Search Results - EGA European Genome-Phenome Archive

Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus Trial (The MILES Trial)

Lymphangioleiomyomatosis (LAM) is an uncommon, progressive, cystic lung disease that predominantly affects young women. It is believed to be caused by defects within cellular pathways that regulate nutrient uptake, cell size, cell migration, and cell proliferation. The disease is caused by mutations in tuberous sclerosis complex (TSC) genes. Individuals with Lymphangioleiomyomatosis (LAM) often experience pneumothorax and chylothorax, as well progressive loss of lung function. Lymphangioleiomyomatosis (LAM) is frequently fatal and existing therapies for the disease have not proven effective. Lung transplantation can be considered as a last option, but alternative treatments are needed. Sirolimus is an immunosuppressive drug that is often used in people who have had kidney transplants. It directly affects the genetic pathway that causes Lymphangioleiomyomatosis (LAM). This study will evaluate the safety and effectiveness of sirolimus in stabilizing or improving lung function in people with Lymphangioleiomyomatosis (LAM). Individuals interested in participating in this 2-year, double-blind study will first report to the study sites for pulmonary function testing to determine their eligibility for participation. Participants deemed eligible will be randomly assigned to receive either sirolimus or placebo for 1 year. Sirolimus or placebo will be administered in 2 tablet doses (2 mg for sirolimus) for the duration of the study. Study visits will occur at baseline, Week 3, every 3 months for 12 months, and Months 18 and 24. Study visits will include a physical exam, questionnaires, a pregnancy test, blood and urine collection, and functional lung tests. A 6-minute walk test will occur at most study visits; a chest x-ray will be taken at baseline and Month 24; and a volumetric computed tomography scan will occur at baseline Month 12, and Month 24. Adverse events, medication side effects, and lung function will be assessed at each visit.

Study phs000605

Regulatory T cell transcriptomic reprogramming characterizes adverse events by checkpoint inhibitors in solid tumors

Tregs were sorted as CD4+CD25+CD127- cells from peripheral blood of patients with advanced metastatic melanoma, stage III(B-D)-IV, who were receiving treatment with anti-PD1 (n =26); and patients with kidney, non-small cell lung, liver and bladder cancer who were receiving treatment with anti-PD1. RNA was extracted and polyA libraries were prepared using the Illumina Truseq sample preparation kit v.2. Single-end sequencing was performed on NextSeq500.

Dataset EGAD00001006415

Mitochondrial DNA sequencing of human iPSC, parental cells, and iPSC derived cardiomyocytes

Dataset contains whole mitochondrial DNA sequencing data in fastq format (Illumina MiSeq paired-end) of 62 samples, in total. Those samples include sequencing data of the endothelial cell populations of 10 different donors and of 26 early-passage iPSC clones derived thereof. Moreover, the dataset contains the data of 7 of those iPSC clones sequenced additionally in passage 30 and 50, each. Lastly, 4 iPSC clones were sequenced during directed cardiomyocyte differentiation, each at day 0, 5, and 15 of differentiation.

Dataset EGAD00001008021

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

PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice

The genetic causes of oocyte meiotic deficiency (OMD), a form of primary infertility characterised by the production of immature oocytes, remain largely unexplored. Using whole exome sequencing, we found that 26% of a cohort of 23 subjects with OMD harboured the same homozygous nonsense pathogenic mutation in PATL2, a gene encoding a putative RNA-binding protein. Using Patl2 knockout mice, we confirmed that PATL2 deficiency disturbs oocyte maturation, since oocytes and zygotes exhibit morphological and developmental defects respectively. PATL2's amphibian orthologue is involved in the regulation of oocyte mRNA as a partner of CPEB. However, Patl2's expression profile throughout oocyte development in mice, alongside colocalisation experiments with Cpeb1, Msy2 and Ddx6 (three oocyte RNA-regulators) suggest an original role for Patl2 in Mammals. Accordingly, transcriptomic analysis of oocytes from WT and Patl2-/- animals demonstrated that in the absence of Patl2, expression levels of a select number of highly relevant genes involved in oocyte maturation and early embryonic development are deregulated. In conclusion, PATL2 is a novel actor of mammalian oocyte maturation whose invalidation causes OMD in humans.

