17284 results for "the best way to get coins in fc 26 Navštivte Buyfc26coins.com Společnost známá transparentními transakcemi..CQ2q"

in 36.88 milliseconds.

• Identification of cis-regulatory mutations generating de novo edges in personalized cancer gene regulatory networks

  The identification of functional non-coding mutations is a key challenge in the field of genomics. Here we introduce μ-cisTarget to filter, annotate and prioritize cis-regulatory mutations based on their putative effect on the underlying ‘personal’ gene regulatory network. We validated μ-cisTarget by re-analyzing the TAL1 and LMO1 enhancer mutations in T-ALL, and the TERT promoter mutation in melanoma. Next, we re-sequenced the full genome of ten cancer cell lines and used matched transcriptome data and motif discovery to identify master regulators with de novo binding sites that result in the up-regulation of nearby oncogenic drivers.

  Study EGAS00001002571

• Single-cell atlas of multiple myeloma and precursor diseases

  Single cell profiling of small cohorts of myeloma precursor disease patient samples including monoclonal gammopathy of unknown significance and smoldering multiple myeloma have shown diverse evolutionary patterns and immune changes that occur early in the disease process. Using scRNAseq and scBCRseq in a large cohort of fifty-three patients with myeloma precursor disease in comparison with myeloma and normal donors we describe the early genomic drivers of malignant transformation and describe their divergent clonal expansion in hyperdiploid compared to non-hyperdiploid samples. We describe intra-patient heterogeneity with potential therapeutic implications as well as the distinct evolution patterns (linear/branching) from myeloma precursor disease to myeloma. Finally, we describe the unique adaptations of the microenvironment as a response to distinct genomic changes in myeloma cells. These results further our knowledge to characterize myeloma precursor disease evolution, inform individual patient progression risk stratification and identify potential biomarkers that could be clinically exploited.

  Study EGAS00001006694

• NHLBI TOPMed: Genetic Study of Atherosclerosis Risk (GeneSTAR)

  GeneSTAR began in 1982 as the Johns Hopkins Sibling and Family Heart Study, a prospective longitudinal family-based study conducted originally in healthy adult siblings of people with documented early onset coronary disease under 60 years of age. Commencing in 2003, the siblings, their offspring, and the coparent of the offspring participated in a 2 week trial of aspirin 81 mg/day with pre and post ex vivo platelet function assessed using multiple agonists in whole blood and platelet rich plasma. Extensive additional cardiovascular testing and risk assessment was done at baseline and serially. Follow-up was carried out to determine incident cardiovascular disease, stroke, peripheral arterial disease, diabetes, cancer, and related comorbidities, from 5 to 30 years after study entry. The goal of several additional phenotyping and interventional substudies has been to discover and amplify understanding of the mechanisms of atherogenic vascular diseases and attendant comorbidities.

  Study phs001218

• INdiana GENomics: Implementing an Opportunity for the Under Served (INGENIOUS)

  The INGenious trial planed to enroll a total of 6,000 patients, with 2,000 patients assigned to a pharmacogenetic testing arm and 4,000 to a control arm who will be followed, but not tested. It is randomized between an intervention arm and one that receives no intervention in order that the genotyped group can be compared with one in which undisturbed, routine clinical care is carried out in patients taking the same drugs. Both arms will be followed for a year after being prescribed a targeted medication. Patients randomized into the intervention arm that are prescribed one or more of the 27 targeted index medication will receive pharmacogenomic testing using a custom micro-array measuring 43 Single nucleotide polymorphisms in 14 genes. The study is being conducted by the Indiana University School of Medicine and the Indiana University Institute of Personalized Medicine in collaboration with the Eskenazi and Indiana University Health Systems and will evaluate the economic and clinical outcomes associated with embedding a pharmacogenomics program in a system that serves as the primary health care safety-net in Indianapolis, Indiana. By successfully implementing a pharmacogenomics program and integrating it with the Electronic Health Record and Clinical Decision Support system, physicians will be able to optimize patient care by delivering tailored therapeutic decisions based on the patient's individual genetics.

