16767 results for "sec+and+unspecified+malignant+neoplasm"

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• Analysis of the B cell receptor repertoire in six immune-mediated diseases

  Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn’s disease, Behçet’s disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and—in particular—isotype use. An increase in clonality in systemic lupus erythematosus and Crohn’s disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune- mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.

  Dataset EGAD00001005431

• COVID-19 severity correlates with airway epithelium–immune cell interactions identified by single-cell analysis

  To investigate the immune response and mechanisms associated with severe COVID-19, we performed single-cell RNA-seq on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from 5 healthy controls. We identified airway epithelial cell types and states vulnerable to SARS-CoV-2 infection. In COVID-19 patients, epithelial cells showed an average threefold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells. Compared with moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand–receptor expression profiles, and activated immune cells , including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF . The transcriptional differences in critical cases compared with moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure. Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways may suppress immune hyperactivation in critical COVID-19.

  Dataset EGAD00001006339

• The mutational landscape of human somatic and germline cells

  During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

  Dataset EGAD00001006642

• The mutational landscape of human somatic and germline cells

  During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but their absolute and relative contributions varied substantially. SBS18, potentially reflecting oxidative damage, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The mutation rate was lowest in spermatogonia, the stem cell from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutation processes and may be partially attributable to a low cell division rate of basal spermatogonia. The results provide important insights into how mutational processes affect the soma and germline.

  Dataset EGAD00001006643

• Hypertension delays viral clearance and exacerbates airway hyperinflammation in patients with COVID-19

  In Coronavirus Disease 2019 (COVID-19), hypertension and cardiovascular diseases are major risk factors for critical disease progression. However, the underlying reasons and the effect of the main anti-hypertensive therapies—angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)—remain unclear. Combining clinical data (n = 144) and single-cell sequencing data of airway samples (n = 48) with in vitro experiments, we observed a distinct inflammatory predisposition of immune cells in patients with hypertension that correlated with critical disease progression. ACEI treatment associated with dampened COVID-19-related hyperinflammation and with increased cell intrinsic anti-viral responses, whereas ARB treatment related to enhanced epithelial–immune cell interactions. Macrophages and neutrophils of patients with hypertension, in particular under ARB treatment, exhibited higher expression of the pro-inflammatory cytokines CCL3 and CCL4 and the chemokine receptor CCR1. Although the limited size of our cohort does not allow us to establish clinical efficacy, our data suggest that the clinical benefits of ACEI treatment in patients with COVID-19 who have hypertension warrant further investigation.

  Dataset EGAD00001006828

• Minority Health Genomics and Translational Research Bio-Repository Database

  The Minority Health Genomics and Translational Research Bio-repository Database (MHGRID) Network infrastructure facilitated the collection of biospecimens and related multidimensional data elements within a consortium of minority-serving clinics. This initiative expands the diversity of ancestral groups in national genomic medicine datasets and promises to accelerate the translation of personalized medicine into minority communities. MHGRID has an observational case-control design with severe hypertension as primary outcome.

  Study phs001815

• Maintenance of Genome Sequence Integrity in Long- and Short-lived Rodent Species

  In this study, we compared somatic mutation frequencies and spectra of bleomycin-treated and control fibroblasts of 5 species, i.e., mouse, guinea pig, blind mole-rat, naked mole-rat and humans, by using single-cell whole-genome sequencing. Sequencing data of the human cells are deposited here in the dbGaP. Sequencing data of the rodent cells are in the SRA database, under accession ID: PRJNA753541.

  Study phs002610

• Advanced Genetic and Molecular Analysis of Solid Tumors

  This study is designed to understand the role of immunosuppressive regulatory B cells (Breg) in pancreatic cancer. Breg and conventional B cells (Bcon) from patients are compared by RNA sequencing analysis. Bregs and Bcon were isolated from freshly isolated PBMCs in peripheral blood. These data represent the examination of differentially expressed genes in these two blood-derived B cell subsets from both healthy and pancreatic cancer patients.

  Study phs001999

• Cellular Origins and Genetic Landscape of Cutaneous GD T Cell Lymphoma

  Cutaneous gamma-delta T cell lymphomas are a rare and aggressive subtype of cutaneous lymphoma. In the present study, we analyzed these cancers by DNA and RNA sequencing in order to illuminate the genetic landscape for this rare disease. We obtained tumor samples from multiple institutions, including Northwestern University (Chicago, IL), University of Chicago (Chicago, IL), University of Virginia (Charlottesville, VA), and Massachusetts General Hospital (Boston, MA).

  Study phs001969

• Integrated Genetic and Pharmacologic Interrogation of Rare Cancers

  Due to the paucity of patient derived models in rare cancers, identification of therapeutic targets remains challenging. We developed a patient derived model, CLF-PED-015-T, from a patient with an undifferentiated sarcoma. From this model, we performed pooled RNAi and CRISPR-Cas9 negative selection screens and integrated that with a small molecule screen. Integration of these data identified CDK4 and XPO1 as potential therapeutic targets.

  Study phs001121

• Project for Development of Innovative Research on Cancer Therapeutics;Shuttle system between petient-derived xenograft and ex vivo culture for innovative platform of evaluating drug sensitivity.

  We developed CTOS (cancer tissue-originated spheroid) panel covering diversity among patients for colorectal cancer, lung cancer and cervical small cell carcinoma. We then carried out exome sequence analysis of tumor tissues, cell lines and CTOS derived from patients to validate qualitative changes in preparation, culture, cell line, transplantation and passage of CTOS pathologically, biochemically, molecular biologically.