Study EGAS00001002903

Whole Exome Sequencing of Chronic Lymphocytic Leukemia

The somatic genetic basis of chronic lymphocytic leukemia (CLL), a common and clinically heterogenous adult leukemia, remains poorly understood. Massively parallel sequencing technology now provides a method for systematic discovery of genetic alterations that underlie disease, and for uncovering new therapeutic targets and biomarkers. In study version 2 we presented a dataset consisting of DNA sequencing from 169 CLL samples (with matched germline controls). Samples were collected from patients displaying a wide range of characteristics representing the broad clinical spectrum of CLL. Understanding the mutational landscape of CLL provides a starting point for systematic analyses to address fundamental questions in CLL, including how mutated genes alter cellular networks and phenotypes, and thereby contribute to disease heterogeneity. Intratumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of >100 primary chronic lymphocytic leukemias (CLLs; data presented in study version 3). Compared with 26 normal B cell samples, CLLs consistently displayed higher intrasample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylationdisorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to that of genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories.

Study phs000435

EstMB cohort participants sequenced with MGISEQ-2000 platform

Participants collected a fresh stool sample immediately after defecation using a sterile Pasteur pipette and placed it in a 15 mL conical polypropylene tube. They were instructed to collect the sample as close as possible to their study center visit. Samples were transported and stored at −80 °C until DNA extraction. Microbial DNA was extracted from 200 mg of stool using a QIAamp DNA Stool Mini Kit (Qiagen), following manufacturer's instructions, after all samples were collected. DNA was quantified using a Qubit 2.0 Fluorometer with a dsDNA Assay Kit (Thermo Fisher Scientific). Library preparation and circularization of equimolarly pooled libraries were done with MGIEasy FS DNA Library Prep Set (MGI Tech Co, Ltd, Shenzhen, China) according to the standard protocol. The sequencing was performed with MGISEQ-2000 High-throughput Sequencing Set (FCL PE150) according to the manufacturer’s instructions (MGI Tech, Shenzhen, China)

Dataset EGAD50000002213

WES Elucidation of Pathogenetic Mechanisms for Immune System Disorders and NIAID Pilot of Genetic Incidental Finding Management

Background: - There are many types of immune disorders. These range from rare immune deficiencies to allergies to autoimmune disease like rheumatoid arthritis. Genes are the instructions our body uses to work and develop. A new technology called whole exome sequencing may help find the cause of these disorders. Whole exome sequencing is a way to look at many genes at once for errors. Researchers hope to find new gene changes that lead to immune disorders. Additionally, researchers are interested in finding the best way to manage unexpected but important findings by whole exome sequencing. Objectives: - To better understand genetic causes of immune system disorders. Also, to better understand people s thoughts and feelings about immune system disorders and new genomic testing. Eligibility: - People ages 0 100 with an immune disorder or a relative with an immune disorder. People must be at least 2 to be evaluated at the NIH clinical center. People must be at least 12 to do the survey/interview portion of the study. Design: Participants will have their genes sequenced. They may be asked for a new sample of blood. If participants cannot come for a study visit, they can have a blood sample collected by their local lab or doctor and sent by mail. Researchers may or may not find the cause of the participant s immune disorder. Participants will learn that information. Some participants may be asked to return to NIH to get results and have more tests. Researchers may share information with other studies. The data will be anonymous. For the survey part of the study, participants will answer questions about their or their relative s immune disorder. They will also answer about their thoughts and feelings about genomic testing. Some participants will be asked for a brief interview to ask more about the survey topics. There may be more follow-up after several months. From clinicaltrials.gov

Study phs001561

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

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

Study EGAS00001006902

QUANTitative Chest Computed Tomography UnMasking Emphysema Progression in Alpha-1 Antitrypsin Deficiency

