonic epithelium signature, including stem/progenitor, goblet, and enteroendocrine cells colonocytes. Characteristic gene expression changes related to lipid metabolism, inflammation, and cell-cell adhesion were observed in cocultured live Bifidobacterium longum and Caco-2 or MHCO cells. B. longum-stimulated MHCO cells exhibited barrier-enhancing characteristics, as demonstrated in clinical trials. Our data represent a valuable resource for understanding gut microbe and host cell communication.

  Study JGAS000740

• High Grade Serous Ovarian Carcinomas Originate in the Fallopian Tube

  High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian cancer and has a poor outcome. It has been proposed that fallopian tube cancers may be precursors of HGSOC but evolutionary evidence for this hypothesis has been limited. To provide insights into the origins of HGSOC, we We performed whole-exome sequence and copy number analyses of laser-capture microdissected fallopian tube lesions (p53 signatures, serous tubal intraepithelial carcinomas (STICs), and fallopian tube carcinomas), ovarian cancers, and metastases from nine patients with HGSOC. The majority of tumor-specific sequence and structural alterations in ovarian cancers were present in STICs, including those affecting TP53, BRCA1, BRCA2 or PTEN genes. An eEvolutionary analyseis revealed that p53 signatures and STICs were are the precursors of ovarian carcinoma which in turn gave rise to metastatic lesionsand identify a. In one patient we identified a second STIC as a metastasis in the fallopian tube opposite from the affected ovary. These analyses revealed a window of seven years between the development of a STIC and the initiation of ovarian carcinomas, with development of metastases following rapidly thereafter. Our results provide insights into the etiology of ovarian cancer and have implications for the prevention, early detection and therapeutic intervention of this disease.

  Study EGAS00001002589

• METABRIC: Data from Batra et al (2021); DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation

  DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, RRBS-based profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, the study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.

  Study EGAS00001004327

• PETAL Network: Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among Inpatients With Symptomatic Disease (ORCHID) Trial

  ORCHID was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US between April 2 and June 19, 2020. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients with five interim analyses; however, the trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients.The distribution of the day 14 clinical status score (measured using a 7-category ordinal scale) was not significantly different for patients randomized to receive hydroxychloroquine compared with placebo.Instructions for requesting individual-level data are available on BioData Catalyst at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BioData Catalyst. For questions about availability, you may contact the BioData Catalyst team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs002299

• Genetic Effects on Gene Expression and Splicing during Human Neurogenesis

  Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing quantitative trait locus (e/sQTL) analyses is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs, and allele-specific expression in cultured cells representing two major developmental stages, primary human neural progenitors (n=85) and their sorted neuronal progeny (n=74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome-wide association, we uncover cell-type specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL for CENPW co-localized with common variant associations for cortical surface area and educational attainment.

  Study phs002493

• A Genome-Wide Association Study in Patients Experiencing Drug-Induced Long-QT Syndrome and/or Torsades de Pointes; A Collaboration Between the NIH Pharmacogenomics Research Network and the RIKEN Yokohama Institute Center for Genomic Medicine

  The goal of this study was to identify genetic risk factors for drug-induced prolongation of the QT interval (diLQT) and the ventricular arrhythmia torsades de pointes (TdP). We conducted a genome-wide association study (GWAS) focusing on subjects with a history of long QT and/or TdP after taking medication. Controls for this study were individuals with a history of cardiac arrhythmias who had begun treatment with potentially QT-prolonging antiarrhythmics. An additional control group of normal volunteers were given ibutilide, a drug with documented proarrhythmic properties. All study participants were recruited and treated/evaluated at Vanderbilt University Medical Center. This study was conducted by the Pharmacogenomics of Arrhythmia Therapy subgroup of the Pharmacogenetics Research Network, a nationwide collaboration of scientists studying the genetic contributions to drug response variability. Genotyping was performed by the RIKEN research institute in Japan using the Illumina 610 Quad Beadchip platform.

  Study phs000331

• Genetics of Inherited Muscle Disease

  The samples are drawn from a collection of patients with a heterogeneous set of neuromuscular disorders, including congenital muscular dystrophy, congenital myopathy, limb-girdle muscular dystrophy, Emery-Dreifuss muscular dystrophy, and arthrogryposis, along with unaffected parents and siblings in some cases. The samples were collected by the following clinicians affiliated with the associated institutes: Kathryn North and Nigel Clarke (Institute for Neuroscience and Muscle Research, Children&#39;s Hospital at Westmead, Australia) Hanns Lochmuller and Kate Bushby (The Newcastle Muscle Centre, Newcastle University, UK) Peter Kang (Boston Children&#39;s Hospital) Carsten Bonnemann (National Institutes of Health, Bethesda, MD, USA) Nigel Laing (University of Western Australia) All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Agilent SureSelect Human All Exon Kit v2 or Illumina&#39;s Rapid Capture Exome enrichment kit and sequencing was performed on an Illumina HiSeq 2000. In addition some samples were whole genome sequenced on Illumina HiSeq X Ten.

