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• This study explored and validated the clinical application of targeted NGS of circulating tumor DNA in identifying tumor-specific mutations and uncovering clinical actionable targets in a variety of solid tumors in large patient cohorts.

  Cancer is a disease of genetic alterations. Comprehensive genetic diagnosis is needed to match each patient to appropriate cancer therapy. However, acquisition of representative tumor samples is invasive and often infeasible. Circulating tumor DNA (ctDNA) is a promising non-invasive biomarker for cancer mutational profiling. Here we implemented targeted next generation sequencing (NGS) with a customized pan-cancer gene panel on 605 clinical ctDNA samples in multiple cancer types. Overall, tumor-specific mutations were identified in 87% of ctDNA samples, with mutation spectra highly concordant with their matched tumor tissues. 71% of patients have at least one clinical actionable mutation with 76% of which have suggested drugs approved or in clinical trials. In particular, our study reveals a unique mutation spectrum in Chinese lung cancer patients, which could be used to guide treatment decision and monitor the appearance of drug-resistant mutations. Taken together, our study demonstrated the clinical utility of target NGS-based ctDNA mutational profiling to guide cancer treatment decision.

  Study EGAS00001002251

• Sequencing_component_for_the_whole_genome_methylation_analysis_in_PBMCs_and_cell_subsets__pilot_study_

  DNA methylation has been shown to play a major role in determining cellular phenotype by regulating gene expression. Moreover, dysregulation of differentially methylated genes has been implicated in disease pathogenesis of various conditions including cancer development as well as autoimmune diseases such as systemic Lupus erythematosus and rheumatoid arthritis. Evidence is rapidly accumulating for a role of DNA methylation in regulating immune responses in health and disease. However, the exact mechanisms remain unknown. The overall aim of the project is to investigate the role of epigenetic mechanisms in regulating immunity and their impact on autoimmune disease pathogenesis.The aim of this pilot study is to perform whole genome methylation analysis in peripheral blood mononuclear cells (PBMCs) and cell subsets (CD4, CD8, CD14, CD19, CD16 and whole PBMCs) obtained from 6 healthy volunteers. Whole genome methylation analysis will be performed using two methodological approaches, the Infinium Methylation Bead Array K450 (Illumina) and MeDIP-seq. mRNA expression arrays will also be performed in order to correlate DNA methylation with gene expression as well as genotyping on the Illumina OmniExpress chip

  Study EGAS00001000490

• RNA Editing in breast cancer

  High-throughput sequencing screens suggest that RNA editing, which consists in the substitution of adenosine with inosine by the RNA-specific adenosine deaminase (ADAR) enzyme, occurs at several thousand positions across the human genome. Recent evidences have shown that RNA-editing could promote proliferation and carcinogenesis; however, the general principles of ADAR activity on the transcriptome and how ADAR is controlled in cancers remain to be established. The main aim of this project was to investigate the phenomenon of RNA editing in breast and other cancers. The frequency of A-to-I editing was evaluated in 58 breast cancers equally distributed among the different molecular subtypes and 10 normal breast tissues. The analysis was focused on defining: the relationship between the global amount of editing and ADAR expression; the ability to predict the level of editability of specific sites; the distribution of editing in normal and tumour samples and among different breast cancer subtypes; and the clinical, pathological and genomic factors affecting editing.

  Study EGAS00001000495

• Circulating Tumor DNA Analysis Detects Minimal Residual Disease and Predicts Recurrence in Patients with Stage II Colon Cancer

  Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify those at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively-parallel-sequencing–based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected post-operatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8 %) of the 164 patients with negative ctDNA (HR, 18; 95% confidence interval [CI], 7.9 to 36; P<0.001). In patients treated with chemotherapy, the presence of ctDNA following completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 to 68; P=0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence.