AAT deficiency is a genetic disorder associated with emphysema. Spirometry, the lung function test that measures how well the lungs exhale air, is used to diagnose and track the progression of emphysema. Some studies have suggested that forced expiratory volume in 1 second (FEV1) measurements, a type of spirometry test, may lack accuracy in detecting disease progression in cases of severe AAT deficiency. Another method, high resolution chest CT scans, may be more accurate at measuring the progression of emphysema. The purpose of this study is to determine if high resolution CT scans are better at detecting the progression of emphysema than lung function tests. Results from this study may lead to the development of a more accurate way to assess lung tissue loss and may improve the understanding of lung destruction in AAT deficiency. This study will last 4 years and will enroll people with AAT deficiency who have nearly normal lung function test results. Study visits, each lasting about 4 hours, will occur at baseline and months 6, 12, 18, 24, and 36. At each visit, participants will undergo lung function tests, a CT scan, blood collection, and a physical exam. Female participants will have urine collected for a pregnancy test. All participants will also complete questionnaires to assess health status and lung function. Study researchers will call participants every 2 months to collect information on lung disease symptoms and medication changes.

Study phs000698

Cerebrospinal fluid cfDNA sequencing for classification of central nervous system glioma

Primary central nervous system (CNS) gliomas can be classified by characteristic genetic alterations. In addition to solid tissue obtained by surgery or biopsy, cell-free DNA (cfDNA) derived from cerebrospinal fluid (CSF) is an alternative source of material for genomic analyses. Experimental design: We performed targeted next-generation sequencing (NGS) of CSF cfDNA in a representative cohort of 85 patients presenting with with suspicion of primary or recurrent glioma at two neurooncological centers. Copy-number variation (CNV) profiles, single nucleotide variants (SNVs), and small insertions/ deletions (indels) were combined into a molecular-guided tumor classification. Comparison with the solid tumor was performed for 38 cases with matching solid tissue available. Results: Cases were stratified into four groups: glioblastoma (n = 32), other glioma (n = 19), non-malignant (n = 17) and no confirmed diagnosis available (n = 17). We introduce a molecular-guided tumor classification, enabling identification of tumor entities and/ or cancer specific alterations in 75.0 % (n = 24) of glioblastoma and 52.6 % (n = 10) of other glioma cases. The overlap between CSF and matching solid tissue was highest for CNVs (26-48 %) and SNVs at pre-defined gene loci (44 %), followed by SNVs/indels identified via uninformed variant calling (8-14 %). A molecular-guided tumor classification was made 23.5 % (n = 4) of cases with no confirmed diagnosis available. Conclusions: We developed a workflow for targeted sequencing of CSF cfDNA as well as a strategy for interpretation and reporting of sequencing results based on a molecular-guided tumor classification in glioma.

Study EGAS50000000060

single cell RNA-seq of peripheral blood from analysis in infants with MLL-rearranged Acute Lymphoblastic Leukemia

This dataset contains two experiments. 1) Single cell RNA-seq of peripheral blood diagnostic samples from patients with MLL-rearranged infant ALL that underwent relapse or not (samples ending in R relapsed, samples ending in N did not), sequenced with SORT-seq (see cell systems, 2016, doi:10.1016/j.cels.2016.09.002). For some of the patients, multiple indipendent plates were produced (each plate is a sample). Barcode-well correspondence can be found here: https://bitbucket.org/princessmaximacenter/sharq/src/master/data/celseq2_bc384-v4.csv . 2) Single cell RNA-seq of peripheral blood diagnostic samples from patients with MLL-rearranged infant ALL that underwent relapse or not (samples ending in R relapsed, samples ending in N did not), sequenced with10x Genomics Version 2.

Dataset EGAD00001007752

Metabolic reprogramming towards OXPHOS identifies a novel therapeutic target for mantle cell lymphoma

Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomics analysis of clinical specimens, we show that metabolic reprogramming towards oxidative phosphorylation (OXPHOS) and glutaminolysis is associated with therapeutic resistance to the Bruton’s tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma (MCL), an incurable B-cell lymphoma with poor clinical outcomes. Inhibition of OXPHOS with a novel, clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in significant growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies.

Dataset EGAD00001004577

86 paired-end MiSeq 16S rRNA sequencing samples

We compared bacterial communities in breast milk from teen (≤19 yr, n = 26) vs. adult (>19 yr, n = 56) mothers, normal weight (BMI 18.5-24.9, n = 63) vs. overweight (BMI ≥ 25, n = 19) mothers, primiparous (parity = 1, n = 41) vs. multiparous (parity > 1, n = 44), early (5-46d postpartum, n = 39) vs. established lactation (4-6 mo postpartum, n = 45), breastfeeding (EBF: PBF, n = 72) vs. mixed feeding (n = 11) and mothers with (Na/K ratio < 0.6, n = 75) and without SCM (Na/K ration ≥ 0.6, n = 10).