  Study phs000655

• Circulating Tumor DNA as a Biomarker in Patients with Stage III and IV Wilms Tumor: Analysis from a Children's Oncology Group Trial, AREN0533

  We evaluated the utility of circulating tumor DNA (ctDNA) as a biomarker in the serum and urine of 50 patients with Stage III or Stage IV Wilms tumor (WT) that were enrolled on Children's Oncology Group&nbsp;(COG) trial AREN0533. 49 out of 50 patients had matched tumor samples available for comparison. We profiled samples with ultra-low pass whole genome sequencing (ULP-WGS) and detected ctDNA in 82% of serum samples and 26% of urine samples. We also identified copy-number changes and single-nucleotide variants in the serum and urine samples, and compared them to the tumor data. Our study highlights the advantages of using ctDNA as non-invasive prognostic biomarker with the potential to detect tumor heterogeneity in patients with WT. We believe that prospective validation of ctDNA as a prognostic biomarker in patients with WT is warranted. The ULP-WGS and targeted next-generation sequencing (OncoPanel) data are available in this study.

  Study phs002847

• Genome Sequencing Reveals That RAD50 Hypomorphism Results in Enhanced Sensitivity to Checkpoint Kinase Inhibition Combined with Chemotherapy

  Outlier analyses represent a versatile method to identify predictive biomarkers of response to both targeted agents and chemotherapy. We performed whole genome sequencing (WGS) of tumor and germline blood from a patient with metastatic small cell carcinoma of the ureter who experienced a durable complete response to a combination of irinotecan plus AZD7762, a checkpoint kinase inhibitor. The patient initially had resection of the ureter followed by metastatic recurrence within the kidney and lymph nodes and underwent nephrectomy with lymph node dissection. Through WGS of tissue from the second surgery, we detected a hypomorphic L1237F mutation within RAD50, a component of the Mre11 double strand break repair complex, which resulted in heightened sensitivity to the combination of checkpoint inhibition and clastogenic chemotherapy. We validated the WGS findings using a combination of an exon capture assay and validation in model systems. The tumor samples sequenced by exon capture were derived from tissue taken from both the initial and second surgeries.

  Study phs000706

• Discovery of Novel Melanoma Predisposing Mutations by Exome Sequencing

  Melanoma risk shows clear heritability, but the inherited genetic factors remain largely unknown. Rare high risk mutations in CDKN2A, CDK4, BAP1 and TERT have been described but these variants, in aggregate, account for less than 50% of the kindreds reporting a family history of melanoma. This project will seek to identify new genes which may confer melanoma susceptibility. Identifying melanoma predisposing mutations can provide new biological insights and may impact important clinical decision making regarding treatment, surveillance and preventive approaches. Hereditary melanoma patients (defined as those individuals with multiple primary melanomas and those patients with a family history of melanoma) were collected from melanoma clinics at the Massachusetts General Hospital in Boston and the A. Sygrous Hospital in Athens, Greece. All exome sequencing was performed at the Broad Institute of Harvard and MIT; samples sequence capture was performed using Agilent SureSelect Human All Exon Kit v2 and sequencing was performed on an Illumina HiSeq 2000 or 2500.

  Study phs000823

• Sézary Syndrome Originates from Heavily Mutated Hematopoietic Progenitors

  The pathogenesis of cutaneous T cell lymphoma (CTCL) remains unclear. To study the malignant transformation of CTCL, we collected matched hematopoietic stem cell (HSC) extracts from bone marrow, CD4+CD26- malignant T cells, CD4+CD26+ normal T cells, and CD34+ HSCs from apheresis performed on 4 patients. To establish the baseline for calling true mutations without using hematopoietic cells, we also cultured bone marrow fibroblasts from each patient to use as normal controls. Whole exome sequencing (WES) was performed on all samples for somatic mutation calling. We identified &gt;200 mutations in CD34+ HSCs derived from either bone marrow or apheresis. Previously reported key oncodrivers in Sezary Syndrome were identified in autologous HSCs and malignant peripheral cells, but not in progenitor (bone marrow HSCs) cells. Also, we identified specific mutations shared by autologous HSCs and malignant peripheral cells in every patient. WES data of bone marrow HSCs, apheresis HSCs, CD4+CD26- T cells, CD4+CD26+ T cells, and fibroblasts will be available through dbGaP.

  Study phs003158

• 1000 Genomes Used for Cloud Testing

  WARNING: This is a test data set. The phenotype data was not checked to match 1000 Genomes project. Use with caution.This study provides public access to a demonstration subset of 1000 genomes sequence data in dbGaP. It is intended to be used by software developers who design, implement and validate pipelines for dbGaP data. While this project distributes only public data, it uses dbGaP security mechanisms which include a project-specific security key and a decryption password. Since the data are public, the key and password for this project will be included by SRA into public demonstration packages that permit users to test and validate the security of their computational pipelines. Note that all public users of this data will be logged under the same project and account ID. The datasets attached to this project must be restricted to 1000 Genomes data identical to the project's public FTP site. To access these test data using SRA toolkit use prj_phs710EA_test.ngc.

  Study phs000710

• Single-cell transcriptional mapping reveals genetic and hierarchy-based determinants of aberrant differentiation in AML

  Therapeutic targeting of acute myeloid leukemia (AML) has in part been hampered by profound cell state heterogeneity among leukemia cells. To develop a more precise understanding of leukemia cell states in AML, we constructed a reference atlas of human hematopoiesis from 263,519 single cell transcriptomes spanning 55 cellular states. Using this atlas, we mapped over 1.2 million single-cell transcriptomes spanning 318 myeloid leukemia samples. This uncovered twelve recurrent patterns of aberrant differentiation in AML and additional leukemia cell states involving lymphoid and erythroid progenitors. Systematic mapping of genotype-to-phenotype associations revealed specific differentiation landscapes associated with >45 genetic drivers. Importantly, AML samples sharing common genetic driver alterations can have distinct cellular origins which inform the cellular identity of their disease-sustaining leukemia stem cell (LSC). Further, distinct LSC-driven hierarchies can co-exist within individual patients. Thus, precise mapping of malignant cell states provides insights into leukemogenesis, refines disease classification, and informs therapy development.