  Study JGAS000089

• Identification Of Pathogenic Mutations And Application Of Polygenic Risk Scores In Early-Onset Diabetes Patients

  Maturity-onset Diabetes of the Young (MODY) presents a diagnostic challenge. In this study we investigate the genetic background of Latvian early-onset diabetes patients, using whole-genome sequencing data. Additionally, we investigate the utility of previously published and available type 1 diabetes (T1D) and type 2 diabetes (T2D) polygenic risk scores in differentiating monogenic diabetes (MODY) from T1D and T2D cases.

  Study EGAS50000000991

• RNASeq from PPGL-derived PC12 cell lines cultivated in normoxia and hypoxia conditions.

  PC12 cells derived from rat PPGL were then either continued cultivated in the same normoxia condition (37˚C, 5% CO2 and 21% O2 balanced with N2) or were placed in a hypoxic incubator, that maintained a constant hypoxic environment (37˚C, 5% CO2 and 1% O2 balanced with N2), for different short (12h, 24h, and 48h) or prolonged time (36 days, approximately 860h).

  Study EGAS50000000814

• Molecular underpinnings of dedifferentiation and aggressiveness in chromophobe renal cell carcinoma

  This study expands our understanding of aggressive chromophobe renal cell carcinoma (ChRCC), provides insight into molecular mechanisms of tumor progression, and informs pathologic classification and diagnostics. Tumor and adjacent normal samples were collected from 11 patients treated in affiliated hospitals of the University of Texas Southwestern Medical Center (UTSW), including Parkland Hospital. Seven of the eleven patients consented to depositing their genomic data to public repository.

  Study EGAS50000000287

• Comprehensive molecular portrait reveals genetic diversity and distinct molecular subtypes of small intestinal neuroendocrine tumors

  This study aims to characterize neuroendocrine tumors of the small intestine (siNETs) from genomic, transcriptomic, epigenomic, and clinical perspectives. Involving 122 patients and 219 samples, we generated whole-genome sequencing data, RNA sequencing data, genotyping arrays, and methylation arrays to conduct an integrative analysis of this rare tumor type. Our findings identify distinct molecular subtypes that correlate with siNET clinical features.

  Study EGAS50000000642

• Bulk RNAseq FASTQ files of WNT7B reporter PDAC organoids (P28 and P40) sorted by mNeonGreen high and low

  This dataset contains raw FASTQ files from bulk RNA sequencing of two patient-derived PDAC organoid lines (P28 and P40) carrying a WNT7B reporter knock-in. Organoids were sorted into mNeonGreen high (WNT-high) and low (WNT-low) populations, with three biological replicates per sorted population. RNA was extracted using the Qiagen QiaSymphony SP system, and libraries were prepared with the Illumina Truseq stranded polyA kit. Sequencing was performed on an Illumina NextSeq2000 platform using single-end 50bp reads. Quality control was conducted with FastQC, and reads were trimmed with TrimGalore as appropriate. Data are controlled-access and intended for transcriptomic analysis of WNT7B expression-dependent transcriptional programs in PDAC organoids.

  Dataset EGAD50000002218

• WES analysis of tumor samples from ER+ breast cancer patients treated with CDK4/6 inhibitor

  We performed whole exome sequencing of paired fresh frozen tumor from 4 ER+ advanced breast cancer patients. Samples were obtained for each patient prior to combined CDK4/6 inhibitor and endocrine therapy and at disease progression (N=8). DNA was extracted using the Maxwell® RSC FFPE and Tissue DNA Kit (Promega). WES was performed at the Department of Molecular Medicine, Aarhus University Hospital on matched tumor DNA (derived from primary fresh frozen and FFPE tissue) and buffy coat DNA. Libraries of tumors and matching germline DNA were prepared using 50 ng DNA and captured by Twist Comprehensive Exome with custom spike-ins, sequenced on the Illumina NovaSeq 6000 platform to an average coverage of 413x (range: 148-515x). The dataset include the analysis data files (vcf files).

  Dataset EGAD50000000622

• Transcriptomic subgroups in soft tissue tumors correlate with morphologic subtype, genomic features, and outcome

  We assessed gene expression (GGE) profiles and gene fusions as detected by transcriptome sequencing (RNA-seq) of 704 soft tissue tumors (STT) representing 56 different tumor types. Comparison with follow-up data identified transcriptional subclusters among sarcomas with complex genomes and among adipocytic tumors that correlated with metastasis-free survival and local recurrences, respectively. Thus, RNA-seq analysis of STT provides clinically important information.

  Study EGAS50000001472

• Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

  Gray Platelet Syndrome (GPS) is a rare recessive bleeding disorder resulting from biallelic variants in NBEAL2. As part of a comprehensive evaluation of the phenotype and genotype in 47 patients with GPS, four different blood cell-types (platelets, neutrophils, monocytes, and CD4-lymphocytes) were evaluated using bulk RNA-seq in five patients and five controls. These data are deposited in this archive in FASTQ format.

  Study EGAS00001004216

• HipSci HumanExome BeadChip analysis - Usher syndrome and congenital eye defects

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Genotyping analysis using the Infinium HumanExome BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Usher syndrome and congenital eye defects.

  Study EGAS00001002008

• HipSci HumanExome BeadChip analysis - Bleeding and Platelet disorders

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Genotyping analysis using the Infinium HumanExome BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Bleeding and Platelet disorders.

  Study EGAS00001002013

• HipSci___Whole_Exome_sequencing___Usher syndrome and congenital eye defects

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we perform whole exome sequencing using Agilent whole exome pulldown method on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Usher syndrome and congenital eye defects.