Dataset EGAD00001004160

Neoadjuvant immune checkpoint blockade in mismatch-repair proficient colon cancers

Immune checkpoint blockade has led to paradigm shifts in the treatment of various tumour types, yet limited efficacy has been observed in patients with metastatic mismatch-repair proficient (pMMR) colorectal cancer. Here we report an in-depth analysis of patients with early-stage pMMR colon cancer from the phase II NICHE study (ClinicalTrials.gov: NCT03026140). A total of 31 patients received neoadjuvant treatment of nivolumab plus ipilimumab followed by surgery. The response rate was 26% and included six patients with a major pathological response (≤10% residual viable tumour). One patient with an ongoing clinical complete response did not undergo surgery. Responses were observed despite a low tumour mutational burden in all tumours, while chromosomal genomic instability scores were significantly higher in responders compared to non-responders. Responding tumours were more likely to be TP53 mutant, KRASG12 wildtype and had significantly higher baseline expression of proliferation signatures and TCF1. Imaging mass cytometry also revealed a higher percentage of Ki-67+ cancer and Ki-67+ CD8+ T cells in responders compared to non-responders. Meanwhile, in non-responders, we observed an enrichment for an inflamed-fibrotic microenvironment associated with TGF-β expression, hinting towards possible resistance mechanisms. These results provide a comprehensive analysis of response to neoadjuvant ICB in early-stage pMMR colon cancers and identify potential biomarkers for patient selection.

Study EGAS50000000856

JMML targeted sequencing (2013)

Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations (Chang, Dvorak et al. 2014). Clinical evolution is heterogeneous, with acute myeloid leukemia (AML) transformation in 1/3 of cases and frequent relapses after hematopoietic-stem-cell transplantation (HSCT), although some patients experience spontaneous remission (Locatelli, Nollke et al. 2005; Matsuda, Shimada et al. 2007; Takagi, Piao et al. 2013; Locatelli and Niemeyer 2015). The initiating lesion incompletely predicts outcome, suggesting the involvement of additional mutations. Genetic profiling of a large JMML cohort (n=118), including whole-exome sequencing (WES) in 30 cases, uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38/case/Mb) and restricted to sporadic (47/78; 60%) or NF1-associated (8/8; 100%) JMML. Multiple concomitant genetic hits were identified targeting the RAS pathway in 13/78 (17%), RAC2D63V, which activates the PI3K/PDK1/AKT and the mTORC2 pathways, and a novel pathway for JMML, the polycomb repressive complex 2 (PRC2), in 26/78 (33%) of the sporadic JMML cases. Interestingly, PRC2 imbalance was recently shown to synergize with RAS activation (De Raedt, Beert et al. 2014). JMML outcome was associated to the mutational profile, suggesting a dose-dependent effect for RAS-pathway activation, distinguishing very aggressive JMML rapidly progressing to AML.

Study EGAS00001001324

Unraveling the transcriptomic profile of utero-tubal lavage fluid of ovarian cancer patients

The majority of ovarian cancers are diagnosed at an advanced stage and have a high mortality rate. Current screening strategies fail to improve prognosis because markers of early stage disease are lacking. This medical need justifies the search for biomarkers enabling early detection of ovarian cancer. In this study, we explore the extracellular transcriptome of utero-tubal lavage fluid obtained from 26 ovarian cancer patients and 48 controls using messenger RNA (mRNA) capture and small RNA sequencing. Because of its contact with the fallopian tube and the ovaries, collection of utero-tubal lavage might be the preferred non-invasive method to identify localized lesions compared with analyses based on peripheral blood samples. We observed an enrichment of ovarian and fallopian tube specific messenger RNAs in utero-tubal lavage fluid compared to other human biofluids. Over 300 mRNAs and 41 miRNAs were upregulated in ovarian cancer samples compared with controls. Upregulated genes were enriched for genes involved in cell cycle activation and proliferation, hinting at a tumor derived signal. In conclusion, we provide proof-of-principle that mRNA capture sequencing of utero-tubal lavage fluid is technically feasible, and that the extracellular transcriptome of utero-tubal lavage should be further explored in larger cohorts to assess the diagnostic value of the biomarkers identified in this study.