  Study EGAS50000000918

• Direct genetic transformation bypasses tumor-associated DNA methylation alterations

  Tumors represent dynamically evolving populations of mutant cells, and many advances have been made in understanding the biology of their progression. However, key unresolved questions remain about the conditions that support their initial transformation, which cannot be easily captured in patient populations but are instead modeled using transgenic cellular or animal systems. Here, we used extensive patient atlas data to define common features of the tumor DNA methylation landscape as they compare to healthy human cells and used this benchmark to screen 21 engineered human and mouse models for their ability to reproduce these patterns. Notably, we find that genetically induced cellular transformation can trigger global changes in DNA methylation levels that are consistent with extensive proliferation but rarely recapitulate the widespread de novo methylation of Polycomb targets as found in clinical samples. Our results raise pertinent questions about the relationship between genetic and epigenetic aspects of tumorigenesis and provide an important molecular reference for evaluating existing as well as newer tumor models.

  Study EGAS50000000902

• Genomic Landscape of Apical Periodontitis

  We undertook the first genome-wide association (GWAS) study of apical periodontitis, enrolling 932 patients with deep carious lesions at UTHealth School of Dentistry and the University of Pittsburgh School of Dental Medicine. We used a case-control design to compare those with apical periodontitis to those without. Genotype data was generated for all participants and imputed using the TOPMed reference panel. We performed a single-variant association testing, a subphenotype analysis, and a genetically regulated expression association analysis, and generated a polygenic risk score and performed phenome-wide association analysis. We identified eight near-genome-wide significant loci for our primary outcome, eight genes where genetically regulated expression was associated with apical periodontitis status, and 33 phecodes that were associated with the generated polygenic risk score. We also replicated three loci previously reported in the literature. Genotype, phenotype, and results from the primary association analysis will be available via dbGaP.

  Study phs003252

• Variant allele frequency changes in TP53 predict pembrolizumab response in patients with metastatic urothelial carcinoma

  Prognoses for patients with metastatic urothelial carcinoma (mUC) have strikingly improved with pembrolizumab, an immune checkpoint inhibitor (ICI), but clinical benefits are limited to a subset of patients. Therefore, a non-invasive biomarker to predict pembrolizumab response is urgently required. We retrospectively examined genomic alterations in 25 plasma circulating tumor DNA (ctDNA) samples using a targeted sequencing of 77 genes from 16 mUC patients during pembrolizumab treatment. Eleven (68.8%) patients had two or more genomic alterations, including TP53 mutations (as defined by ctDNA-positive status). The proportion of responders to pembrolizumab in the ctDNA-positive group was higher than the ctDNA-negative group (72.7% vs. 20.0%). Furthermore, among all detected genomic alterations, variant allele frequency decreases in TP53 during pembrolizumab treatment were mainly associated with therapeutic response. Collectively, we suggest that profiling of ctDNA in plasma, especially TP53, is useful for predicting and monitoring therapeutic responses to pembrolizumab in mUC patients.

  Study JGAS000622

• Delineation of the heterogeneous molecular landscape of HRS cells and their biological contributions to forming comprehensive TME ecosystems.

  The tissue architecture of classic Hodgkin Lymphoma (CHL) is unique among cancers and characterized by rare malignant Hodgkin and Reed-Sternberg cells that are co-evolving in a complex ecosystem of immune cells in the tumor microenvironment. The lack of a comprehensive systems-level interrogation has hindered the description of disease heterogeneity and clinically relevant molecular subtypes. Here, we employed an integrative, multimodal approach to characterize CHL tumors using malignant cell sequencing, spatial transcriptomics and imaging mass cytometry. We identified four molecular subtypes (CST, CN913, STB, and CN2P) each characterized by distinct clinical features, mutational patterns, malignant cell gene expression profiles, and spatial architecture of immune cell populations. Functional modeling of CSF2RB mutations, a characteristic feature of CST, revealed dysregulated oncogenic signaling and changes in tumor microenvironment crosstalk. These findings highlight the significance of multi-dimensional profiling in elucidating patterns of molecular alterations that drive immune ecosystems and underlie therapeutically exploitable vulnerabilities.

  Study EGAS00001008064

• STimage: Robust and interpretable prediction of gene markers and cell types from spatial transcriptomics data

  Spatial transcriptomics (ST) links tissue morphology with gene expression values, opening new avenues for digital pathology. Deep learning models are used to predict gene expression or classify cell types directly from images, offering significant clinical potential but still requiring improvements in interpretability and robustness. We present STimage as a comprehensive suite of models to predict spatial gene expression and classify cell types directly from standard H\&E images. STimage enhances robustness by estimating gene expression distributions and quantifying both data-driven (aleatoric) and model-based (epistemic) uncertainty using ensemble approach with foundation models. Interpretability is achieved through attribution analysis at single-cell resolution integrated with histopathological annotations, functional genes, and latent representations. We validated STimage across diverse datasets, demonstrating its performance across various platforms. STimage-predicted gene expression can stratify patient survival and predict drug response. By enabling molecular and cellular prediction from routine histology, STimage offers a powerful tool to advance digital pathology.