  Study EGAS00001001839

• Pilot_experiment_on_functional_genomics_in_osteoarthritis

  The aim of this work is to apply an integrated systems approach to understand the biological underpinnings of large joint (hip and knee) osteoarthritis which culminates in the need for total joint replacement (TJR). In this pilot we will assess the feasibility of the approach in the relevant tissue. We will obtain diseased and non-diseased tissue (cartilage and endochondral bone) following TJR, coupled with a blood sample, from 12 patients. We will generate genotype data on the HumanCoreExome array and will characterise the 12 pairs of diseased and non-diseased tissue samples in terms of methylation (Illumina 450k array), transcription (RNASeq) and expression (quantitative proteomics). The pilot will help assess the feasibility of isolating sufficient levels of starting material for the different approaches, and will instigate the development of analytical approaches to synthesising the resulting data. If successful, it is envisaged that we will proceed with expanding the work to 500 patients in the first year, with a target total sample size of 3,000 in the longer term. The key collaborators in this work are Mark Wilkinson (Sheffield) and Jyoti Choudhary

  Study EGAS00001001213

• Cell-free DNA TAPS for early cancer detection

  Multimodal, genome-wide characterization of epigenetic and genetic information in circulating cell-free DNA (cfDNA) could enable more sensitive early cancer detection. However, due to technological challenges associated with DNA methylation sequencing in low input cfDNA samples, most studies have been limited by DNA damage caused by bisulfite sequencing, or the qualitative nature of enrichment-based sequencing. Recently, we developed TET-assisted Pyridine Borane Sequencing (TAPS), which is a mild, bisulfite-free method for base-resolution direct DNA methylation sequencing. Here we optimized TAPS for cfDNA (cfTAPS) to provide high-quality and high-depth whole-genome cell-free methylomes. We applied cfTAPS to 85 cfDNA samples from patients with hepatocellular carcinoma (HCC) or pancreatic ductal adenocarcinoma (PDAC) and non-cancer controls. From just 10 ng cfDNA (1-3 mL of plasma), we generated the most comprehensive cfDNA methylome to date. We demonstrated that cfTAPS provides multimodal information about cfDNA characteristics, including DNA methylation, tissue of origin, and DNA fragmentation. Integrated analysis of these epigenetic and genetic features enables accurate identification of early HCC and PDAC.

  Study EGAS00001004962

• Mutations in SPINK2 induce azoospermia

  Azoospermia, characterized by the absence of spermatozoa in the ejaculate is a common cause of male infertility with a poorly characterized etiology. Exome sequencing analysis of two azoospermic brothers allowed the identification of a homozygous splice mutation in SPINK2, encoding a serine protease inhibitor believed to target acrosin, the main sperm acrosomal protease. In accord with these findings we observed that homozygous Spink2 KO male mice had azoospermia. Moreover, despite normal fertility, heterozygous male mice had a high rate of morphologically abnormal spermatozoa and a reduced sperm motility. Further analysis demonstrated that in the absence of Spink2, protease-induced stress initiates Golgi fragmentation and prevents acrosome biogenesis leading to spermatid differentiation arrest. We also observed a deleterious effect of acrosin overexpression in HEK cells, effect that was alleviated by SPINK2 coexpression confirming its role as acrosin inhibitor. These results demonstrate that SPINK2 is necessary to neutralize proteases during their cellular transit towards the acrosome and that its deficiency induces a pathological continuum ranging from oligoasthenoteratozoospermia in heterozygotes to azoospermia in homozygotes.

  Study EGAS00001002450

• Somatic_mutation_profiling_of_intestinal_crypts_from_IBD

  In this project we want to investigate the role that somatic mutations in intestinal stem cells play in IBD. We will use laser capture microdissection to ascertain epithelial cells from an individual crypts/vilus. We will extract DNA from these and use a new low-input material library prep methods to make accurate libraries for sequencing. In this pilot phase of the project we will perform 15X whole-genome sequencing of a small number of crypts biopsied from four patients. Biopsies have been taken from inflammed and noninflammed patches to compare mutation rates and mutational signatures. We will also test if crypts from inflammed patches of a single patient are clonal (either within a given inflammed patch or across inflammed patches). We will quantify the rate of cancer driver mutations in inflammed and non-inflammed crypts. 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 EGAS00001002896