Study EGAS00001005498

Cell-free DNA fragmentation patterns and personalized sequencing reveal circulating tumor DNA in urine and plasma of glioma patients

Glioma-derived cell-free DNA (cfDNA) is challenging to detect using liquid biopsy as levels in body fluids are low. We determined the glioma-derived DNA fractions in tumor biopsies, in cerebrospinal fluid (CSF), plasma and urine samples, using deep sequencing of personalized capture panels. By sequencing cfDNA across thousands of mutations identified individually in each patient’s matched tumor we detected tumor-derived DNA in plasma (10/12) and urine samples (8/11). The median tumor fraction was 6.4x10-3 in CSF, 3.1x10-5 in plasma and 4.7x10-5 in urine. We identified a shift in the size distribution for mutant cfDNA fragments in these body fluids. Next, we analyzed cfDNA fragment sizes with paired-end shallow whole genome sequencing (WGS) in urine samples from 35 patients with gliomas, 8 individuals with non-malignant brain disorders, and 26 controls (n=69 individuals, 96 samples). cfDNA in urine of glioma patients was significantly more fragmented compared to urine from patients with non-malignant brain disorders (t-test, p=1.7x10-2) and compared to urine of controls (t-test, p=5.2x10-9). The proportion of DNA fragments <60 bp was higher in glioma patients urine and could be used for classification (AUC=0.93). Machine learning models integrating fragment lengths could identify urine samples from glioma patients (AUC=0.97 in cross-validation).

Study EGAS00001004355

A Phase I/II Trial of Sirolimus (Rapamune®) and Cyclosporine in Patients with Refractory Aplastic Anemia

The most successful treatment for aplastic anemia is bone marrow transplantation. However, few patients are eligible for this procedure. For others, treatment usually consists of immunosuppressive agents, such as antithymocyte globulin (ATG) and cyclosporine. Unfortunately, even with immunosuppressive therapy, relapse is common. New combinations of medications may offer alternative and more effective treatment options. Sirolimus and cyclosporine are two drugs routinely used to suppress the immune system and prevent rejection in patients who have received organ transplants. While cyclosporine has been proven effective for treating aplastic anemia, sirolimus has not been tested for this disease. This study will evaluate the safety and efficacy of sirolimus in combination with cyclosporine for treating individuals with aplastic anemia that have not responded to other treatments. This study will last at least 6 months. Participants will first be screened to verify diagnosis of aplastic anemia. The screening will include a physical examination, blood test, bone marrow biopsy from the pelvic bone, and review of medications and medical history. Individuals who are eligible will then start the first treatment period. Participants will receive two medications: cyclosporine will be taken twice a day and sirolimus will be taken once a day. Depending on side effects, the dose of either drug may be temporarily stopped or lowered. On Day 1, blood will be drawn and females will undergo a pregnancy test. Subsequent study visits will occur weekly for the first month, every 2 weeks for 2 months, and then once a month for the remainder of the study. Each visit will include a physical examination, vital sign assessment, and review of side effects and medications. Blood tests will be performed weekly for the first 3 weeks, and then every 2 weeks. After 6 months of treatment, if a participant has shown improvements in disease status without major side effects, the treatment will continue. Over time the doses may be lowered. If a participant has not improved while on the study medication, treatment will stop at 6 months. Whenever treatment is discontinued, the participant will again undergo a physical examination, blood tests, and bone marrow biopsy.

Study phs000695

NHLBI TOPMed: Genetic Epidemiology Network of Arteriopathy (GENOA)

The Genetic Epidemiology Network of Arteriopathy (GENOA) is one of four networks in the NHLBI Family-Blood Pressure Program (FBPP). GENOA's long-term objective is to elucidate the genetics of target organ complications of hypertension, including both atherosclerotic and arteriolosclerotic complications involving the heart, brain, kidneys, and peripheral arteries. The longitudinal GENOA Study recruited European-American and African-American sibships with at least 2 individuals with clinically diagnosed essential hypertension before age 60 years. All other members of the sibship were invited to participate regardless of their hypertension status. Participants were diagnosed with hypertension if they had either 1) a previous clinical diagnosis of hypertension by a physician with current anti-hypertensive treatment, or 2) an average systolic blood pressure = 140 mm Hg or diastolic blood pressure = 90 mm Hg based on the second and third readings at the time of their clinic visit. Only participants of the African-American Cohort were sequenced through TOPMed. The Family Blood Pressure Program (FBPP), GENOA's parent program, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators created a single confederation with program-wide and network-specific goals. Comprehensive phenotypic data for GENOA study participants are available through dbGaP phs001238.