  Study EGAS50000001503

• GEenetic landscape of hypodiploid acute lymphoblastic leukemia

  Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive leukemia characterized by aneuploidy and poor outcome. The genetic basis of hypodiploid ALL is unknown. Here, using complementary genome-wide profiling approaches, we show that hypodiploid ALL comprises two subtypes that differ in the severity of aneuploidy, transcriptional profile and submicroscopic genetic alterations. Near haploid cases with 24-31 chromosomes frequently harbor alterations targeting receptor tyrosine kinase- and Ras signaling (71%) and IKZF3 (AIOLOS; 13%). In contrast, low hypodiploid ALL cases with 32-39 chromosomes are characterized by TP53 alterations, almost half of which are present in non-tumor cells, and have alterations of IKZF2 (HELIOS; 53%) and RB1 (41%). Both near haploid and low hypodiploid tumors exhibit activation of Ras and PI3K signaling pathways, and are sensitive to PI3K inhibition, indicating that these drugs should be explored as a new therapeutic strategy for this frequently lethal form of leukemia.

  Study EGAS00001000380

• Serial assessment of measurable residual disease in medulloblastoma liquid biopsies

  Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial. Using low-coverage whole-genome sequencing, tumor-associated copy-number variations (CNVs) in CSF-derived cfDNA are investigated as an MRD surrogate. MRD is detected at baseline in 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients decline with therapy, yet those with persistent MRD have significantly higher risk of progression. Importantly, MRD detection precedes radiographic progression in half who relapse. Our findings advocate for the prospective assessment of CSF-derived liquid biopsies in future trials for medulloblastoma.

  Study EGAS00001005592

• Human induced pluripotent stem cells display a similar mutation burden as embryonic pluripotent cells in vivo

  Induced pluripotent stem cells (iPSCs) hold great promise for regenerative medicine, but genetic instability is a major concern. Embryonic pluripotent cells also accumulate mutations during early development, but how this relates to the mutation burden in iPSCs remains unknown. Here, we directly compared the mutation burden of cultured iPSCs with their isogenic embryonic cells during human embryogenesis. We generated developmental lineage trees of human fetuses by phylogenetic inference from somatic mutations in the genomes of multiple stem cells, which were derived from different germ layers. Using this approach, we characterized the mutations acquired pre-gastrulation and found a rate of 1.65 mutations per cell division. When cultured in hypoxic conditions, iPSCs generated from fetal stem cells of the assessed fetuses displayed a similar mutation rate and spectrum. Our results show that iPSCs maintain a genomic integrity during culture at a similar degree as their pluripotent counterparts do in vivo.

  Study EGAS00001005939

• Genomic analyses of gynecologic carcinosarcomas reveal frequent mutations in chromatin remodeling genes

  Malignant Mixed Müllerian Tumors, also known as carcinosarcomas, are rare tumors of gynecological origin. Here we perform whole exome analyses of 22 tumors using massively parallel sequencing to determine the mutational landscape of this tumor type. On average, we identify 43 mutations per tumor, excluding four cases with a mutator phenotype that harbored inactivating mutations in mismatch repair genes. In addition to mutations in TP53 and KRAS, we identify genetic alterations in chromatin remodeling genes, ARID1A and ARID1B, in histone methyltransferase MLL3, in histone deacetylase modifier SPOP, and in chromatin assembly factor BAZ1A, in nearly two thirds of cases. Alterations in genes with potential clinical utility are observed in more than three quarters of the cases and included members of the PI 3-kinase and homologous DNA repair pathways. These findings highlight the importance of the dysregulation of chromatin remodeling in carcinosarcoma tumorigenesis and suggest new avenues for personalized therapy.

  Study EGAS00001000941

• Immune-awakening revealed by peripheral T cell dynamics after one cycle of immunotherapy

  BACKGROUND: Our understanding of T cell evolution under checkpoint inhibitors (CPI) is still incomplete, restraining the achievement of full benefit from CPI.OBJECTIVES: We studied peripheral T cell turnover and evolution and their prognostic value after 3weeks on treatment with CPI (one cycle) analysing T cell receptor-β (TCR) sequences in plasma cell-free DNA (cfDNA) and PBMC, and performing a phenotypic analysis of peripheral T cell subsets.RESULTS: Peripheral T cell turnover and TCR repertoire dynamics correlated with response. Additionally, the cfDNA TCR repertoire reorganisation fingerprint correlated with the expansion of an immune-effector subset of peripheral T cells that predicted treatment response and identified the patients with longer overall survival.CONCLUSIONS: Here we show that prognostic changes in peripheral T cells occur within 3 weeks of commencing CPI treatment. This dynamic immune-awakening informs on the immune-system reorganization can be monitored using minimally invasive liquid biopsies.