  Study EGAS00001001985

• RNA sequencing data from visceral and abdominal subcutaneous adipose tissue from morbidly obese women with normal glucose tolerance or type 2 diabetes

  The study group consisted of 17 obese women with normal glucose tolerance and 15 obese women with T2DM. Adipose tissue specimens were taken from the epigastric region of the abdominal wall (SAT) and from the major omentum (VAT). RNA was isolated and RNA sequencing was used to analyse the transcriptome. Dharuri H et al, Diabetologia. 2014;57(11):2384-92.

  Study EGAS00001001872

• HipSci HumanHT 12 Expression BeadChip analysis - Bleeding and Platelet disorders

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we performed Expression analysis using the Illumina HumanHT -12 Expression BeadChip on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with Bleeding and Platelet disorders.

  Study EGAS00001002028

• Whole-genome sequencing identifies ADGRG6 enhancer mutations and FRS2 duplications as angiogenesis-related drivers in bladder cancer

  Bladder cancer is one of the most common and highly vascularized cancers. To better understand its genomic structure and underlying etiology, we conducted whole-genome sequencing in 65 urothelial bladder carcinomas (the most common type of bladder cancer) and identified recurrent genetic alterations in a set of angiogenesis genes, facilitating the understanding of molecular mechanisms underlying pathological angiogenesis in this type of cancer.

  Study EGAS00001003388

• Gene regulation of human stimulated and cultured CD4+ Treg cells

  This dataset maps gene expression regulation in human primary regulatory CD4+ T cells (Tregs) stimulated using PMA and ionomycin or cultured without stimulus for 18 hours. It includes whole genome sequence data for ChM-seq (18 H3K4me3, 20 H3K27ac and 3 inputs), ATAC-seq (42 samples) and whole transcriptome (39 samples). All individuals were genotyped using coreExome Illumina SNP chip array (included in EGAS00001003516).

  Study EGAS00001003515

• Single-cell Transcriptomic and TCR Repertoire Profiling of DENV-specific CD8+ T Cells Across Dengue Disease Severities

  This dataset contains single-cell RNA sequencing (Smart-seq2) and paired TCR repertoire data of sorted dengue virus (DENV)-specific CD8⁺ T cells from individuals with differing clinical outcomes: asymptomatic dengue (AD), dengue fever (DF), and dengue hemorrhagic fever (DHF). Samples were obtained from HLA-A11⁺ and HLA-A24⁺ individuals during acute and convalescent phases, with antigen-specific CD8⁺ T cells isolated using HLA tetramers loaded with immunodominant DENV epitopes. The study identifies phenotypically distinct T cell subsets associated with disease severity, TCR avidity, and antigen reactivity to current or prior DENV serotypes. The dataset supports the understanding of CD8⁺ T cell heterogeneity, TCR features, and potential mechanisms of CD8⁺ T cell-mediated protection versus immunopathogenesis in dengue infection.

  Dataset EGAD00001015637

• Shallow whole genome sequencing and targeted capture sequencing data of PCNSL and PTL primary and relapse pairs

  Shallow whole genome sequencing for copy number analysis and targeted capture sequencing data for translocation and mutation anslysis of paired primary and relapse PCNSL and PTL samples

  Dataset EGAD00001008387

• eIMPACT Trial: Modernized Collaborative Care to Reduce the Excess CVD Risk of Older Depressed Patients

  Cardiovascular disease (CVD) is the #1 killer of American men and women, and its economic burden is substantial and on the rise. Adults with depression are at elevated risk of CVD events and poor CVD prognosis. Unfortunately, past clinical trials of depression treatments have not observed the anticipated cardiovascular benefits. A novel explanation for these null results is that the depression interventions in these trials, which all involved patients with preexisting CVD, were delivered too late in the natural history of CVD. Accordingly, the objective of this single-center, parallel-group, assessor-blinded randomized controlled trial was to determine whether successful depression treatment before, versus after, the onset of clinical CVD reduces CVD risk in depression. Primary care patients with depression and elevated CVD risk from a safety net healthcare system (N = 216, Mage = 59 years, 78% female, 50% Black, 46% with income <$10,000/year) were randomized 1:1 to 12 months of the eIMPACT intervention (a modernized collaborative stepped care program involving internet cognitive-behavioral therapy [CBT], telephonic CBT, and/or select antidepressants) or usual primary care for depression (primary care providers supported by embedded behavioral health clinicians and psychiatrists). The primary outcome was endothelial dysfunction (brachial flow-mediated dilation) at 12 months, and the secondary outcomes were self-reported depressive symptoms (Hopkins Symptom Checklist-20), autonomic dysfunction (high-frequency heart rate variability), systemic inflammation (interleukin-6 and high-sensitivity C-reactive protein), and platelet activation (β-thromboglobulin and platelet factor 4) at 12 months. The central hypothesis was that the eIMPACT intervention would improve endothelial dysfunction in depressed adults by decreasing depressive symptoms, autonomic dysfunction, systemic inflammation, and platelet activation. Primary results are posted to ClinicalTrials.gov at NCT02458690. The de-identified limited dataset available on BDC consists of only the individual phenotypic data needed to confirm this trial’s primary results – i.e., randomization status, primary and secondary outcome variables, and participant characteristics utilized in the hypothesis-testing models (age, sex, race, education, income, and systolic blood pressure). We also provide the SAS code to replicate the results of the hypothesis-testing models reported in Table 4 and Supplemental Tables 1-3 in the main outcomes paper (#2 in Selected Publications). Of note, the user will need to specify the file path for the dataset to run the SAS code. Instructions for requesting individual-level data are available on BDC at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BDC. For questions about availability, you may contact the BDC team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs003283