  Study phs001701

• GAW16 Framingham and Simulated Data

  Important links to apply for individual-level data Genetic Analysis Workshop Instructions to Request Authorized Access Data Use Certification Requirements (DUC) Apply here for controlled access to individual level data Research Use Statement Questions regarding GAW16 should be directed to Vanessa Olmo at vanessa@business-endeavors.com. Problem 2: Description of the Framingham Heart Study In GAW16, we use data drawn from the Framingham Heart Study. The Framingham Heart Study — under the direction of National Heart, Lung, and Blood Institute; NHLBI — began in 1948 with the recruitment of adults from the town of Framingham, Massachusetts. At the time, little was known about the general causes of heart disease and stroke, but the death rates for cardiovascular disease (CVD) had been increasing steadily since the beginning of the 20th century and had become an American epidemic. The Framingham Heart Study is now conducted in collaboration with Boston University. The objective of the Framingham Heart Study was to identify the common factors or characteristics that contribute to CVD by following its development over a long period of time in a large group of participants who had not yet developed overt symptoms of CVD or suffered a heart attack or stroke. Between 1948 and 1953 the researchers recruited 5,209 subjects (2,336 men and 2,873 women) between the ages of 29 and 62 from the town of Framingham, Massachusetts and began the first round of extensive physical examinations and lifestyle interviews that they would later analyze for common patterns related to CVD development. Subjects were recruited from lists of addresses recorded for the town. Two out of every three households were approached for participation in the study. While there was no intention to recruit families for family studies, the plan was to recruit all household members in the ages 30-60 within each house that was selected for study. Hence, many biologically related individuals were recruited, including 1644 spouse pairs. Since 1948, these participants have returned to the study every two years for a detailed medical history, physical examination, and laboratory tests. Now in 2008 at 60 years of follow up, there remain about 500 participants from this cohort. Between 1971 and 1975 the study enrolled a second-generation group — 5,124 of the original participants' children and the spouses of these children — to participate in similar examinations. 2,616 subjects are offspring of the original spouse pairs and 34 are stepchildren. A total of 898 offspring are children of cohort members where only one parent was a study participant and 1,576 are spouses of the offspring. The Offspring Cohort has been followed every four years through 2001 (except between Exams 1 and 2 with an intervening 8 years) using protocols similar to those used for study of the Original Cohort. Between 2002 and 2005 the study enrolled the third generation (Gen3) of the Framingham Heart Study - 4095 offspring of the second generation. None of their spouses were recruited. An additional 103 parents of this third generation, who were not recruited between 1971 and 1975, were also recruited at this time. The latter group is not included in the GAW16 data. With the recruitment of this third generation, the study has increasingly focused on genetic factors associated with the development of cardiovascular disease and its associated risk factors. To date, there is only one examination of this generation of participants. A description of the recruitment of this third generation and comparison with the earlier generations at their initial recruitment is presented in Splansky GL et al., 2007. Further information on the Study can be found at http://www.nhlbi.nih.gov/about/framingham/index.html. Genome-wide Dense SNP Scan in Framingham Heart Study Genetic studies did not begin in the FHS until the 1990s. In the late 1980s and through the 1990s DNA was extracted from blood samples of surviving FHS participants. In 2007, the FHS entered a new phase with the conduct of genotyping for the FHS SHARe (SNP Health Association Resource) project, for which dense SNP genotyping was performed using approximately 550,000 SNPs (GeneChip® Human Mapping 500K Array Set and the 50K Human Gene Focused Panel) in 10,775 samples (some duplicates) from the three generations of subjects (including over 900 pedigrees). Affymetrix conducted all genotyping