  Study EGAS00001004043

• Transcriptome analysis in very preterm infants with chronic lung disease after birth

  Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and is characterized by impaired alveolar and vascular development. The aim of the study was to identify early BPD-relevant pathways by applying whole genome transcriptional profiling combined with protein measurements from umbilical arterial blood samples of preterm infants with and without BPD. Only newborn infants &lt;32 weeks gestational age (GA) were prospectively included in this study. Blood was obtained from an indwelling umbilical artery catheter at birth and after 72 hours after birth and subjected to gene expression analysis using the Codelink Human I 10k Bioarray and the the Codelink Human Whole Genome Bioarray. The study reveals a monocyte-centered immune response at birth characterizing preterm infants later developing BPD. The findings provide potential markers for early risk stratification in the preterm infant with respect to the development of chronic pulmonary disease and may subsequently enable the development of new treatment strategies in this high risk patient cohort.

  Study EGAS00001002586

• H014: HES5 mediates NOTCH signaling by interaction with AKT to drive liver carcinogenesis

  Notch signaling plays a pivotal role in liver development and aberrant Notch signaling may lead to hepatocellular (HCC) or cholangiocellular carcinoma (CCA) development. Using whole exome sequencing of 54 human HCC samples, we discovered 19 somatic missense mutations in 15 different Notch pathway genes affecting 24.6% (14 of 57) of patients. Prediction of functional impact of these Notch pathway mutations revealed HES5-R31G to have high relevance. We found HES5 to be strongly activated by Notch signaling. In vitro, HES5 reduced cell migration and clonogenicity and in vivo, HES5 inhibited MYC-dependent liver tumor formation. But together with AKT, HES5 increased liver tumor formation in a mouse model. HES5 directly binds to AKT and AKT expression leads to increase HES5 protein levels. Furthermore, HES5 exhibits a negative feed-back loop by inhibiting NOTCH1 and HES1 gene expression. In contrast, HES5-R31G appears to be non-functional possibly by loss of nuclear translocation

  Study EGAS00001003329

• The spatial organization of intratumor heterogeneity andevolutionary trajectories of metastases in hepatocellular carcinoma

  Hepatocellular carcinoma (HCC) has one of the poorest survival amongst cancers. Using multi-regional sampling of nine resected HCC with different etiologies, we find that phylogenetic relationships of these sectors show diverse levels of genetic sharing spanning early to late diversification. Unlike the variegated pattern found in colorectal cancers, a large proportion of HCC display a clear Isolation-By-Distance pattern where spatially closer sectors are genetically more similar. Two resected intra-hepatic metastases showed genetic divergence occurring before and after primary tumor diversification respectively. Interestingly, metastatic tumors had much higher variability than their primary tumors, suggesting that intra-hepatic metastasis is accompanied by rapid diversification at the distant location. The presence of co-existing mutations offers the possibility of drug repositioning for HCC treatment. Taken together, these insights into intra-tumor heterogeneity allow for a comprehensive understanding of the evolutionary trajectories of HCC and suggest novel avenues for personalized therapy.

  Study EGAS00001001603

• Exome_sequencing_of_blastic_plasmacytoid_dendritic_cell_neoplasms

  Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive haematological malignancy derived from precursors of plasmacytoid dendritic cells. Due to the rarity of BPDCNs our knowledge of their molecular pathogenesis was until recently confined to observations describing reccurent chromosomal deletions involving chromosomes 5q, 12p, 13q, 6q, 15q and 9. A recent publication went on to delineate the common deleted regions using aCGH and demonstrated that these centred around known tumour suppressor genes including CDKN2A/B (9p21.3), RB1 (12p13.2-14.3), CDKN1B (13q11-q12) and IKZF1 (7p12.2).These mutations are found recurrently in several different cancers and in most cases are thought to be involved in tumour progression rather than initiation. However, the well-defined nature and cellular ontogeny of these neoplasms suggests strongly that they share one or a few characteristic mutations as has been demonstrated for other uncommon but well-defined neoplasms such as Hairy Cell Leukemia (BRAF) and ovarian Granulosa Cell tumours (FOXL2).

  Study EGAS00001000171

• Integrated genetic and epigenetic analysis defines novel molecular clusters in rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. To unravel the genetic/epigenetic basis of RMS, we studied 60 RMS cases using whole exome/transcriptome sequencing, copy number (CN) profiling, and DNA methylome analysis. Based on DNA methylation patterns, RMS was clustered into 4 distinct subtypes, which exhibited remarkable correlation with mutation/CN profiles, histological phenotypes, and clinical behaviors. A1 and A2 subtypes, especially A1, largely corresponded to alveolar histology with frequent PAX3/7 fusions and alterations in cell cycle regulators. In contrast, mostly showing embryonal histology, both E1 and E2 subtypes were characterized by high frequency of CN alterations and/or allelic imbalances, FGFR4/RAS/AKT pathway mutations and PTEN mutations/methylation and in E2, also by p53 inactivation. Despite generally poor prognosis in RMS, patients in E1 cluster exceptionally showed excellent prognosis. Our results highlight the close relationship between DNA methylation status and gene mutations and biological behavior in RMS.

  Study EGAS00001000884

• CTCF-dependent enhancer hijacking by the EVI1 oncogene in leukemia

  Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements which are often therapy resistant. In a cohort of primary t(3;8)(q26;q24) AML samples we observed the translocation of a MYC super-enhancer to EVI1. We generated a patient-based t(3;8)(q26;q24) model in vitro using CRISPR-Cas9 technology and demonstrated hyper-activation of EVI1 by the hijacked MYC super-enhancer. One MYC super-enhancer element in particular, which recruits early hematopoietic regulators, is critical for EVI1 expression and enhancer-promoter interaction. This interaction is facilitated by a CTCF-bound motif upstream of the EVI1 promoter that acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of 3q26-rearranged AML samples point to a common mechanism by which EVI1 uses this CTCF-bound enhancer-docking site to hijack early hematopoietic enhancers.

