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• Targeted Linked-Read DNA-seq Analysis of Castration-Resistant Prostate Cancers

  Androgen receptor (AR) inhibition is standard of care for advanced prostate cancer (PC). However, its efficacy is limited by progression to castration-resistant PC (CRPC), usually due to AR re-activation via mechanisms that include AR amplification and structural rearrangement. These two classes of AR alterations often co-occur in CRPC tumors, but it is unclear whether this reflects intercellular or intracellular heterogeneity of AR. It is important to resolve the mechanisms of AR genomic rearrangements to develop new therapies and predictive biomarkers for PC. We developed a targeted linked-read DNA sequencing assay to interrogate alterations in AR and a panel of genes known to be amplified or mutated in CRPC. Linked-read DNA-sequencing libraries were generated using the 10X Genomics Chromium platform and subjected to hybridization enrichment using a custom-designed Agilent SureSelect bait panel. Post-capture DNA-seq libraries were pooled and sequenced on an Illumina HiSeq 2500 using 2x150 bp settings. This targeted linked-read DNA-seq assay was used to interrogate a set of 6 benchmarking samples harboring known AR gene rearrangements and other alterations in AR, as well a panel of 6 patient-derived xenograft CRPC tumors and 23 clinical CRPC tumors. In this cohort, we identified a subset of samples that developed complex, multiply-rearranged AR gene structures in conjunction with very high AR copy number. The data that will be made available through dbGaP are raw FASTQ files.

  Study phs003343

• Development of cell lines and mouse models of bone and soft tissue sarcoma to establish novel treatment

  Malignant giant-cell tumors are extremely rare bone sarcomas that transform from conventional giant-cell tumors during long periods of treatment. We have applied the culture methods and succeeded in establishing patient-derived organoids (PDO) of rare sarcomas. This study aimed to investigate the genomic characteristics of our established novel organoids from human malignant giant-cell tumors. The developed tumors with xenograft were genomically analyzed to compare their characteristics with those of the original tumors. Genetic changes over time throughout treatment were analyzed, and the genomic status of the established organoid was confirmed. Next generation sequencing revealed that the established organoids lacked the H3-3A G34W mutation. The xenografted organoids of the malignant giant-cell tumor had phenotypes genetically similar to those of the original tumor. The established organoids were confirmed to be derived from human malignant giant-cell tumors. In summary, the present study demonstrated a novel organoid model of a malignant giant-cell tumor that was genetically confirmed to be a malignant transformed tumor. Our organoid model could be used to elucidate the molecular pathogenesis of a malignant giant-cell tumor and develop novel treatment modalities.

  Study JGAS000618

• A Single Cell Transcriptomic Analysis of Human Neocortical Development

  Defining the number, proportion, or lineage of distinct cell types in the developing human brain is an important goal of modern brain research. We produced single cell transcriptomic profiles for 40,000 cells at mid-gestation to define deep expression profiles corresponding to all known major cell types at this developmental period and compare this with bulk tissue profiles. We identified multiple transcription factors (TFs) and co-factors expressed in specific cell types, including multiple new cell-type-specific relationships, providing an unprecedented resource for understanding human neocortical development and evolution. This includes the first single-cell characterization of human subplate neurons and subtypes of developing glutamatergic and GABAergic neurons. We also used these data to deconvolute single cell regulatory networks that connect regulatory elements and transcriptional drivers to single cell gene expression programs in the developing CNS. We characterized major developmental trajectories that tie cell cycle progression with early cell fate decisions during early neurogenesis. Remarkably, we found that differentiation occurs on a transcriptomic continuum, so that differentiating cells not only express the few key TFs that drive cell fates, but express broad, mixed cell-type transcriptomes prior to telophase. Finally, we mapped neuropsychiatric disease genes to specific cell types, implicating dysregulation of specific cell types in ASD, ID, and epilepsy, as the mechanistic underpinnings of several neurodevelopmental disorders. Together these results provide an extensive catalog of cell types in human neocortex and extend our understanding of early cortical development, human brain evolution and the cellular basis of neuropsychiatric disease.