Study phs001345

Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE-BioLINCC)

Accessing Data Please refer to “Authorized Access” below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP. Objectives To test whether pulmonary artery catheter use was safe and could improve clinical outcomes in participants hospitalized with recurrent heart failure. Background Pulmonary artery catheters have been used to guide adjustment of therapy in multiple settings, but recent studies have raised concern that pulmonary artery catheters may lead to increased mortality in hospitalized participants. Participants A total of 433 participants at 26 sites were enrolled, and randomly assigned to receive therapy guided by clinical assessment and the pulmonary artery catheter or clinical assessment alone. Patients with acute decompensation in which the attending heart failure physician considered pulmonary artery catheterization (PAC) was required or likely to be required within the next 24 hours were entered into a PAC registry. A total of 439 patients were added to the registry. Conclusions Therapy to reduce volume overload during hospitalization for heart failure led to marked improvement in signs and symptoms of elevated filling pressures, with or without the pulmonary artery catheter. Addition of the pulmonary artery catheter to careful clinical assessment did not impact overall mortality and hospitalization. Future trials should test noninvasive assessments with specific treatment strategies that could be used to better tailor therapy for both survival time and survival quality as valued by participants. (Binanay, C. et al., JAMA, 2005)

Study phs003782

Non-coding mutations reveal cancer driver cistromes in luminal breast cancer

Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and non-coding cancer driver plexuses from somatic mutations. However, differentiating between driver and passenger events among non-coding genetic variants remains a challenge to understand the etiology of cancer and inform the delivery of personalized cancer medicine. Herein, we reveal enrichment of non-coding mutations in cis-regulatory elements that cover a subset of transcription factors linked to tumor progression in luminal breast cancers. Using a cohort of 26 primary luminal ER+PR+ breast tumors, we compiled a catalogue of ~100,000 unique cis-regulatory elements from ATAC-seq data. Integrating this catalogue with somatic mutations from 350 publicly available breast tumor whole genomes, we identified four recurrently mutated individual cis-regulatory elements. By then partitioning the non-coding genome into cistromes, defined as the sum of binding sites for a transcription factor, we uncovered cancer driver cistromes for ten transcription factors, namely CTCF, ELF1, ESR1, FOSL2, FOXA1, FOXM1 GATA3, JUND, TFAP2A, and TFAP2C in luminal breast cancer. Nine of these ten transcription factors were shown to be essential for growth in breast cancer, with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of non-coding mutations over cis-regulatory elements concatenated into a functional unit drawn from an accessible chromatin catalogue derived from primary cancer tissues.

Study EGAS00001005235

Germline RUNX1 Variation and Predisposition to Childhood Acute Lymphoblastic

Somatic mutations of RUNX1, which encodes the myeloid and lymphoid transcriptional factor RUNX1, are common in both B- and T- acute lymphoid leukemia (ALL) and are associated with poor prognosis of T-ALL. However, there has been no comprehensive investigation of the pattern or prevalence of RUNX1 germline mutation in both B- and T-ALL. Here we report germline RUNX1 variants in 1.23% of B-ALL and 2.11% of T-ALL, identifying 31 unique variants in 62 B-ALL and 18 unique variants in 26 T-ALL children. The majority of frameshift and nonsense variants affected RUNX1 function in transcriptional regulation, hematopoiesis, and cellular proliferation. We identified JAK3 as the most frequent somatic mutation in T-ALL with RUNX1 variants. These results not only identify RUNX1 as a leukemia predisposition gene but also further underline the importance of germline genetic variants to the development of ALL

Study EGAS00001005403

NextGen Consortium: The iPSCORE (iPSC Collection for Omic Research) Resource for Studying the Impact of Genetic Variation on Molecular Phenotypes