  Study EGAS00001004808

• A Universal Gut Metagenomic-Derived Signature Predicts Cirrhosis

  Dysregulation of the gut microbiome has been implicated in the progression of nonalcoholic fatty liver disease (NAFLD) to advanced fibrosis and cirrhosis. To determine the diagnostic capacity of this association, stool microbiomes were compared across 163 well-characterized participants encompassing non-NAFLD controls, NAFLD-cirrhosis patients and their first-degree relatives. Interrogation of shotgun metagenomic and untargeted metabolomic profiles using the Random Forest machine learning algorithm and differential abundance analysis identified discrete metagenomic and metabolomic signatures that were similarly effective in detecting cirrhosis (diagnostic accuracy 0.91, AUC). Combining the metagenomic signature with age and serum albumin levels accurately distinguished cirrhosis in etiologically and genetically distinct cohorts from geographically separated regions. Additional inclusion of serum aspartate aminotransferase levels, which are increased in cirrhosis patients, enabled discrimination of cirrhosis from earlier stages of fibrosis. These findings demonstrate that a core set of gut microbiome species may offer universal utility as a non-invasive diagnostic test for cirrhosis.

  Study EGAS00001004600

• Physiological and genetic adaptations to diving in Sea Nomads

  Understanding the physiology and genetics of human hypoxia tolerance has important medical implications, but this phenomenon has thus far only been investigated in high-altitude human populations. Another system, yet to be explored, is humans who engage in breath-hold diving. The indigenous Bajau people (“Sea Nomads”) of Southeast Asia live a subsistence lifestyle based on breath-hold diving and are renowned for their extraordinary breath holding abilities. However, it is unknown whether this has a genetic basis. Using a comparative genomic study, we show that natural selection on genetic variants in the PDE10A gene have increased spleen size in the Bajau, providing them with a larger reservoir of oxygenated red blood cells. We also find evidence of strong natural selection specific to the Bajau on BDKRB2, a gene affecting the human diving reflex. Thus, the Bajau, and possibly other natural diving populations, provide a new opportunity to study human adaptation to hypoxia tolerance.

  Study EGAS00001002823

• Single-cell landscapes of primary glioblastomas and matched organoids and cell lines reveal variable retention of inter- and intra-tumor heterogeneity

  Glioblastomas (GBMs) are aggressive primary malignant brain tumors characterized by extensive levels of inter- and intra-tumor genetic and phenotypic heterogeneity. Patient-derived organoids (PDOs) have recently emerged as useful models to study such heterogeneity. Here, we present bulk exome as well as single-cell genome and transcriptome profiles of primary IDH wild type GBMs from ten patients, including two recurrent tumors, as well as PDOs and brain tumor-initiating cell (BTIC) lines derived from these patients. We find that PDOs are genetically similar to and variably retain gene expression characteristics of their parent tumors. At the phenotypic level, PDOs appear to exhibit similar levels of transcriptional heterogeneity as their parent tumors, whereas BTIC lines tend to be enriched for cells in a more uniform transcriptional state. The datasets introduced here will provide a valuable resource to help guide experiments using GBM-derived organoids, especially in the context of studying cellular heterogeneity.

  Study EGAS00001005227

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

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

  Study EGAS00001003255

• Single_cell_analysis_of_cytokine_induced_T_cell_states

  We isolated T cells from healthy platelet donors and cultured them in resting and stimulated conditions with addition of a range of cytokines. We performed scRNA sequencing to assess the variability of polarization in different cytokines treated cells. Cytokines affect T cell responses by polarising them to different phenotypes. Given that the inflammation and and autoimmune tissue distruction is driven by the local production of cytokines, we investigated cytokine induced changes in T cells by using a combination of immunological and genomics approaches. To characterize, the efficacy of cytokine induced porization, here we stimulated naive and memory CD4+ T cells in the presence of cytokine polarizing coctails and profiled single cell transcriptome five days following polarization. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003215

• Tocilizumab treatment leads to early resolution of myeloid dysfunction and lymphopenia in patients hospitalized with COVID-19

  Tocilizumab, an anti-interleukin-6 receptor inhibitor, is recommended in global treatment guidelines for patients hospitalized with severe COVID-19. Using proteomic and transcriptomic analysis, we characterized the immune profile and identified cellular and molecular pathways directly modified by tocilizumab in peripheral blood samples collected from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial, to assess the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19 pneumonia. We identified factors predicting disease severity and clinical outcomes, including markers of inflammation, lymphopenia, myeloid dysfunction, and organ injury. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysfunction associated with severe COVID-19 thus supporting an underlying anti-inflammatory mechanism of action for the beneficial effects of tocilizumab in patients hospitalized with COVID-19.