• Multimodal single-cell and bulk glioma analyses

  Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to therapeutic resistance. We integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes, and bulk multi-omic profiles across 11 adult IDH-mutant or IDH-wild-type gliomas to delineate sources of intratumoral heterogeneity. We show that local DNA methylation disorder associates with cell-to-cell DNA methylation differences, is elevated in more aggressive tumors, links with transcriptional disruption, and is altered in environmental stress response. Glioma cells under in vitro hypoxic and irradiation stress increased local DNA methylation disorder and shifted cell states. We identified a positive association between genetic and epigenetic instability that was supported in bulk longitudinally collected DNA methylation data. Increased DNA methylation disorder associated with accelerated disease progression, and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work identifies an epigenetically facilitated adaptive stress response process and highlights the importance of epigenetic heterogeneity in shaping therapeutic outcomes.

  Study EGAS00001005300

• Comprehensive pharmacogenomic characterization of gastric cancer

  Gastric cancer is among the most lethal human malignancies. Previous studies have identified molecular aberrations that constitute dynamic biological networks and genomic complexities of gastric tumors. However, the clinical translation of molecular-guided targeted therapy is hampered by challenges. Notably, solid tumors often harbor multiple genetic alterations, complicating the development of effective treatments. To address such challenges, we established a comprehensive dataset of molecularly annotated patient derivatives coupled with pharmacological profiles for 60 targeted agents to explore dynamic pharmacogenomic interactions in gastric cancers. We identified lineage-specific drug sensitivities based on histopathological and molecular subclassification, including substantial sensitivities toward VEGFR and EGFR inhibition therapies in diffuse- and signet ring-type gastric tumors, respectively. We identified potential therapeutic opportunities for WNT pathway inhibitors in ALK-mutant tumors, a significant association between PIK3CA-E542K mutation and AZD5363 response, and transcriptome expression of RNF11 as a potential predictor of response to gefitinib. Collectively, our results demonstrate the feasibility of drug screening combined with tumor molecular characterization to facilitate personalized therapeutic regimens for gastric tumors.

  Study EGAS00001004106

• Cancer immune control needs senescence induction by Stat1 dependent cell cycle regulator pathways in tumours

  Immune checkpoint bloackade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, we show that deletion of the senescence-inducing cell cycle regulators p16Ink4a/p19Arf (Cdkn2a) or p21Cip1 (Cdkn1a) in the tumour cells abrogated both, the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest those cancer cells that escape from eradication.

  Study EGAS00001004151

• Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosissusceptibility

  Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG)and associated myelin by immune cells, which are thought to be the main drivers of MS susceptibility. Assessing chromatin accessibility and the transcriptome simultaneously at the single cell level, we found that immune genes exhibit a primedchromatin state in mouse and human OLG in a non-disease context, compatible withrapid transitions to immune-competent states in MS. We identified transcription factors as BACH1 and STAT1 involved in immune gene regulation in oligodendrocyteprecursor cells (OPCs). A subset of immune genes present bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon-gamma (IFNg) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse andhuman OLG, and treatment of mouse OPCs with IFNg leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Our data indicates that susceptibility for MS may involve OLG, which therefore constitute novel targets for immunological-based therapies for MS.

  Study EGAS00001005911

• Infiltrative and drug-resistant slow-cycling cells support metabolic heterogeneity in glioblastoma

  Metabolic reprogramming has been described in rapidly growing tumors, which are thought to mostly contain fast-cycling cells (FCCs) that have impaired mitochondrial function and rely on aerobic glycolysis. Here, we characterize the metabolic landscape of glioblastoma (GBM) and explore metabolic specificities as targetable vulnerabilities. Our studies highlight the metabolic heterogeneity in GBM, in which FCCs harness aerobic glycolysis, and slow-cycling cells (SCCs) preferentially utilize mitochondrial oxidative phosphorylation for their functions. SCCs display enhanced invasion and chemoresistance, suggesting their important role in tumor recurrence. SCCs also demonstrate increased lipid contents that are specifically metabolized under glucose-deprived conditions. Increased fatty acid transport in SCCs is targetable by pharmacological inhibition or genomic deletion of FABP7, both of which sensitize SCCs to metabolic stress. Furthermore, FABP7 inhibition, whether alone or in combination with glycolysis inhibition, leads to overall increased survival. Our studies reveal the existence of GBM cell subpopulations with distinct metabolic requirements and suggest that FABP7 is central to lipid metabolism in SCCs and that targeting FABP7-related metabolic pathways is a viable therapeutic strategy.

