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• Targeted de-methylation of the FOXP3-TSDR

  CD4+ regulatory T cells (Tregs) are key mediators of immunological tolerance and promising effector cells for immuno-suppressive adoptive cellular therapy to fight autoimmunity and chronic inflammation. Their functional stability is critical for their clinical utility and has been correlated to the demethylated state of the TSDR/CNS2 enhancer element in the Treg lineage transcription factor FOXP3. However, proof for a causal contribution of the TSDR de-methylation to FOXP3 stability and Treg induction is so far lacking. We here established a powerful transient-transfection CRISPR-Cas9-based epigenetic-editing method for the selective de-methylation of the TSDR within the endogenous chromatin environment of a living cell. The induced de-methylated state was stable over weeks in clonal T cell proliferation cultures even after expression of the editing complex had ceased. Epigenetic editing of the TSDR resulted in FOXP3 expression, even in its physiological isoform distribution, proving a causal role for the de-methylated TSDR in FOXP3 regulation. However, successful FOXP3 induction was not associated with a switch towards a functional Treg phenotype, in contrast to what has been reported from FOXP3 overexpression approaches. Thus, TSDR de-methylation is required, but not sufficient for a stable Treg phenotype induction. Therefore, targeted demethylation of the TSDR may be a critical addition to published in vitro Treg induction protocols which so far lack FOXP3 stability.

  Study EGAS00001004867

• Sensitive and robust liquid biopsy-based detection of PIK3CA mutations

  Over the last years, the treatment of hormone receptor-positive metastatic breast cancer patients has dramatically changed. Combination strategies attempting to overcome resistance to endocrine therapy such as targeting the PI3 kinase pathway are gaining importance. The phase III SOLAR-1 trial demonstrated the benefit of the addition of alpelisib to fulvestrant, thereby providing further clinical evidence of the increasing importance of PIK3CA testing. Here, we performed a comparison of liquid biopsy and tissue-based detection of PIK3CA mutations in HR-positive metastatic breast cancer patients. Plasma samples and the latest available tumor tissue from 69 patients with metastatic hormone-receptor positive breast cancer were analyzed for PIK3CA hotspot mutations. A high-resolution NGS assay (SiMSen-Seq) was used for plasma samples covering 11 recurrent PIK3CA mutations, used for stratification in SOLAR-1. Additionally, mFAST-SeqS was used to estimate the tumor fractions in the plasma samples. For tumor tissue samples, targeted Ion Torrent NGS was employed. Matched tissue and plasma samples were available from 63 patients. PIK3CA mutations were detected in 46.1% of the tissue samples and in 50.7% of the plasma samples. The variant allele frequency (VAF) ranged from 4.36% to 72.93% with a median of 28.60% in tissue samples, and from 0.28% to 49.85% with a median of 1.17% in plasma samples. The most frequent variants in tissue and plasma were H1047R, E545K, and E542K. We detected at least one of 11 PIK3CA mutations from the SOLAR-1 trial in 51/63 patients, both in tissue and plasma. In 7 patients, such mutations were found only in plasma. In 5 patients, PIK3CA mutations found in tissue were not detectable in ctDNA, 2 of which had a low tumor fraction.Together, in 33/67 plasma samples without detectable PIK3CA mutations, 18 samples had elevated tumor fraction, implicating true negative results. In the remaining 15 patients with low tumor fraction, additional tissue analysis was needed. SiMSen-Seq-based detection of PIK3CA mutations in plasma shows advantageous concordance with the tissue analyses. A combination with an untargeted, mutation-independent approach for detecting ctDNA fractions may confirm a negative PIK3CA result and thereby enhance the performance of the SiMSen-Seq test. This combinatory approach for selecting suitable patients for alpelisib treatment should be validated in larger patient cohorts.

  Study EGAS00001004940

• Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease

  Population level variation and molecular mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized despite ramifications for personalized nutrition. We now define prototypical insulin secretion dynamics in response to the three macronutrients in islets from 140 cadaveric donors, including those diagnosed with type 2 diabetes. We leverage the insulin response heterogeneity and use transcriptomics and proteomics to identify molecular pathways of specific nutrient responsiveness. Surprisingly, we find robust insulin secretion to fatty acid stimulus in ~8% of donors, challenging the idea that fat has negligible effects on insulin release. Distinct islet proteomes with differences in metabolic signalling networks convey this hyper-responsiveness to fat relative to carbohydrate. By comparing human islets to human embryonic stem cell-derived islet clusters, we show that, unlike glucose-responsiveness, fat hyper-responsiveness is equivalent and may be a hallmark of functionally immature cells. Our study represents the first comparison of dynamic responses to nutrients and multi-omics analysis in human insulin secreting cells. Responses of different people’s islets to carbohydrate, protein, and fat lay the groundwork for personalized nutrition.