  Study EGAS00001006688

• GRIDSS, PURPLE, LINX: Unscrambling the tumor genome via integrated analysis of structural variation and copy number

  We have developed a novel, integrated and comprehensive purity, ploidy, structural variant and copy number somatic analysis toolkit for whole genome sequencing data of paired tumor/normal samples. We show that the combination of using GRIDSS for somatic structural variant calling and PURPLE for somatic copy number alteration calling allows highly sensitive, precise and consistent copy number and structural variant determination, as well as providing novel insights for short structural variants and regions of complex local topology. LINX, an interpretation tool, leverages the integrated structural variant and copy number calling to cluster individual structural variants into higher order events and chains them together to predict local derivative chromosome structure. LINX classifies and extensively annotates genomic rearrangements including simple and reciprocal breaks, LINE, viral and pseudogene insertions, and complex events such as chromothripsis. LINX also comprehensively calls genic fusions including chained fusions. Finally, our toolkit provides novel visualisation methods providing insight into complex genomic rearrangements.

  Study EGAS00001004034

• Single-cell atlas of multiple myeloma and precursor diseases

  Single cell profiling of small cohorts of myeloma precursor disease patient samples including monoclonal gammopathy of unknown significance and smoldering multiple myeloma have shown diverse evolutionary patterns and immune changes that occur early in the disease process. Using scRNAseq and scBCRseq in a large cohort of fifty-three patients with myeloma precursor disease in comparison with myeloma and normal donors we describe the early genomic drivers of malignant transformation and describe their divergent clonal expansion in hyperdiploid compared to non-hyperdiploid samples. We describe intra-patient heterogeneity with potential therapeutic implications as well as the distinct evolution patterns (linear/branching) from myeloma precursor disease to myeloma. Finally, we describe the unique adaptations of the microenvironment as a response to distinct genomic changes in myeloma cells. These results further our knowledge to characterize myeloma precursor disease evolution, inform individual patient progression risk stratification and identify potential biomarkers that could be clinically exploited.

  Study EGAS00001006694

• An isogenic human iPSC model unravels neurodevelopmental abnormalities in SMA

  Whether neurodevelopmental defects underlie the selective neuronal death that characterizes neurodegenerative diseases is becoming an intriguing question. To address it, we focused on the motor neuron (MN) disease Spinal Muscular Atrophy (SMA), caused by reduced levels of the ubiquitous protein SMN. Taking advantage of the first isogenic human induced pluripotent stem cell-derived SMA model that we have generated and a spinal cord organoid system, here we report that the relative and temporal expression of early neural progenitor and MN markers is altered in SMA. Furthermore, the corrected isogenic controls only partially reverse these abnormalities. These findings raise the relevant clinical implication that SMN-increasing treatments might not fully amend SMA pathological phenotypes. The approach we have taken demonstrates that the discovery of new disease mechanisms is greatly improved by using human isogenic models. Moreover, our study implies that SMA has a developmental component that might trigger the MN degeneration.

  Study EGAS00001007259

• Serial TERT rearrangement breakpoint quantification in circulating tumor DNA enables minimal residual disease monitoring in patients with neuroblastoma

  Approximately 30% of high-risk neuroblastomas harbor genomic TERT rearrangements at diagnosis, resulting in high TERT transcript levels and active telomerase. Combined with mutations in the RAS/MAPK/ALK signaling transduction network, these patients have a dismal prognosis. Our objective was to establish a liquid biopsy-based monitoring strategy for this particularly vulnerable patient subgroup, for whom no in-time molecular diagnostic tools exist to date. Detection and quantification of TERT rearrangement breakpoints in cell-free tumor DNA circulating in peripheral blood and bone marrow plasma from patients with TERT-driven neuroblastoma improved minimal residual disease monitoring and early relapse detection in individual patients. TERT rearrangement breakpoints, as a single marker or combined with mutations in the RAS/MAPK/ALK signaling transduction network, can be reliably analyzed from 1ng DNA using droplet digital PCR assays fit for clinical routine use. TERT rearrangement breakpoints are reflected in cell-free tumor DNA and can serve as robust biomarkers for disease activity.

  Study EGAS00001007365

• Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting behavior

  Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), including the immune infiltrate. Here, we characterize the TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic and proteomic, including spatial single-cell approaches. Resolution of immune lineages indicates uniform high-infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoints, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M models tested. We show these myeloid populations communicate with H3-mutant cells mediating immunosuppression and sustaining tumor formation and maintenance. Dual inhibition of myeloid cells and immune checkpoints showed significant therapeutic benefit in pre-clinical syngeneic models. Our findings provide valuable characterization of the TME of oncohistone-mutant gliomas, and insights into means to modulate the myeloid infiltrate for the benefit of patients.

  Study EGAS00001007510

• ARHGAP11A Maintains Cortical Progenitor Identity Through RHOA–ROCK Signalling During Human Brain Development

  Mammalian brain development involves coordinated progenitor amplification, migration, and differentiation. Apical progenitors (APs) establish the ventricular zone (VZ) and are key determinants of brain size and complexity. Rho-family guanosine triphosphatases (Rho GTPases) regulate cytoskeletal dynamics and AP behaviour, but how specific Rho GTPase-activating proteins (Rho GAPs) influence progenitor identity and VZ architecture remains unclear. Using human forebrain organoids, we investigated the Rho GAP ARHGAP11A in human corticogenesis. CRISPR/Cas9-mediated ARHGAP11A knockout revealed its essential role in maintaining VZ integrity. Loss of ARHGAP11A impaired neuroepithelial organisation and randomised mitotic cleavage plane orientation via the RHOA–ROCK–actin axis. This led to premature AP delamination, AP depletion, and reduced cell density and glial numbers. Pharmacological inhibition of RHOA or ROCK rescued these defects, highlighting ARHGAP11A’s role in cytoskeletal remodelling to maintain cortical progenitors. Our findings establish ARHGAP11A as a critical regulator of AP identity and VZ integrity, with broad implications for human corticogenesis.