for the FHS SHARe project, using the 250K Sty, 250K Nsp, and the supplemental 50K platforms. Eighty-nine percent of the DNA samples were collected during the 1990s. To maximize the power of the study, we also extracted DNA from 1133 blood samples, drawn from subjects who had no DNA, to include in the SHARe project. These samples had been sitting in our refrigerators for some time, a few as far back as the 1970s. We refer to these DNA samples as the legacy samples. These samples had a higher failure rate in the genotyping process (40%) than the other eighty-nine percent (3%). Affymetrix invoked its own criteria for a sample to succeed in genotyping. All non-legacy samples must succeed on all three platforms, while legacy samples needed to pass on at least one platform. When a sample failed, additional attempts were made. Samples that repeatedly failed 2-4 times were called failures. Other samples failed due to issues of genotyped sex identification not matching our records or low SNP concordance among SNPs common across arrays or contamination. Eighty-nine percent of the legacy samples for which genotyping results are available passed all three platforms. The genotyping data from the 10,043 samples from 9354 subjects that passed the Affymetrix criteria were additionally checked for gender consistency and consistency with family structure, resulting in genotyping data for 9,274 participants in FHS SHARe. Genotype calls were made with the BRLMM algorithm. The SHARe database is housed at the National Center for Biotechnology Information database of genotypes and phenotypes (NCBI dbGaP) and contains all ~550,000 SNPs. This genome-wide dense SNP scan and a subset of phenotypes from the Framingham Heart Study are the focus of the Genetic Analysis Workshop 16. Further information on the specific variables in the Problem 2 dataset can be found by clicking on the Documents tab at the top of the page. Problem 3: Description of the Simulated Data Set The focus of this simulation is gene discovery in genome-wide association scans (GWAS). The Framingham Heart Study data set (distributed as "Problem 2") is the basis for the FHS* simulated data. The pedigree structures are derived from the data distributed for Problem 2, and we distribute an accompanying triplet file (triplet_sim) containing person ID, father ID, mother ID, to ensure the identical subjects, pedigrees, and singletons are used in the simulated data analysis. Consistent with standard practice, founders and singletons are designated as subjects with both fshare and mshare equal to zero (missing). The simulated data includes a total of 6,479 subjects with both phenotype and genotype data, in 942 pedigrees distributed among 3 generations and 188 singletons. Data inclusion is consistent with the subjects' consent for use by both for-profit and not-for-profit researchers. The genotypes for all Problem 3 replicates are fixed as measured and distributed for Problem 2 for both the genomewide scan and the additional candidate gene SNPs, for a total of approximately 550,000 SNPs (GeneChip® Human Mapping 500K Array Set and the 50K Human Gene Focused Panel). Thus, to analyze the Problem 3 simulated data you also will need to download the Problem 2 genotypes. Note that there are slight discrepancies in counts between Problems 2 and 3 due to a change in consents between the two datasets. Several phenotypes that contribute to coronary heart disease (CHD) were simulated for all individuals with genotypes across three different time points, 10 years apart. All genotyped individuals have complete data; the effects of missing values can be investigated by user-specified missing value patterns. There are 200 longitudinal datasets created, based on the generating model, and each replication is found in a separate dataset. We suggest that if only one replication is to be analyzed, that it be replication 1 to enable more precise comparisons among analytical approaches. The 'shareid' will allow you to merge the simulated phenotype data with the Problem 2 genotype data, and reconstruction of the pedigrees using the distributed 'triplet_sim' file or for larger families' relationships with the triplet distributed with the Problem 2. The simulated data problem is further described in the associated readme file, and a data dictionary is provided defining all the variables. For disclosure of the generating model for these data, please contact Jean MacCluer at jean@sfbrgenetics.org.