  Dataset EGAD50000000519

• Characterizing the Role of the Immune Microenvironment in Multiple Myeloma Progression at a Single Cell Level

  The plasma cell disease multiple myeloma (MM) is highly dependent on its bone marrow microenvironment (BMME). Early alterations within the bone marrow microenvironment that contribute to the progression of multiple myeloma (MM) from its precursor stages could hold the key to identifying novel therapeutic approaches, yet the intrinsic variability in cellular populations between patients together with differences in sample processing and analysis methods have made it difficult to identify consistent changes between datasets. Here, we used single-cell RNA sequencing of BM cells from precursor stages, monoclonal gammopathy of unknown significance (MGUS), smoldering MM (SMM) and newly diagnosed MM and analyzed our data in combination with a previously published dataset that used a similar patient population and sample processing. Despite vast interpatient heterogeneity, some alterations were seen consistently in both datasets. We identified changes in immune cell populations as disease progressed that were characterized by a substantial decrease in memory and naïve CD4 T cells and an increase in CD8+ effector T cells and T-regulatory cells. These alterations were further accompanied by an enrichment of non-clonal memory B cells and an increase of CD14 and CD16 monocytes in MM compared to its precursor stages. These results provide crucial information of the immune changes associated with the progression to clinical MM and can help to develop immune based strategies for patient stratification and early therapeutic intervention. 

  Study phs002756

• Epigenetics of Cocaine and Nicotine Addiction

  This project characterizes DNA methylation and gene expression changes that occur in the human brain, specifically in neurons from the rostral striatum. Major advances from NIDA funded initiatives for noninvasive neuroimaging studies have made it possible to study neuroanatomical, neurochemical and functional changes in the human brain that contribute to the vulnerability to abuse drugs, together with the neurotoxic consequences of years of drug misuse. Animal models have been developed to explain the fundamental behavioral and biological mechanisms of addiction, including reward, tolerance and dependence. From these studies, we learned that cocaine abuse not only alters the epigenetic status of genes, but also induces particular epigenetic modifications depending on the frequency of the drug's administration. Certain genes are switched on by infrequent (short-term exposure) administration, while others are switched on only after chronic administration (addiction/dependence). Animal studies have also suggested that cocaine-seeking habits modeling chronic cocaine addiction in humans depend upon dopamine-dependent serial connectivity linking the ventral (nucleus accumbens) with the dorsal striatum (caudate nucleus). The primary goal of this study is to identify DNA methylation and gene expression changes that occur in the transition from recreational cocaine use to cocaine addiction. High throughput sequencing studies were designed to investigate unique postmortem human brain specimens from individuals that met criteria for cocaine dependence, as compared to unaffected age-matched controls. Brain biospecimens were available from the University of Miami Brain Endowment BankTM, from a collection of phenotypically well-characterized postmortem tissues sampled from chronic cocaine abusers that came to autopsy. This biobank of postmortem brain specimens and annotated genomic data serve as a research resource to support NIDA's scientific mission.

  Study phs001377

• Digital tEchnology For Lung Cancer Treatment

  The aim of the DEFLeCT project (Digital tEchnology For Lung Cancer Treatment) is to generate a technological platform for precision medicine in order to set predictive personalised algorithms for patient diagnosis and therapy. All resectable patients having histologically confirmed stage IB-IIIA non-small cell lung cancer(NSCLC) will be enrolled in the PROMOLE study, a related and ongoing observational prospective clinical study, for tissue sampling. A large biobank of lung cancer samples and the corresponding healthy tissues and biological components (ie, blood, stools, etc.) with complete clinical, pathological and molecular information will be collected. The project will lay the basis of a knowledge hub and qualified technology aimed not only at answering the medical and scientific community's questions, but also meant to be useful to individual patients by predicting the response to adjuvant and second-line drugs in case of relapse of the disease.

  Study EGAS00001007219

• The Human Pancreas Analysis Program (HPAP)

  The past decade has seen a dramatic improvement in our ability to phenotype and molecularly profile human tissues with unprecedented resolution at the genomic, epigenomic, protein, and functional levels. The Human Pancreas Analysis Program (HPAP), part of the Human Islet Research Network and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) through multiple NIH grants, is performing deep phenotyping of the human endocrine pancreas to better understand the cellular and molecular events that precede and lead to beta-cell loss and/or dysfunction in type 1 diabetes (T1D) and type 2 diabetes (T2D) as well as to accumulate, analyze, and distribute high-value data sets to the diabetes research community through the HPAP PANC-DB database (and additional details provided at that site). To this end, HPAP employs state-of-the-art technologies to perform comprehensive analyses of pancreas biology as it pertains to organ donors with T1D, autoantibody-positive donors without diabetes, donors with T2D, and control donors. Pancreas procurement and analyses take advantage of the expertise and extensive network of Organ Procurement Organizations (OPOs) and autoantibody screening centers established through the JDRF/The Lenona M. and Harry B. Helmsley Charitable Trust (HCT) – funded nPOD program. In contrast to nPOD, the major product provided by HPAP is not archived biomaterial subject to broad distribution, but rather, the delivery of extensive and high-quality molecular data sets to the diabetes research community in order to facilitate further discovery. Together, nPOD and HPAP are complementary programs that assist the diabetes community and afford the maximal opportunity for advancing knowledge about the pathogenesis of T1D and T2D.