• Charles R. Bronfman Institute for Personalized Medicine (IPM) BioBank Genome Wide Association Study of Cardiovascular, Renal and Metabolic Phenotypes

  The Institute for Personalized Medicine (IPM) Biobank Project is a consented, EMR-linked medical care setting biorepository of the Mount Sinai Medical Center (MSMC) drawing from a population of over 70,000 inpatients and 800,000 outpatient visits annually. MSMC serves diverse local communities of upper Manhattan, including Central Harlem (86% African American), East Harlem (88% Hispanic Latino), and Upper East Side (88% Caucasian/white) with broad health disparities. IPM Biobank populations include 28% African American (AA), 38% Hispanic Latino (HL) predominantly of Caribbean origin, 23% Caucasian/White (CW). IPM Biobank disease burden is reflective of health disparities with broad public health impact: average body mass index of 28.9 and frequencies of hypertension (55%), hypercholesterolemia (32%), diabetes (30%), coronary artery disease (25%), chronic kidney disease (23%), among others. Biobank operations are fully integrated in clinical care processes, including direct recruitment from clinical sites, waiting areas and phlebotomy stations by dedicated Biobank recruiters independent of clinical care providers, prior to or following a clinician standard of care visit. Recruitment currently occurs at a broad spectrum of over 30 clinical care sites. Minorities are strikingly underrepresented in GWAS, including Coronary Artery Disease (CAD) and Chronic Kidney Disease; multigenic genetic risk scores for CAD have been recently validated in European ancestry populations, but not in AA or HL populations. Several important opportunities exist for extending additional GWAS to minority populations with a shared risk spectrum of CAD and CKD. For example, progressive CKD is a major and independent risk factor for CVD with an inverse relationship between estimated GFR (eGFR), and risk for mortality and cardiovascular events. This increased risk is only partially explained by the prevalence of cardiovascular risk factors among these patients. We conducted a GWAS of CAD and CKD related phenotypes in IPM Biobank with the primary objective to explore the genetics of overlapping CAD and CKD predominantly in minority populations characterized by increased risk.

  Study phs000388

• Mechanism and Response of Thymoglobulin in Patients with Myelodysplastic Syndrome (MDS)

  In people with MDS, the bone marrow stops making healthy blood cells and instead produces poorly functioning, malformed, and immature blood cells. This can lead to anemia resulting from too few healthy red blood cells, infection resulting from too few healthy white blood cells, and bleeding resulting from too few healthy platelets. The exact cause of MDS remains unknown, but it may be caused by abnormal autoimmune activity in which activated T cells, a type of white blood cell, prevent normal bone marrow production. ATG, a medication that inhibits immune function, can restore normal blood production in some people with MDS, but it is not known how this happens and why it does not happen in all MDS patients. The purpose of this study is to examine the effects of ATG in adults with MDS and to determine which individuals with MDS are most likely to benefit from treatment with ATG. Based on disease severity and likely disease progression, participants will be separated into either a high-risk group or a low-risk group. Participants will be hospitalized for a 4-day period during which they will receive daily infusions of ATG. Oral prednisone will be given 2 days before hospitalization, throughout hospitalization, and then for 14 days after hospitalization to limit the side effects of ATG. Antihistamines and acetaminophen will also be given during hospitalization to reduce the chances of an allergic reaction to ATG. After discharge, all participants will attend monthly study visits that will include blood collection, review of disease symptoms, and evaluation of medication response. At Week 16, participants in the high-risk group will undergo additional blood collection, a bone marrow biopsy, and a thorough evaluation of disease progression and the effects of MDS on daily living abilities. Participants in the low-risk group will undergo these same procedures at Week 24. Follow-up for all participants may last up to 2 years.

  Study phs000697

• GATA2 Deficiency and the MonoMAC Syndrome

  The aim of this study was to identify the germline mutation(s) in an extended family with individuals having MonoMAC Syndrome/GATA2 deficiency but lacking a canonical GATA2 mutation. GATA2 deficiency patients develop bone marrow failure, severe immunodeficiency and may progress to myeloid malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). The definitive treatment for GATA2 deficiency is a bone marrow transplant. Approximately 90% of GATA2 deficiency patients have a known de novo or inherited germline mutation in the GATA2 gene, but ~10% have no identified mutation. The study was initiated with the first patient and her second cousin, both of whom were treated for MonoMAC Syndrome and received bone marrow transplants at the NIH. Pedigree analysis and clinical evaluation identified the individuals in several generations of these patients' near and distant relatives who are/were presenting or carrying the disease manifestations of GATA2 deficiency. Whole Genome Sequencing (WGS) was employed on these patients' two related nuclear families to identify variants that segregated with the disease trait and carrier status of their families. Genotyping was confirmed with direct DNA sequencing of these and other family members within the extended family across generations. A single base adenine-to-thymidine change was identified in a highly conserved enhancer element ~117,000 bp upstream of the GATA2 gene. It creates a new Composite Element, a DNA motif known to be critical in the regulation of hematopoiesis. This variant is unique to this family and is not present in dbSNP or other variant databases. It segregates with the disease trait and obligate carriers throughout a large pedigree. In vitro studies show that this variant drives allele-specific overexpression of the GATA2 gene in cultured cells and luciferase assays. The WGS sequence from the nuclear families will be shared on dbGaP.