  Study EGAS00001003251

• RNA-seq of M-CSF differentiated human peripheral monocyte-derived macrophages (MDMs) - Validation macIDR

  Macrophages represent multifunctional leukocytes defined by their stimulus-specific transcriptional reprogramming. As in vivo macrophages are often difficult to obtain, in vitro macrophage models are often used. We aggregated public expression data to define consensus expression profiles for eight commonly-used in vitro macrophage models and built the classifier macIDR, capable of distinguishing macrophage subsets with high accuracy (>0.95). Classification of in vivo macrophages suggested that alveolar macrophages resembled interleukin-10 activated macrophages in general whereas chronic obstructive pulmonary disease patients displayed decreased similarity to interferon-γ stimulated macrophages. Adipose tissue-derived macrophages were classified as unstimulated macrophages, but would resemble LPS-stimulated macrophages more in diabetic-obese patients. Rheumatoid arthritic synovial macrophages were similar to macrophages stimulated with interleukin-10 or interferon-γ. Altogether, our results suggest that macIDR is capable of identifying in vitro macrophages. By projecting in vivo macrophages onto the in vitro macrophages, we were capable of elucidating macrophage-specific changes as a result of tissue and disease.

  Study EGAS00001003451

• 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

• The miR-185/PAK6 Axis Predicts Therapy Response and Regulates Survival of Drug-Resistant Leukemic Stem Cells in Chronic Myeloid Leukemia

  Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. To investigate the role of miRNAs in regulating drug resistance and leukemic stem cell (LSCs) fate, we performed global transcriptome profiling in treatment-naïve chronic myeloid leukemia (CML) stem/progenitor cells and identified that miR-185 levels anticipate their response to ABL tyrosine kinase inhibitors (TKIs). miR-185 functions as a tumor suppressor; its restored expression impaired survival of drug-resistant cells, sensitized them to TKIs in vitro, and markedly eliminated long-term repopulating LSCs and infiltrating blast cells, conferring a survival advantage in pre-clinical xenotransplantation models. Integrative analysis with mRNA profiles uncovered PAK6 as a crucial target of miR-185 and pharmacological inhibition of PAK6 perturbed the RAS/MAPK pathway and mitochondrial activity, sensitizing therapy-resistant cells to TKIs. Thus, miR-185 presents as a potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL may provide a valuable strategy for overcoming drug resistance in patients.

  Study EGAS00001004153

• Detection of isoforms and genomic alterations by high-throughput full-length single-cell RNA sequencing in HGSOC

  Understanding the complex background of cancer requires genotype-phenotype information in single-cell resolution. Long-read single-cell RNA sequencing (scRNA-seq), capturing full-length transcripts, lacked the depth to provide this information so far. Here, we increased the PacBio sequencing depth to 12,000 reads per cell, leveraging multiple strategies, including artifact removal and transcript concatenation, and applied the technology to samples from three human ovarian cancer patients. Our approach captured 152,000 isoforms, of which over 52,000 were novel, detected cell type- and cell-specific isoform usage, and revealed differential isoform expression in tumor and mesothelial cells. Furthermore, we identified gene fusions, including a novel scDNA sequencing-validated IGF2BP2::TESPA1 fusion, which was misclassified as high TESPA1 expression in matched short-read data, and called somatic and germline mutations, confirming targeted NGS cancer gene panel results. With multiple new opportunities, especially for cancer biology, we envision long-read scRNA-seq to become increasingly relevant in oncology and personalized medicine.

  Study EGAS00001006807

• Genotype data from 'Dense sampling of ethnic groups within African countries reveals fine-scale genetic structure and extensive historical admixture.'