  Study phs001836

• Chromatin accessability in cytokine induced immune cell states (2019-03-19)

  We isolated T cells and monocotyes from healthy platelet donors and cultured them in resting and stimulated conditions with addition of a range of cytokines. We performed K27Ac ChM sequencing to assess the chromatin activity in different cytokines treated cells. These cellular profiles were used to map risk variants to the cytokine-induced cell states relevant for autoimmune diseases. . This dataset contains all the data available for this study on 2019-03-19.

  Dataset EGAD00001004852

• Chromatin accessability in cytokine induced immune cell states (2019-03-11)

  We isolated T cells and monocotyes from healthy platelet donors and cultured them in resting and stimulated conditions with addition of a range of cytokines. We performed ATAC sequencing to assess the chromatin accessability in different cytokines treated cells. These cellular profiles were used to map risk variants to the cytokine-induced cell states relevant for autoimmune diseases. . This dataset contains all the data available for this study on 2019-03-11.

  Dataset EGAD00001004831

• The long term effects of chemotherapy on normal blood - Nanoseq dataset

  In developed countries, ~10% of individuals are exposed to systemic chemotherapy for cancer and other diseases. Many chemotherapeutic agents act by increasing DNA damage in cancer cells, hence triggering cell death. However, there is limited understanding of the extent and consequences of collateral DNA damage to normal tissues. To investigate the impact of chemotherapy on mutation burdens and cell population structure of a normal tissue we sequenced blood cell genomes from 23 individuals, aged 3-80 years, treated with a range of chemotherapy regimens. Substantial additional mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but there were differences in burden between different classes of agent, different agents of the same class and different blood cell types. Chemotherapy also induced premature changes in the cell population structure of normal blood, similar to those of normal ageing. The results constitute an initial survey of the long-term biological consequences of cytotoxic agents to which a substantial fraction of the population is exposed during the course of their disease management, raising mechanistic questions and highlighting opportunities for mitigation of adverse effects.

  Dataset EGAD00001015340

• Genetic and Epigenetic Screens in Primary Human T Cells Link Candidate Causal Autoimmune Variants to T Cell Networks

  We aimed to define the target genes and pathways in which autoimmune disease-associated genetic variants operate. We performed single cell-CRISPR-interference screens in primary human T cells and bulk RNA-seq on T cells containing CRISPRi and single gRNAs to assess how T cell regulatory regions containing autoimmune-associated genetic variants affect nearby gene expression and cellular programs.

  Study phs004072

• Single-cell multi-omics reveals clonal evolution and T-cell dynamics underlying differential responses to ibrutinib in Waldenström macroglobulinemia.

  To elucidate the molecular basis underlying differential response and resistance to ibrutinib in Waldenström’s macroglobulinemia (WM), we conducted a prospective phase II trial (NCT02604511) of ibrutinib monotherapy in treatment-naïve patients. Seventy-four sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell RNA and V(D)J sequencing.

  Study EGAS50000001596

• Atherosclerosis Risk in Communities Study (ARIC-BioLINCC)