  Study phs003269

• Childhood Cancer Data Initiative (CCDI): Enhancement of Data Sharing in Pediatric, Adolescent and Young Adult Cancers

  NCI's Childhood Cancer Data Initiative (CCDI) is building a community centered around childhood cancer care and research data. Through enhanced data sharing, we can improve our understanding of cancer biology to improve preventive measures, treatment, quality of life, and survivorship, as well as ensure that researchers learn from every child with cancer. While childhood cancers represent the leading cause of death in children over the age of 1, they are collectively rare, comprising approximately 1%‒3% of cancers diagnosed annually in the United States. Information on diagnosis, treatment, and outcomes is often stored at the hospital or institution where a child is treated, making it difficult to answer scientific questions about childhood cancer. Sharing clinical care and research data generated by children's hospitals, clinics, or networks broadly with the community can help us learn faster and, on a scale much larger than any single institution caring for children can learn on its own. To exploit the rapid advances in high-throughput DNA sequencing technologies and realize the goals of precision cancer medicine, the UMICH Cancer Center established the Michigan Oncology Sequencing Center (MI-ONCOSEQ). This UMICH Cancer Center provisions genomic data derived from the Michigan Oncology Sequencing Center (MI-ONCOSEQ) clinical sequencing assay for patients that fall within the inclusion criteria of the CCDI data sharing initiative. An "integrative sequencing approach" carried out in a CLIA-certified laboratory is utilized to provide a comprehensive landscape of the genetic alterations in individual tumor specimens for the purpose of identifying informative and/or actionable mutations. Using a number of computational pipelines that we have developed in-house or have adapted from the public domain, candidate molecular aberrations are nominated and then analyzed by scientists for clinical significance and/or relevance. This approach enables the detection of point mutations, insertions/deletions, gene fusions and rearrangements, amplifications/deletions, and outlier expressed genes. Furthermore, we can identify certain germline alterations that may also be relevant.

  Study phs002431

• Deep single-cell RNA sequencing data for 11138 T cells from tumour, adjacent normal tissue and peripheral blood of treatment-naive CRC patients. The DATA ACCESS AGREEMENT is provided at https://github.com/zhangyybio/single-T-cell-data-access. Applicants can request access to the data by directly downloading it or by sending an email to cancerpku@pku.edu.cn. The process that is used to approve an application includes verifying the institution, participants and research purposes of the application. In general this process will take about two weeks. In principal, any scientific research program complying with the laws and bioethic regulation policies of China will be approved.

  T cells are central players in cancer immunotherapy1, yet some of their fundamental properties such as development and migration within tumours remain elusive. The enormous T cell receptor (TCR) repertoire, required for recognising foreign and self-antigens2,3, could serve as lineage tags to track these T cells in tumours4. Here, we obtained transcriptomes of 11,138 single T cells from 12 colorectal cancer (CRC) patients and developed STARTRAC (Single T-cell Analysis by Rna-seq and Tcr TRACking) indices to quantitatively analyse dynamic relationships among 20 identified T cell subsets with distinct functions and clonalities. While both CD8+ effector and “exhausted” T cells exhibited high clonal expansion, they were independently connected with tumour-resident CD8+ effector memory cells, implicating a TCR-based fate decision. Of the CD4+ T cells, the majority of tumour-infiltrating Tregs showed clonal exclusivity, whereas certain Treg clones were developmentally linked to multiple TH clones. Notably, we identified two IFNG+ TH1-like clusters in tumours, the GZMK+ TEM and CXCL13+ TH1-like clusters, which were associated with distinct IFN-γ-regulating transcription factors, EOMES/RUNX3 and BHLHE40, respectively. Only CXCL13+BHLHE40+ TH1-like cells were preferentially enriched in tumours of microsatellite-instable (MSI) patients, which might explain their favourable response rates to immune-checkpoint blockade. Furthermore, we found IGFLR1 to be highly expressed in both CXCL13+BHLHE40+ TH1-like and CD8+ exhausted T cells and possessed co-stimulatory functions. Our integrated STARTRAC analyses provides a powerful avenue to comprehensively dissect the T cell properties in CRC, which could shed new insights into the dynamic relationships of T cells in other cancers

  Study EGAS00001002791

• University of North Carolina at Chapel Hill (UNC) Hepatocellular Carcinoma Study by Exome Sequencing (HCCSES)

  Genetic alterations in specific driver genes lead to disruption of cellular pathways and are critical events in the instigation and progression of hepatocellular carcinoma. As a prerequisite for individualized cancer treatment, we sought to characterize the landscape of recurrent somatic mutations in hepatocellular carcinoma. We performed whole exome sequencing on 87 hepatocellular carcinomas and matched normal adjacent tissues to an average coverage of 59x. The overall mutation rate was roughly 2 mutations per Mb, with a median of 45 non-synonymous mutations that altered the amino acid sequence (range 2 to 381). We found recurrent mutations in several genes with high transcript levels: TP53 (18%), CTNNB1 (10%), KEAP1 (8%), C16orf62 (8%), MLL4 (7%) and RAC2 (5%). Significantly affected gene families include the nucleotide-binding domain and leucine rich repeat containing family, calcium channel subunits, and histone methyltransferases. In particular, the MLL family methyltransferases for histone H3 lysine 4 were mutated in 20% of tumors. Conclusion: The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of hepatocellular carcinoma.

  Study phs000627

• Role of the Cervico-Vaginal Microbiome in Spontaneous Preterm Birth

  Preterm birth is the leading cause of neonatal morbidity and mortality. A failure to predict and understand the causes of preterm birth have limited effective interventions and therapeutics. From a cohort of 2,000 pregnant women, we performed a nested case control study on 107 well-phenotyped cases of spontaneous preterm birth (sPTB) and 432 women delivering at term. Modern and innovative Bayesian modeling of vaginal microbiota identified features of these communities associated with PTB. Seven bacterial taxa were shown to have relative abundances significantly associated with an increased risk of sPTB, with a stronger effect in African American women. However, higher vaginal levels of β-defensins significantly decreased the risk of sPTB associated with the vaginal microbiota in an ethnicity-dependent manner. These findings hold promise for the development of novel diagnostics that could more accurately identify women at risk for sPTB early in pregnancy and offer new therapeutic strategies that would include immune modulators and microbiome-based therapeutics to reduce this significant health burden.