  Study phs000128

• A Whole Genome Association Search for Type 2 Diabetes Genes in African Americans

  Over 2.8 million African Americans have type 2 diabetes mellitus (T2DM). This represents approximately 13% of the African American population and a significant proportion of the 21 million Americans living with diabetes. On average, an African American individual is twice as likely to have T2DM as a European American peer. Our research group has been actively involved in the study of African American diabetes genetics for over 15 years. We hypothesize that genes contributing to the development of T2DM in African Americans exist and can be located using modern molecular genetic methods. With the exception of TCF7L2(Transcription factor 7-like 2) evidence to date suggests variants that contribute T2DM risk in European-derived populations are not significant contributors to African American T2DM risk. We have performed a SNP-based Whole Genome Association (WGA) analysis on the Affymetrix 6.0 in a case control population of over 1000 African American T2DM cases and over 1000 non-diabetic controls. The DNAs have been collected from participants using uniform criteria from North Carolina and neighboring states. Genotype data will be subjected to extensive genetic analysis with the goal of defining a priority list of SNPs for genotyping in independent populations for confirmation and further detailed analysis.

  Study phs000140

• Whole Exome Sequencing data of six chRCC tumors corresponding to three patients

  Mammalian target of rapamycin (mTOR) is a central regulator of mammalian metabolism and physiology. Aberrant hyperactivation of the mTOR pathway promotes tumor growth and metastasis, and can also promote tumor resistance to chemotherapy and cancer drugs; this makes mTOR an attractive cancer therapeutic target. mTOR inhibitors have been approved to treat cancer; however, the mechanisms underlying drug sensitivity remain poorly understood. Here, whole exome sequencing of three chromophobe renal cell carcinoma (chRCC) patients with exceptional mTOR inhibitor sensitivity revealed that all three patients shared somatic mutations in the deubiquitinase USP9X. The clonal characteristics of the mutations, which were amassed by studying multiple patients’ primary and metastatic samples from various years, together with the low USP9X mutation rate in unselected chRCC series, reinforced a causal link between USP9X and mTOR inhibitor sensitivity. Rapamycin treatment of USP9X-depleted HeLa and renal cancer 786-O cells, along with the pharmacological inhibition of USP9X, confirmed that this protein plays a role in patients’ sensitivity to mTOR inhibition. USP9X was not found to exert a direct effect on mTORC1, but subsequent ubiquitylome analyses identified p62 as a direct USP9X target. Increased p62 ubiquitination and the augmented rapamycin effect upon bortezomib treatment, together with the results of p62 and LC3 immunofluorescence assays, suggested that dysregulated autophagy in USP9X-depleted cells can have a synergistic effect with mTOR inhibitors. In summary, we show that USP9X constitutes a potential novel marker of sensitivity to mTOR inhibitors in chRCC patients, and represents a clinical strategy for increasing the sensitivity to these drugs.

  Study EGAS00001007104

• Analysis of TKI resistant mechanism for gastrointstinal stromal tumor

  Gastrointestinal stromal tumors are the most common mesenchymal tumor of the digestive tract and the proliferation is driven by gain-of-function mutations in KIT. Despite its proven benefits, half of the patients treated with imatinib develop disease progression within 2 years due to secondary resistance mutations in the KIT kinase domains. To characterize the changes associated with imatinib resistance, we performed genomic and transcriptomic analyses of four resistant cell lines and one cell line briefly exposed to imatinib. We also performed exome sequencing of drug-resistant clinical samples.

  Study JGAS000039

• Somatic_mutation_and_clonal_evolution_in_premalignant_lung_disease___WGS

  Cancer is a genetic disease caused by an accumulations of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from the lung tissue of individuals with a variety of lung diseases (COPD, UIP, IPF, Emphysema, pulmonary hypertension). This will allow us to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. Smoking is a large risk factor for developing many of these lung diseases so we are particularly keen to determining whether there is evidence of a smoking signature in these patients.

  Study EGAS00001002747

• Tumor Fraction Guided Cell-Free DNA Profiling in Metastatic Cancer Patients

  Cell-free DNA (cfDNA) profiling is increasingly used to guide cancer care, yet mutations are not always identified. The ability to detect somatic mutations in plasma depends on both assay sensitivity and the fraction of circulating DNA in plasma that is tumor-derived (i.e cfDNA tumor fraction). We hypothesized that cfDNA tumor fraction could inform the interpretation of negative cfDNA results and guide the choice of subsequent assays of greater genomic breadth or depth. Plasma samples collected from 118 metastatic cancer patients were analyzed with cf-IMPACT, a modified version of the FDA-authorized MSK-IMPACT tumor test that can detect genomic alterations in 410 cancer-associated genes. Shallow whole genome sequencing (sWGS) was also performed in the same samples to estimate cfDNA tumor fraction based on genome-wide copy number alterations using z-score statistics. The results show that cfDNA tumor fraction can inform the interpretation of negative cfDNA results and guide the selection of subsequent sequencing platforms that are most likely to identify clinically-relevant genomic alterations.