  Study phs002465

• Prevention and Early Treatment of Acute Lung Injury (PETAL) Acetaminophen in Sepsis: Targeted Therapy to Enhance Recovery (ASTER) (PETAL ASTER-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. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL ASTER include plasma, urine and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis participants compared with placebo.Background: Acetaminophen (paracetamol) has many effects that can be beneficial in sepsis treatment, including analgesia, antipyresis, cyclooxygenase-2 inhibition, as well as a potent and specific hemoprotein reduction that can block hemoglobin-induced oxidation of lipids and other substrates. The majority of sepsis participants experience elevated circulating cell-free hemoglobin levels, which is associated with development of organ dysfunction including acute respiratory distress syndrome (ARDS) and death.Acetaminophen has been found in observational studies to be associated with improved survival in critically ill sepsis participants with elevated plasma cell-free hemoglobin, and small clinical trials have had positive sepsis participant outcomes such as reduced plasma biomarkers of lipid peroxidation and improved kidney function. However, a large, randomized trial of acetaminophen administration for treatment of fever in participants with suspected infection did not show a mortality benefit. The NHLBI PETAL Network initiated ASTER as a larger phase trial to examine the utility of plasma cell-free hemoglobin level as a biomarker for future sepsis trials and whether acetaminophen would increase the number of days alive and free of organ support for participants with sepsis and respiratory or circulatory organ dysfunction. Participants: A total of 447 participants were enrolled and randomized, 227 to the acetaminophen arm and 220 to the placebo arm. Data from 40 participants who were randomized to the Vitamin C arm, which was stopped early (see Design section below), is also included.Design: ASTER was a phase 2b multicenter, randomized, double-blind trial. The study originally had a 3-arm platform trial in which participants were randomized 1:1:1 to treatment with intravenous acetaminophen, vitamin C, or a common placebo. The vitamin C arm of the trial was stopped after enrolling 79 participants due to external clinical trial data for vitamin C.Participants randomized to the acetaminophen arm received acetaminophen at the dose of 1 g in 100 mL diluent (or 15 mg/kg if actual body weight was Conclusions: Intravenous acetaminophen was considered to be safe but did not significantly improve days alive and free of organ support in critically ill sepsis participants. There was no significant interaction between cell-free hemoglobin levels and acetaminophen.

  Study phs003900

• 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

• Center for Common Disease Genomics [CCDG] - Cardiovascular: TexGen

  Cardiovascular disease (CVD), especially coronary heart disease, heart failure and cerebrovascular disease remain the leading causes of death in men and women across all race groups in the United States. Substantial evidence exists for genetic factors underlying CVD risk, and their discovery offers an opportunity to enhance understanding of disease mechanisms, to provide specific diagnostic and prognostic indicators, and to identify novel therapeutic targets. The Centers for Common Disease Genomics (CCDG) are a large-scale genome sequencing effort undertaken as a collaboration to identify rare risk and protective alleles for common chronic diseases, with a current focus on early onset heart disease, hemorrhagic stroke, and autism. In this study, whole genome sequencing (WGS) was performed in 6,146 individuals with any personal or family history of CVD from the TexGen study who were recruited from several institutions in the Texas Medical Center located in Houston, Texas. The participants included patients who were admitted with a variety of diagnoses including acute coronary syndromes, strokes, and transient ischemic attacks, or who underwent percutaneous coronary interventions or coronary artery bypass grafting (CABG) (Virani SS et al. Am J Cardiology 107:1504-1509, 2011). Patients in the TexGen cohort with a confirmed diagnosis of acute coronary syndrome (ACS) or CABG when discharged from the hospital between 2001-2008 were eligible for a follow-up study of recurrent myocardial infarction (Virani SS et al. Circulation J 76:950-956, 2012), while those presenting with ACS beginning in 2007 were recruited for an investigation of the role of depressive symptoms in the risk of major adverse coronary events (Sanner J et al. Biol Res Nurs 20:168-176, 2018). In addition, the initial criterion for enrollment in a third TexGen sub-study undertaken between 2007 and 2013 was the occurrence of premature acute myocardial infarction in men ≤ 50 years and women ≤ 55 years in order to establish a blood sample collection resource with the intention of localizing genes that contribute to disease risk. This definition was later expanded to include individuals with a clinical history of premature coronary heart disease such as CABG or percutaneous coronary interventions.

  Study phs003010