  Previous studies have highlighted how African genomes have been shaped by a complex series of historical events. Despite this, genome-wide data has only been obtained from a small proportion of present-day ethnolinguistic groups. By analysing new autosomal genetic variation data of 1333 individuals from over 150 ethnic groups from Cameroon, Republic of the Congo, Ghana, Nigeria and Sudan, we demonstrate a previously underappreciated fine-scale level of genetic structure within these countries, for example correlating with historical polities in western Cameroon. By comparing genetic variation patterns among populations, we infer that many northern Cameroonian and Sudanese groups share genetic links with multiple geographically disparate populations, likely resulting from long-distance migrations. In Ghana and Nigeria, we infer signatures of intermixing dated to over 2000 years ago, corresponding to reports of environmental transformations possibly related to climate change. We also infer recent intermixing signals in multiple African populations, including Congolese, that likely relates to the expansions of Bantu language-speaking peoples.

  Study EGAS00001006944

• Modulation of the peripheral blood immune cell transcriptome by vitamin D3 supplementation in people with a first demyelinating event: a randomized placebo-controlled trial

  Vitamin D deficiency is a risk factor for developing multiple sclerosis (MS). Both in vitro and animal studies suggest an immunomodulatory effect of vitamin D. The PrevANZ trial, a phase IIb randomized placebo-controlled trial of oral vitamin D3 supplementation in people with a first demyelinating event (FDE), was conducted to determine if supplementation can prevent recurrent disease activity in this cohort at high risk of developing definite MS. As a sub-study of this trial, we used whole blood transcriptomic analyses to investigate the effect of vitamin D3 supplementation on peripheral immune cells in people with an FDE, and to gain insight into potential mechanisms by which vitamin D3 may regulate MS risk and disease activity. The PrevANZ trial randomized participants to 1000 IU, 5000 IU or 10,000 IU daily of oral vitamin D3 or placebo. Peripheral blood was collected at baseline and 12 weeks in PAXgene Blood RNA tubes. Transcriptomic datasets were generated by RNA sequencing.

  Study EGAS00001007346

• Relation between transcriptome, karyotype and age in cases of sex chromosome aneuploidies.

  Why women live longer than men is still an open question in human biology. Sex chromosomes have been proposed to play a role in the observed sex gap in longevity, and the Y male chromosome has been suspected of having a potential toxic genomic impact on male longevity. It has been hypothesized that transposable element (TE) repression declines with age, potentially leading to detrimental effects such as somatic mutations and disrupted gene expression, which may accelerate the aging process. Given that the Y chromosome is rich in repeats, age-related increases in TE expression could be more pronounced in males, likely contributing to their reduced longevity compared to females. In this work, we first studied whether TE expression is associated with the number of sex chromosomes in humans. We analyzed blood transcriptomic data obtained from individuals of different karyotype compositions: 46,XX females (normal female karyotype), 46,XY males (normal male karyotype), as well as males with abnormal karyotypes, such as 47,XXY, and 47,XYY.

  Study EGAS00001007462

• Assessment of genetic and epigenetic variation in human IPS cells-RNA

  In order to progress human induced pluripotent stem cells (hiPSCs) towards the clinic, several outstanding questions must be addressed. It is possible to reprogram different somatic cell types into hiPSCs and from studies in the mouse, it appears that an epigenetic memory of the starting cell type is carried over to hiPSCs. However a comprehensive comparative study of the characteristics of these hiPSCs has been missing from the literature. Importantly studies which aimed to address these aspects of hiPSCs have used cells from different patients. In order to avoid this important confounding variable and to keep the genetic background constant, tissue samples were procured from the patients and reprogrammed to iPS cells. The transcriptomes of these iPS cells will be compared. Protocol: primary cultures of cells were reprogrammed to iPS cells. RNA was extracted using a standard column extraction kit.