The iPSC Collection for Omic Research (iPSCORE) Resource was created as part of the Next-Gen Consortium funded by NHLBI. The overarching purpose of the resource is to provide a large collection of human induced pluripotent stem cells (iPSCs) for use in studying the impact of genetic variation on molecular and physiological phenotypes. The resource has been used in a number of studies in the Dr. Kelly A. Frazer's Lab examining both the characteristics of human iPSCs and a variety of iPSC-derived cell types including cardiovascular progenitor cells (iPSC-CVPCs), pancreatic precursor cells (iPSC-PPCs), and retina pigment epithelium cells (iPSC-RPEs). We have shown that the iPSCs, CVPCs, and PPCs are suitable surrogate models to identify genetic factors active in early developmental processes because they exhibit fetal-like molecular properties. A total of 273 individuals have participated in the study, of which 222 have had iPSCs generated from fibroblasts. Of the 273 individuals, 181 are part of 55 families that include 24 monozygotic twin pairs and 5 dizygotic twin pairs, allowing for the incorporation of familial relationships into genetic analyses. Germline DNA has been sequenced from blood or fibroblast samples for all 273 individuals (available through dbGaP phs001325) and other genomic data (RNA-seq, DNA methylation, genotype arrays, ATAC-seq, H3K27ac ChIP-seq, HiC-seq) have been generated from the 222 iPSCs as well as derived cell types (available through dbGaP phs000924). QTL analyses were conducted for multiple omics data types and summary statistics are available through dbGaP phs0001325. Important note: Of the 273 individuals, 268 are consented for general research use and 5 are consented for cardiac research only. For detailed information about iPSCORE Collection including samples, methods used to generate the data, and how to access the datasets visit the Frazer lab website.The 222 well characterized iPSC lines that constitute the iPSCORE resource are available, please contact Dr. Kelly A. Frazer (kafrazer@health.ucsd.edu) if you are interested in obtaining the collection.

Study phs000924

Framingham Heart Study-Cohort (FHS-Cohort) - Imaging

The Framingham Heart Study (FHS) is a population-based, observational cohort study initiated in 1948 to prospectively investigate the determinants of cardiovascular disease to guide public health prevention. The FHS began by recruiting an Original Cohort of 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts, who had not yet developed overt symptoms of cardiovascular disease or suffered a heart attack or stroke. The Original cohort Exam 1 took place between 1948 and 1953. Since that time the cohort has had a total of 32 biennial exams (ending in 2014) and event follow-up through 2022. In 1971, the FHS added the Offspring cohort, comprising 5124 children whose parents were enrolled in the Original cohort and the spouses of the children. This cohort on average has been examined every three to four years. However, there was an eight year gap between Exam 1 and Exam 2 and a seven year gap between Exam 7 and Exam 8. The latest exam (10) was completed in 2022. In 2002, the transgenerational FHS design was facilitated with the recruitment of 4095 children of the Offspring cohort (Third Generation), and 103 spouses of the Offspring who were not previously enrolled in the study (New Offspring Spouses, NOS). These cohorts have completed 3 exams through 2019. To reflect the changing demographic characteristics of the greater Framingham community, the FHS additionally recruited and enrolled 2 cohorts comprising racial and ethnic minority groups, termed Omni-1 and Omni-2, (n = 506 and 410, respectively) in 1995 and 2002, respectively. These cohorts included individuals of African American, Hispanic, Asian, Indian, Native American, and Pacific Islander descent. The OMNI-1 cohort have completed 5 exams through 2022. The OMNI-2 cohort have completed 3 exams through 2019. Data available for request include Echocardiogram images, available from the following exams in each cohort. Original Cohort: exams 18-32; Offspring cohort: exams 3-10; Third Generation, NOS and OMNI-2 cohorts: exams 1-3; OMNI-1 cohort: exams 1-5.CT image data at one or two timepoints were added for 4427 participants in the offspring, third generation, and OMNI1 and OMNI2 cohorts.Summary level phenotypes for the Framingham Cohort study participants can be viewed at the top-level study page phs000007 Framingham Cohort. Individual level phenotype data and molecular data for all Framingham top-level study and substudies are available by requesting Authorized Access to the Framingham Cohort study phs000007.

Study phs003593

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