  Study phs002290

• Multi-Ethnic Study of Atherosclerosis (MESA) Cohort

  MESA The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced clinical signs and symptoms) and the risk factors that predict progression to clinically overt cardiovascular disease or progression of the subclinical disease. MESA researchers study a diverse, population-based sample of 6,814 asymptomatic men and women aged 45-84. Thirty-eight percent of the recruited participants are white, 28 percent African-American, 22 percent Hispanic, and 12 percent Asian, predominantly of Chinese descent. Participants were recruited from six field centers across the United States: Wake Forest University, Columbia University, Johns Hopkins University, University of Minnesota, Northwestern University and University of California - Los Angeles. Each participant received an extensive physical exam to determine coronary calcification, ventricular mass and function, flow-mediated endothelial vasodilation, carotid intimal-medial wall thickness and presence of echogenic lucencies in the carotid artery, lower extremity vascular insufficiency, arterial wave forms, electrocardiographic (ECG) measures, standard coronary risk factors, sociodemographic factors, lifestyle factors, and psychosocial factors. Selected repetition of subclinical disease measures and risk factors at follow-up visits allows study of the progression of disease. Blood samples have been assayed for putative biochemical risk factors and stored for case-control studies. DNA has been extracted and lymphocytes cryopreserved (for possible immortalization) for study of candidate genes and possibly, genome-wide scanning, expression, and other genetic techniques. Participants are being followed for identification and characterization of cardiovascular disease events, including acute myocardial infarction and other forms of coronary heart disease (CHD), stroke, and congestive heart failure; for cardiovascular disease interventions; and for mortality. In addition to the six Field Centers, MESA involves a Coordinating Center, a Central Laboratory, and Central Reading Centers for Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Ultrasound, and Electrocardiography (ECG). Protocol development, staff training, and pilot testing were performed in the first 18 months of the study. The first examination took place over two years, from July 2000 - July 2002. It was followed by four examination periods that were 17-20 months in length. Participants have been contacted every 9 to 12 months throughout the study to assess clinical morbidity and mortality. MESA Family The general goal of the MESA Family Study, an ancillary study to MESA funded by a grant from NHLBI, is to apply modern genetic analysis and genotyping methodologies to delineate the genetic determinants of early atherosclerosis. This is being accomplished by utilizing all the current organizational structures of the Multi-Ethnic Study of Atherosclerosis (MESA) and Genetic Centers at Cedars-Sinai Medical Center and University of Virginia. In the MESA Family Study, the goal is to locate and identify genes contributing to the genetic risk for cardiovascular disease (CVD), by looking at the early changes of atherosclerosis within families (mainly siblings). 2128 individuals from 594 families, yielding 3,026 sibpairs divided between African Americans and Hispanic-Americans, were recruited by utilizing the existing framework of MESA. MESA Family studied siblings of index subjects from the MESA study and from new sibpair families (with the same demographic characteristics) and is determining the extent of genetic contribution to the variation in coronary calcium (obtained via CT Scan) and carotid artery wall thickness (B-mode ultrasound) in the two largest non-majority U.S. populations. In a small proportion of subjects, parents of MESA index subjects participating in MESA Family were studied but only to have blood drawn for genotyping. The MESA Family cohort was recruited from the six MESA Field Centers. MESA Family participants underwent the same examination as MESA participants during May 2004 - May 2007. DNA was extracted and lymphocytes immortalized for study of candidate genes, genome-wide linkage scanning, and analyzed for linkage with these subclinical cardiovascular traits. While linkage analysis is the primary approach being used, an additional aspect of the MESA Family Study takes advantage of the existing MESA study population for testing a variety of candidate genes for association with the same subclinical traits. Genotyping and data analysis will occur throughout the study. MESA Air The general goal of the Multi-Ethnic Study of Atherosclerosis and Air Pollution ('MESA Air') is to prospectively examine the relation between an individual level assessment of long-term ambient air pollution exposures (including PM2.5 and the progression of subclinical cardiovascular disease in a multi-city, multi-ethnic cohort. MESA Air will also prospectively examine the relationship between an individual level assessment of long-term ambient air pollution exposures and the incidence of cardiovascular disease, including myocardial infarction and cardiovascular death. MESA AIR is funded by a grant from the United States Environmental Protection Agency to the University of Washington and subcontracts from the UW to other participating institutions. MESA Air will assess if ambient air pollution is associated with changes over time in subclinical measures of atherosclerosis and plasma markers of inflammation, oxidative damage, and endothelial activation in a longitudinal data model, adjusting for age, race/ethnicity, socioeconomic status, and specific cardiovascular risk factors (such as diabetes, hypertension, smoking, and diet). The study will similarly assess if the incidence of cardiovascular events is associated with long-term exposure to ambient air pollution, using a proportional hazards model. The study includes refinement of statistical tools, and explores joint/independent effects of acute and long-term pollutant exposure in the occurrence of cardiovascular disease. The MESA Air study is built on the foundation of the ongoing MESA study. The parent MESA Study cohort is located in six geographic areas ('Field Centers') that capture tremendous exposure heterogeneity, comparable to or greater than the variability in locations of prior U.S. cohort studies. In addition to the six Field Centers, the study involves a Coordinating Center, a Central Laboratory, and Reading Centers for Computed Tomography (CT), ultrasound and air pollution data. The cohort for the MESA Air study currently includes 6226 subjects: 5479 enrolled in the parent MESA study; 257 recruited specifically for this study, and 490 recruited from the MESA Family study. The entire MESA Air cohort will be followed over a 10-year project period for the occurrence of cardiovascular disease events. On two occasions over the ten-year study period, 3600 subjects from the MESA Air cohort, residing in nine locales, will undergo computed tomography scanning to assess presence and extent of coronary artery calcification (CAC), and ultrasound of the carotid artery to determine intima-media thickness (IMT). We will also repeatedly assess plasma markers of inflammation, oxidative damage, and endothelial function in 720 subjects. MESA Air adds state-of-the-art air pollution exposure assessment information to the MESA cohort study, and introduces new subjects and outcome measures to achieve our aims. The study will assess long-term individual-level exposure to ambient air pollutants for each subject using community-scale monitoring, outdoor spatial variation, subject proximity to pollution sources, pollutants' infiltration efficiency, and personal time-activity information. The exposure models will be validated using detailed monitoring in a subset of subjects. The MESA Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" box located on the right hand side of this top-level study page phs000209 MESA Cohort. phs000420 MESA SHARe phs000283 MESA CARe phs000403 MESA ESP Heart-GO