  Study phs001739

• National Cancer Institute (NCI) Study of Lung Cancer and Smoking Phenotypes in African-American Cases and Controls

  This is a two-stage case-control study designed to evaluate the association between common genetic variants and the risk of lung cancer. The stage 1 studies included 1737 cases and 3602 controls from the following studies: MD Anderson Lung Cancer Epidemiology Study, The Multiethnic Cohort Study (MEC), NCI-MD Lung Cancer-Case Control Study, Northern California Lung Cancer Study, Project CHURCH (Creating a Higher Understanding of Cancer Research δ Community Health), Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), Southern Community Cohort Study (SCCS), and the Karmanos Cancer Institute at Wayne State University (KCI/WSU). The stage 2 studies included an independent set of 866 cases and 796 controls from the following studies: The Black Women's Health Study (BWHS), The Harvard-MGH Lung Cancer Susceptibility Study (HLCS), MD Anderson Lung Cancer Epidemiology Study, MD Anderson/LBJ Hospital Biorepository, NCI-MD Lung Cancer Case-Control Study, Northern California Lung Cancer Study, Philadelphia Lung Cancer Study on Gene Environment Interactions (Plus-Gene), Southern Community Cohort Study (SCCS), and KCI/WSU.

  Study phs001210

• DCCT/EDIC Epigenetics (DNA Methylation) Study

  Metabolic memory (persistent benefits of early glycemic control on preventing/delaying diabetic complications development) was observed in the Diabetes Control and Complications Trial (DCCT) and follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, dbGaP phs000086.v3.p1, but mechanisms are unclear. We investigated the involvement of epigenetic DNA methylation (DNAme) by examining its associations with preceding glycemic history, and subsequent complications development over 18 years in blood DNAs of 499 randomly-selected DCCT/EDIC participants with type 1 diabetes. We found associations between DNAme near DCCT-closeout and mean-DCCT-HbA1c at 186 CpGs (FDR<15%, including 43 at FDR<5%), many located in complications-related genes. These CpGs are enriched in C/EBP motifs, enhancer/transcription regions in blood cells/progenitors, and open chromatin-states in myeloid cells. Remarkably, several CpGs in combination explain 68-97% of the mean-DCCT-HbA1c risk of complications development during EDIC. DNAme at key CpGs appears to mediate the association between hyperglycemia and complications in metabolic memory, through modifying myeloid cell enhancer activity.

  Study phs002024

• Spatiotemporal Evolution of the ccRCC Microenvironment Links Intra-Tumoral Heterogeneity to Immune Escape CINOMA

  We utilize temporal multi-regional multi-omics profiling to uncover the mechanisms of immune escape in clear cell renal cell carcinoma (ccRCC) in 29 patients including 17 patients from a neoadjuvant nivolumab clinical trial. We observe that tumors can be broadly categorized into intra-tumoral heterogeneity (ITH) high and low, which correlates across genomic, transcriptomic, immune and tumor microenvironment (TME) landscapes. We identify several genetic alterations associated with ITH that correlate with a myeloid high and effector T cell low TME. Namely, ITH high tumors are enriched for mutations in SETD2, PBRM1, CDKN2A/B somatic copy number loss and HLA loss of heterozygosity, and they demonstrate the characteristics of immune escape. ITH high tumors demonstrate reduced peripheral blood TCR diversity which is associated with neoantigen depletion. Moreover, we identify a link between neoantigen depletion and immune escape through myeloid activation. A transcriptomic signature associated with neoantigen depletion is strongly associated with response to ICI treatment and targeted therapies in several independent clinical trial cohorts.

  Study phs003079

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

  Cohort DescriptionHispanic Community Health Study/Study of Latinos (HCHS/SOL) is an ongoing population-based prospective cohort study of 16,415 community dwelling Hispanic/Latino adults aged 18-74 years at baseline, recruited from four urban field centers with large populations of Hispanics/ Latinos (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA). The primary goals of the HCHS/SOL are to describe: (1) the prevalence and incidence of cardiovascular, pulmonary, and other major chronic conditions (2) the risk and/or protective factors associated with these conditions; and (3) the relationships between the initial sociodemographic and health profiles and future health events in the target population. Data Being Submitted Wave 1 questionnaire data includes 397 variables for up to 9817 HCHS/SOL participants in C4R. Wave 2 questionnaire data includes 448 variables for up to 7536 HCHS/SOL participants in C4R. Derived data includes 43 variables for up to 11182 HCHS/SOL participants in C4R. Phenotype data includes 113 variables for up to 11182 HCHS/SOL participants in C4R.

  Study phs002908

• Postmortem Analysis of the Caudate Nucleus in Schizophrenia

  This postmortem study examines genomic signatures (gene, transcript, exon, and exon-exon junction) in the caudate nucleus of individuals with or without psychiatric illnesses. We characterized genetic and epigenetic changes across the lifespan of 443 donor subjects, including 245 individuals without psychiatric illness, 154 individuals with schizophrenia, and 44 individuals with bipolar disorder. The subjects are 210 from African and 233 from European ancestries. Combining expression quantitative trait loci (eQTL) analysis, Mendelian randomization with the latest schizophrenia genome-wide association study (GWAS), transcriptome-wide association study (TWAS) and differential expression analysis, we identified many genes associated with schizophrenia risk, including potentially the dopamine D2 receptor short isoform. We found that antipsychotic medication has an extensive influence on caudate gene expression. We constructed caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets. There are 120 subjects in this study which are also present in the study phs000417.