  Dataset EGAD00001000604

• Rapid Acceleration of Diagnostics - Underserved Populations (RADx-UP): COVID-19 Testing and Prevention in Correctional Settings

  This study will work with diverse correctional facilities across MN, RI, WA, and FL to characterize the incidence of COVID-19 disease progression and related outcomes. The goal is to identify barriers and facilitators to develop strategies to improve testing in these under-served populations by: Increasing the reach, access, uptake, and impact of COVID-19 testing among incarcerated people and staff in prison and jails. Individuals in congregate settings have been disproportionately affected by COVID-19, with correctional settings accounting for 39 of the 50 largest cluster outbreaks in the country to date. Schema of Correctional Facilities: Correctional facilities are amplifiers of infectious diseases for structural reasons: 1) Dormitory-style living and overcrowded conditions make social distancing nearly impossible 2) They have a focus primarily on security not health 3) Their medical departments are under-resourced and often disconnected from local public health agencies. Correctional facilities must be the focus of urgent intervention to understand the incidence of COVID-19, how it spreads in correctional facilities, and durable long-term strategies to reduce transmission, including testing and vaccines. However, our work from the COVID Prison Project shows that correctional systems have implemented a range of testing strategies, without coordination, such that synthesizing the information on COVID-19 incidence, outcomes and optimal testing strategies (including repeat testing and contact tracing) has been challenging. Incarcerated people decline testing due to concerns about confidentiality, implications for release, and fear of placement in solitary confinement. Through interviews we will identify ethical concerns and potential solutions for COVID-19 testing and vaccine strategies in correctional facilities using a community-engaged strategy. The project's work from the COVID Prison Project shows that correctional systems have implemented a range of testing strategies, without coordination, such that synthesizing the information on COVID-19 incidence, outcomes and optimal testing strategies (including repeat testing and contact tracing) has been challenging. Incarcerated people decline testing due to concerns about confidentiality, implications for release, and fear of placement in solitary confinement. Through interviews we will Identify ethical concerns and potential solutions for COVID-19 testing and vaccine strategies in correctional facilities using a community-engaged strategy. Goals: 1. Identify ethical concerns and potential solutions for COVID-19 testing and vaccine strategies in correctional facilities using a community-engaged strategy. 2. Characterize incidence of COVID-19, disease progression, and related-outcomes and effectiveness of testing and contact tracing in correctional facilities. Participant Selection: a. Potential subjects must be currently incarcerated at key facilities in Washington, Rhode Island, Minnesota, and Florida. These facilities are Everglades Correctional Institution and Homestead Correctional Institution in Florida, Shakopee and Stillwater correctional facilities in Minnesota, the Rhode Island Department of Corrections, and Yakima County Jail in Washington. b. Participating correctional facilities in Florida, Minnesota, Rhode Island, and Washington will provide de-identified data on approximately 16,859 incarcerated adults and correctional staff. Data sources include deidentified data from medical records, administrative data, and policy documents pertaining to COVID-19. c. 3 series of focus groups (6, 12, 18 months) x 3 distinct groups (incarcerated people, medical providers, and correctional leaders) x 4 sites=36 total focus groups over the study period. d. Will utilize 74,812 COVID-19 tests to test and re-test a total of 16,859 incarcerated people and correctional staff for active infection over a six-month period in the FL, MN, and RI state prison systems and the Yakima County Jail in WA.