  Data Access NOTE:Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. At present, the ARIC sIRB has determined that ARIC data cannot be shared with for-profit entities.Related Studies Other ARIC data available include: Imaging studies (ARIC-Imaging), Genetics and genomics (ARIC, phs000280.v8.p2), Collaborative Cohort of Cohorts for COVID-19 Research (C4R): ARIC (phs002988.v1.p1), and as a component of the Sleep Heart Health Study (SHHS-BioLINCC, phs003637.v1.p1). Available Data Data available for request include ARIC v1-v8 examination cycles, collated annual follow-up communication data for contact years 2-32, and follow-up for mortality, heart disease, and stroke events through 2019. Also included are data from ancillary studies. Objectives The objectives of ARIC are to: 1) investigate associations of factors, including those not previously measured in cohort studies, with prevalence of atherosclerosis and incidence of CHD, clinical stroke and other cardiovascular diseases; and 2) measure cardiovascular disease occurrence and trends and relate these to community levels of, and changes in, risk factors, medical care and atherosclerosis. Background At the time of project initiation, the NHLBI had long recognized the need for longitudinal studies to identify the biochemical and physiological markers and specific environmental factors which place individuals at high risk for the major atherosclerosis diseases. The development of reliable ultrasound examination of peripheral arteries enhanced the expected benefit of such studies. Community surveillance planning began for ARIC in response to recommendations of the 1978 NHLBI Workshop on the Decline in CHD Mortality and has been extended in its purpose to evaluate the large geographic differences in U.S. mortality. Participants Black and white men and women, age 45-64 at entry; sample size: 15,792. Design ARIC is a large-scale, long-term prospective study that measures associations of established and suspected coronary heart disease risk factors with both atherosclerosis and new CHD events in men and women from four geographically diverse communities. The project has two components: community surveillance of morbidity and mortality; and repeated examinations of a representative cohort of men and women in each community. The community surveillance involves abstracting hospital records and death certificates and investigating out-of-hospital deaths. The representative cohorts include approximately 4,000 persons from each community. Community surveillance data includes detailed hospital record abstraction, ECG tracings, and event adjudication. Data from out-of-hospital events in the community include physician, informant, and coroner questionnaires as well as death certificate data and event adjudication. Community surveillance ended in 2014.Cohort participants were examined four times at three year intervals between 1987 and 1998, and have been continuously contacted annually to update their medical histories. Atherosclerosis was measured by carotid ultrasonography. Risk factors studied include: blood lipids, lipoprotein cholesterols, and apolipoproteins; plasma hemostatic factors; blood chemistries and hematology; sitting, supine and standing blood pressures; anthropometry; fasting blood glucose and insulin levels; ECG findings; cigarette and alcohol use; physical activity levels; dietary aspects; and family history. Clinic visits were restarted in 2011 with ARIC visit 5.

  Study phs003738

• Maintenance of Brain Tumor Profile on Organotypic Brain Slice Culture (OBSC)

  We used uncultured tumor resection tissue from an NF2 mutation-driven grade II meningioma (MG-II) to investigate whether tumors engrafted onto organotypic brain slice cultures (OBSCs) maintained the genetic profile of the parent tumor. We prepared three groups of samples for whole exome sequencing (WES) from the same pool of dissociated MG-II tissue. Group HT is the original uncultured human tumor tissue (n = 3). Group CL is the parent tumor tissue expanded in standard in vitro cell culture until the minimum number of cells required for WES had grown. Because of initial cell loss and subsequent clonal expansion, this required six passages over the span of approximately one month (n = 3). Group BSHT is the uncultured tumor resection tissue engrafted onto OBSCs and subsequently dissected from the OBSCs at the conclusion of our standardized assay length (4 days; n = 4). WES analysis showed that tumor tissue engrafted onto OBSCs maintained a significant genetic resemblance to the parent tumor, while tumor tissue expanded in vitro displayed a distinctly different profile. Furthermore, the mutational profiles of all four BSHT biological replicates were markedly similar, indicating that each OBSC-engrafted tumor indeed contained a representative sample of the original patient tumor. A closer look at the hallmark NF2 mutations existing within all samples revealed that while all samples from the original tumor (HT1-3) and the OBSC-engrafted tumor (BSHT1-4) maintain the frame shift deletion at V24, this mutation was lost in all samples expanded in vitro (CL1-3) and replaced by mutations in other areas. Together, this data suggests that the rapid assay design and tumor-accommodating niche of our OBSC platform enables effective maintenance of the original patient tumor profile. The BBsplit algorithm from the BBtools suite was run on all samples to eliminate rat DNA contamination in the BSHT samples as well as to account for any biases that may result as a part of that process. Only the reads that were binned to the human reference were used for subsequent analysis. Reads were then mapped to the GRCh38 version of the human genome with BWA v0.7.17 and realigned together with ABRA2 v.23. Quality control was implemented using the GATK/Picard v4.1.7.0 toolkit. Somatic variants were called for each sample using the MuTect2 algorithm v4.1.7.0. Variants were merged into a single cohort variant call file and then converted to MAF via vcf2maf v1.6.21 tool. Variants were annotated using VEP v87. To identify mutations with potentially high biological impact, multiple filtering steps were applied to somatic mutation calling. First, we selected only the somatic variants that passed all filters from the MuTect2 FilterMutectCalls algorithm and second, only high/moderate impact (change coding) variants as defined by the VEP annotation were further analyzed. Over 1900 single nucleotide variants (SNVs) were detected across all samples. Figures that summarized the results were generated using maftools.

  Study phs003268