  Study phs003495

• Establishment of an iPSC Repository Derived from Healthy Volunteers

  Understanding the interaction between genetic variation and epigenetic variation remains a challenge due to the confounding role of environmental factors. We propose that human induced pluripotent stem cells (iPSCs) are an excellent model to study the relationship between genetic variation and epigenetic variation while controlling for consistent environmental factors. In this study, we have created a comprehensive resource of high-quality genomic, epigenomic, and transcriptomic data of six iPSC lines and three iPS-derived cell types (NSC, Motor Neuron, Monocyte) from three healthy donors. We found that epigenetic variation is most strongly associated with genetic variation at the iPSC stage, and that relationship weakens as epigenetic variation increases in the differentiated cells. Additionally, cell-type is a stronger source of epigenetic variation than genetic variation, highlighting that humans are far more similar than they are different, regardless of genetic background. Further, we have elucidated a utility of studying epigenetic variation in iPSCs and their derivatives for identifying important loci for GWAS studies and the cell-types in which they may be acting.

  Study phs003649

• Timing and trajectory of BCR-ABL1 driven chronic myeloid leukaemia

  Mutation of some genes provide fitness advantages that drive uncontrolled cell proliferation, leading to clinical manifestations of cancer. The discovery of the Philadelphia chromosome in chronic myeloid leukaemia (CML) provided the very first such genetic link to cancer and the hypothesis that this lesion provided an abnormal growth advantage to cells. However, little is known about the trajectory to CML, the rate of BCR::ABL1 driven clonal expansion, and how this impacts on disease presentation. Here, using whole-genome sequencing of 1013 single-cell-derived colonies from patients with CML, we reconstruct phylogenetic trees of haematopoiesis in 9 patients aged 22 to 81 years at diagnosis. The expected intronic breaks in BCR and ABL1 were not always observed, and out-of-frame exonic breakpoints in BCR, requiring exon skipping to derive BCR::ABL1 fusion transcripts, were noted in several patients. Apart from ASXL1 and RUNX1 mutations, additional somatic mutations in myeloid genes were generally present only in wild-type cells and did not contribute to the CML clone. Using phylogenetic analysis, we infer sustained explosive growth attributed to BCR::ABL1 fusion, with clonal expansions beginning 3-14 years (Cl 2-16 years) before diagnosis and annual growth rates exceeding 70,000% per year in some young patients with the most recent and rapid clonal expansions. Mutation rate was higher in BCR::ABL1-positive cells than in wild-type counterparts, together with markedly shorter telomere lengths, reflecting their excessive cell division history. Clonal expansion rates inferred from phylogenetic trees were in line with mutational signature patterns and telomere attrition, and inversely correlated with the time to diagnosis. Whole genome sequencing of advanced phase CML was characterised by genomic evolution within BCR::ABL1-positive cells. Our findings highlight the oncogenic potency of a single BCR::ABL1 fusion and its capacity to drive fast clonal outgrowth to cancer. These data contrast with the early-in-life, slow, and sequential clonal trajectories typical of most cancers, such as Philadelphia-negative myeloproliferative neoplasms, solid organ malignancies, and patterns of clonal expansion in healthy tissue ageing.

  Dataset EGAD00001015473

• Chromatin remodeler CHD7 regulates the stem cell identity of human neural progenitors

  Multiple congenital disorders often present complex phenotypes, but how the mutation of individual genetic factors can lead to multiple defects remains poorly understood. In the present study, we used human neuroepithelial (NE) cells and CHARGE patient-derived cells as an in vitro model system to identify the function of chromodomain helicase DNA-binding 7 (CHD7) in NE?neural crest bifurcation, thus revealing an etiological link between the central nervous system (CNS) and craniofacial anomalies observed in CHARGE syndrome. We found that CHD7 is required for epigenetic activation of superenhancers and CNS-specific enhancers, which support the maintenance of the NE and CNS lineage identities. Furthermore, we found that BRN2 and SOX21 are downstream effectors of CHD7, which shapes cellular identities by enhancing a CNS-specific cellular program and indirectly repressing non- CNS-specific cellular programs. Based on our results, CHD7, through its interactions with superenhancer elements, acts as a regulatory hub in the orchestration of the spatiotemporal dynamics of transcription factors to regulate NE and CNS lineage identities.

  Study JGAS000131

• Fragmentomics Uncover Non-Mutational HRD Features

  Homologous recombination deficiency (HRD) is a key biomarker in prostate cancer (PCa), predicting response to PARP inhibitors and platinum-based therapies. However, current diagnostics often rely solely on BRCA1/2 mutations or genomic scars, missing cases driven by other mechanisms. Tissue-based testing is further limited by tumor heterogeneity and biopsy challenges in metastatic bone disease. Here, we applied a comprehensive multimodal approach to assess HRD in 106 advanced PCa patients using circulating tumor DNA (ctDNA). This included targeted sequencing of homologous recombination repair (HRR) genes, low-pass WGS for genomic instability (sHRD), WES for mutational signatures, and cfDNA fragmentomics and chromatin accessibility profiling. BRCA2 was the most frequently altered gene, often co-occurring with PTEN loss. High sHRD scores correlated with BRCA2/RB1 loss, somatic copy number alterations, and poor survival. HRD tumors showed enrichment of SBS3/ID6 signatures, altered fragment lengths, and reduced accessibility at zinc finger transcription factor sites. These results support ctDNA-based multimodal profiling as a non-invasive strategy for HRD detection and stratification.