  Study phs003361

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

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

  Study phs003597

• ARDSNet 07-08: Randomized, Blinded, Placebo-Controlled, Multi-Center Trial of Omega-3 Fatty Acid, Gamma-Linolenic Acid, and Antioxidants in Acute Lung Injury or ARDS (OMEGA) (ARDSNet-Omega-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-Omega include bronchial lavage, plasma, urine, and DNA. Please note that use of biospecimens in genetic research is subject to a tiered consent.Objectives: To determine if dietary supplementation of omega-3 (n-3) fatty acids, γ-linolenic acid and antioxidants to participants with acute lung injury would increase ventilator-free days to study day 28.Background: Early acute lung injury (ALI) is characterized by neutrophilic lung inflammation, permeability, and intravascular and alveolar fibrin deposition. The type and inflammatory activity of eicosanoids liberated during inflammation depends on the membrane phospholipid composition: omega 6 (n-6) fatty acid arachidonate yields highly reactive and inflammatory dienoic prostaglandins and series 4 leukotrienes, whereas omega-3 (n-3) fatty acids favor production of less active and potentially anti-inflammatory trienoic prostaglandins and series 5 leukotrienes. Participants at risk of developing ALI have n-3 levels approximately 25% of normal and those with established ALI have n-3 levels as low as 6% of normal, suggesting a potential role for n-3 dietary supplementation in participants with ALI.Three randomized controlled studies, conducted in participants with ALI or sepsis-induced respiratory failure, demonstrated an association between the administration of an enteral formula enriched in n-3 fatty acids, GLA, and antioxidants and improved oxygenation and respiratory physiology compared with an unenriched, high-fat formula. However, interpretation of these results is limited by the small sample sizes and as-treated analyses of only those participants who tolerated full enteral nutrition. Participants: The total number of participants in the study was 272.Design: Participants were stratified by hospital and the presence of shock at baseline and then randomized to receive either twice-daily enteral supplementation of n-3 fatty acids, GLA, and antioxidants (n-3 supplement) or an isocaloric-isovolemic carbohydrate-rich control. Participants were also simultaneously randomized to a separate ongoing trial (the EDEN study) comparing low- vs full-calorie enteral nutrition in a 2×2 factorial design.The n-3 or control supplement was administered enterally as twice-daily boluses of 120 mL beginning within 6 hours of randomization. Dosing continued until the earliest of 21 days, 48 hours of unassisted breathing, or extubation. The energy provided by the boluses supplemented that provided by each primary physician's choice of standard continuous non–n-3-enriched enteral formula. The rate of continuous enteral feeding was managed by a protocol with an algorithm for gastrointestinal intolerances. The supplement was administered even if enteral nutrition was interrupted, as long as the patient was tolerating enteral medications. Conclusions: The study was stopped by the DSMB for futility at the first interim analysis after 143 participants had been randomized to receive the n-3 supplement and 129 to receive the isocaloric control. Despite an 8-fold increase in plasma eicosapentaenoic acid levels, participants receiving the n-3 supplement had fewer ventilator-free days, intensive care unit–free days, and nonpulmonary organ failure-free days.

  Study phs003744

• Exome Sequencing to Define the Landscape of Plasma Cells in Systemic Light chain Amyloidosis

  Systemic light chain amyloidosis (AL) is characterized by the deposition of immunoglobulin light chains as amyloid fibrils in different organs, where they form toxic protein aggregates. The underlying disease is a plasma cell disorder, but limited whole exome data are available. We report the findings of an exome sequencing study in AL to define a plasma cell signature and compare this to monoclonal gammopathy of undefined significance (MGUS) and myeloma (MM). Twenty-four samples from unselected newly diagnosed untreated AL patients were analysed. CD138+ cells were isolated from bone marrow cells using MACSorting (Miltenyi Biotech, Bisley, UK). Cells were lysed in RLT+ buffer and DNA/RNA extracted using the AllPrep kit (Qiagen, Manchester, UK). Peripheral blood was isolated from patients, white blood cells purified by Ficoll-Pacque and DNA extracted using the QIAamp DNA mini kit (Qiagen). There were a median of 47 acquired nonsynonymous variants (range 4-253) per patient. Thirty percent of patients yielded a mutation in a myeloma driver gene. These mutations were either clonal or sub-clonal. There was evidence of MAPK activation with NRAS mutations, NF-κB activation and DNA repair pathway alterations. Exome data were used to determine the cytogenetic groups of AL samples and identified hyperdiploidy in 33% of cases and t(11;14) in 33% of cases. All translocations were generated via class switch recombination and breakpoints on chromosome 11 fell into the expected regions. A novel translocation, unlikely to be driving disease progression was identified involving RCC1. Finally, further analysis of the APCS gene encoding for the SAP protein did not show any biased genotype in the AL population in comparison to the general population. We conclude that exome sequencing identifies a genetic make-up of AL that is similar to other plasma cell disorders such as MM and MGUS. This not only includes copy number abnormalities and translocations but also nonsynonymous mutations.

  Study EGAS00001001418