  Study EGAS00001008322

• The Genomics and Randomized Trials Network (GARNET) Vitamin Intervention Stroke Prevention (VISP) Trial

  The VISP trial (PI Jim Toole, M.D., Wake Forest University School of Medicine) was a multi-center, double-blind, randomized, controlled clinical trial that enrolled patients aged 35 or older with homocysteine (Hcy) levels above the 25th percentile at screening and a non-disabling cerebral infarction (NDCI) within 120 days of randomization (Toole, 2002, PMID: 12417369). The trial was designed to determine if daily intake of a multivitamin tablet with high dose folic acid, vitamin B6 and vitamin B12 reduced recurrent cerebral infarction (primary endpoint), and nonfatal myocardial infarction (MI) or mortality (secondary endpoints). Subjects were randomly assigned to receive daily doses of the high-dose formulation (n=1,827), containing 25mg pyridoxine (B6), 0.4mg cobalamin (B12), and 2.5mg folic acid; or the low-dose formulation (n=1,853), containing 200mcg pyridoxine, 6mcg cobalamin and 20mcg folic acid. Enrollment in VISP began in August 1997, and was completed in December 2001, with 3,680 participants enrolled. Within the trial, 2,164 participants from 46 clinic sites provided DNA and agreed for it to be shared for use in a genetic subset study of VISP. This study is part of Genomics and Randomized Trials Network (GARNET), funded by the National Human Genome Research Institute (NHGRI). The overarching goal is to identify novel genetic factors that contribute to stroke through large-scale genome-wide association studies of treatment response in randomized clinical trials. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were performed at the GARNET Coordinating Center at the University of Washington. The data of the VISP trial have been released to dbGaP users in several segments: Version 1 (phs000343.v1.p1), consisted of n=4 phenotype datasets, and all raw, cleaned and imputed genotype data. Version 2 (phs000343.v2.p1) included n=14 additional phenotype datasets (plus pedigree, consent, and sample-mapping data), and increased the available data to a total of n=970 phenotype variables. Version 3 (phs000343.v3.p1) included all n=36 phenotype datasets (plus pedigree, consent, and sample-mapping data), and increased the available data to a total of n=1918 phenotype variables.Version 4 (phs000343.v4.p1), the current release, includes all previous phenotypic datasets, includes one new phenotypic dataset for the untargeted metabolomics data of 50 individuals, includes DNA methylation profiles for n=180 individuals, and sequencing data for n=179 individuals.

  Study phs000343

• NHLBI TOPMed: The Cleveland Family Study (CFS)

  The Cleveland Family Study (CFS) is one cohort involved in the WGS project. The CFS was designed to provide fundamental epidemiological data on genetic and non-genetic risk factors for sleep disordered breathing (SDB). In brief, the CFS is a family-based study that enrolled a total of 2284 individuals from 361 families between 1990 and 2006. The sample was selected by identifying affected probands who had laboratory diagnosed obstructive sleep apnea. All first degree relatives, spouses and available second degree relatives of affected probands were studied. In addition, during the first 5 study years, neighborhood control families were identified through a neighborhood proband, and his/her spouses and first degree relatives. Each exam, occurring at approximately 4 year intervals, included new enrollment as well as follow up exams for previously enrolled subjects. For the first three visits, data, including an overnight sleep study, were collected in the participants' homes while the last visit occurred in a general clinical research center (GCRC). Phenotypic characterization of the entire cohort included overnight sleep apnea studies, blood pressure, spirometry, anthropometry and questionnaires. The GCRC exam (n=735 selected individuals) included more comprehensive phenotype data on a focused subsample of the larger cohort, to permit linking SDB phenotypes with cardio-metabolic phenotypes, with an interest in identifying genetic loci that are associated with these related phenotypes. In this last round of data collection, a subset of 735 individuals was selected based on expected genetic informativity by choosing pedigrees where siblings had extremes of the apnea hypopnea index (AHI). Participants underwent detailed phenotyping including laboratory polysomnography (PSG), ECG, spirometry, nasal and oral acoustic reflectometry, vigilance testing, and blood and urine collection before and after sleep and after an oral glucose tolerance test. A wide range of biochemical measures of inflammation and metabolism were assayed by a Core Laboratory at the University of Vermont. 994 individuals were sequenced as part of TOPMed Phase 1, including 507 African-Americans and 487 European-Americans. Among the sequenced individuals, 156 were probands with diagnosed sleep apnea, an additional 706 were members of families with probands, and 132 were from neighborhood control families. 298 individuals were sequenced as part of TOPMed Phase 3.5, including 169 African-Americans and 129 European-Americans. Among the newly sequenced individuals, 33 were probands with diagnosed sleep apnea, an additional 214 were members of families with probands, and 51 were from neighborhood control families. Please note: Phenotype and pedigree data are available through "NHLBI Cleveland Family Study (CFS) Candidate Gene Association Resource (CARe)", phs000284.

  Study phs000954