  Study EGAS00001008190

• Data upcycling, powered by EGA

  In 2012 a collaborative effort headed by the teams of Carlos Caldas in Cambridge, UK and Samuel Aparicio, Canada, produced a pivotal study aimed at defining the mutational landscape of breast cancer. They gathered a collection of over 2000 breast cancer samples (METABRIC) associated with long-term clinical follow-up. They delineated an array of inherited and somatically acquired genetic variants and associated them to gene expression. This led to the identification of putative cancer-driving events and improved stratification of breast cancer patients. The study elicited huge attention and was tackled as herculean effort by fellow researchers. Cristina Curtis and her colleagues deposited the data in the EGA archive (EGAS00000000083). What they probably could not foresee is that their data would be reused more than 100 times, becoming one of the most downloaded datasets at EGA. In 2015, Frederik S. Varn and colleagues accessed the above-mentioned data from the New Hampshire, USA, to correlate it to transcriptional programs of hematopoietic cells infiltrated in breast tumours and found that those can influence patients' prognosis. Their findings, published in Nature Communications, improved the understanding of the interplay between immune system and cancer. Again, in 2017 the dataset was downloaded by an Italian/Polish collaboration and used to corroborate their mechanistic study that demonstrate how a long non-coding RNA (lncRNA) is aberrantly localized into the chromatin, where it modulates oncogenic isoforms expression, thus contributing to breast cancer. To date, the METABRIC dataset has been reused to contribute to 147 publications. Its impact on breast cancer research is incalculable, and it even spread beyond that, with recent contributions to the understanding of pan-cancer mechanisms and features. Some of the publications are translating into improvements in diagnosis and treatment of different types of breast cancer. This is just an example of how data upcycling can amplify the potential of any dataset, well past the scope of its creation, the imagination of its owners and any geographical border. At EGA, we are proud to empower such fruitful worldwide cycles of knowledge, providing a platform that enables safe sharing of sensitive genetic data.

  Blog data-upcycling-powered-by-ega

• Spatial transcriptomics analysis of triple negative breast cancers

  While triple negative breast cancer (TNBC) is known to be heterogeneous at the genomic and transcriptomic levels, spatial information on tumor organization and cell composition is still lacking. Here, we investigated TNBC tumor architecture including its microenvironment using spatial transcriptomics on a series of 92 patients. We performed an in-depth characterization of tumor and stroma organization and composition using an integrative approach combining histomorphological and spatial transcriptomics. Furthermore, a detailed molecular characterization of tertiary lymphoid structures led to identify a gene signature strongly associated to disease outcome and response to immunotherapy in several tumor types beyond TNBC. A stepwise clustering analysis identified nine TNBC ecotypes, further validated in external datasets. Several ecotypes were associated with disease outcome and characterized by potentially actionable features. In this work, we provideThis is the largest TNBC series providing a comprehensive insight into the complexity of TNBC ecosystem with potential clinical relevance, opening avenues for treatment tailoring including immunotherapy. All the processed data needed to replicate the results from the publication (counts, images, clinical data, etc) are available on Zenodo: https://zenodo.org/records/14204217

  Study EGAS50000000475

• CNA differences between RNA-based subtypes of PDAC

  Pancreatic ductal adenocarcinomas (PDAC) have a dismal prognosis with a 5-year survival of <5%. Chemoresistance and recurrences, seen in approximately 70% of PDAC patients, may partly be explained by intratumor heterogeneity (ITH) through which tumors may develop ‘escape routes’. In the Pancreas Multibiopsy (PM)-project we have obtained multiple fragments from pancreatic and other peri-ampullary carcinomas in order to reveal potential ITH and identify genetic aberrations that predict outcome after surgery and response to chemotherapy. CNA-profiles were used to complement the characterization of liabilities in PDAC that we identified previously using RNAseq in the form of epithelial, secretory, compound pancreatic, and mesenchymal subgroups that showed survival outcomes. Comparison of CNA-profiles between these transcriptomics-based subgroups (with 8, 3, 6, and 6 tumors respectively per group) showed differences, ranging from ‘quiet’(i.e. hardly any CNA) to ‘wild’(i.e. lots of CNA), but these were not statistically significant (Chi2 0.09). When differentiating between the classical and basal-like molecular subtypes of PDAC differences in CNA (high or low) were even less statistically significant (Chi2 0.292).

  Study EGAS50000001218

• ScRNA-seq of human kidney immune cells of patients with ANCA-associated glomerulonephritis, Lupus Nephritis against a "healthy" nephrectomy control

  ANCA-associated glomerulonephritis (AGN) associates with a high risk of end-stage kidney disease. The role of kidney immune cells in local inflammation remains unclear. Here, we investigate kidney immune cell diversity and function. Kidney tissue from AGN patients (n=5) and a lupus nephritis (LN) patient (n=1) were aquired during a biopsy procedure for a clinical indication. Needle-core biopsies were obtained for histopathological examination, and an additional pass was performed to retrieve kidney tissue for scRNA-seq. Healthy kidney tissue (n=1) was obtained from a kidney that was surgically removed do tue due to a (non-invasive) papillary urothelial carcinoma. Immediately after collection, kidney tissue was processed into a single-cell suspension and sorted using a 4-color flow cytometry panel to isolate living, CD45+ immune cells. To aid in the multi-omic characterization, surface markers and T and B cell repertoires were sequenced in 2 samples (1 AGN patient and the nephrectomy control). These samples were incubated with an oligo-antibody TotalSeq-C cocktail containing 130 unique cell surface antigens.

  Study EGAS50000000159

• 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