  Study phs000209

• Spatiotemporal evolution and inter-patient heterogeneity in primary and recurrent/metastatic head and neck squamous cell carcinoma

  Head and neck cancer squamous cell carcinomas (HNSCCs) are heterogeneous in terms of origin and aetiology. In addition, there is uncertainty about the spatiotemporal genetic evolution from initial diagnosis to recurrence/metastasis (R/M) after primary treatments and further disease progression following systemic treatment. Changes in the genetic profile have implications on the selection of appropriate treatments for patients, especially in the era of targeted therapies and immunotherapies. Here, we analysed a cohort of 11 HNSCC patients with metachronous R/M, among whom nine had paired primary and R/M samples suitable for next-generation sequencing (multiple R/M samples collected at different time points were available for some of the patients). At the genomic level, the R/M samples shared a fraction of the somatic single nucleotide variants (SNVs) with the index primary tumours, but they also acquired many additional mutations, while losing only a few others. A similar behaviour was also observed when examining the changes of mutational signatures between primary and R/M samples. Overall, R/M appeared thus more genetically diverse than the respective primary tumours. The transcriptomic analysis showed that R/M samples had lower immune cell infiltration and several genes related to immune response were significantly downregulated compared to the primary samples. Our results underline the importance of analysing multiple samples per patient to obtain a more complete picture of the patient’s tumour and advocates a re-biopsy in the event of R/M and treatment failure, in order to select the most appropriate therapeutic strategy.

  Study EGAS00001007464

• Genomic_landscape_of_liver_cirrhosis

  We are interested in the genomic landscape of liver cirrhosis and its potential manifestations for liver physiology and risk for hepatocellular carcinoma. Previous work in CASM has shown that there is a strong element of clonality within cirrhotic nodules and that some recurring mutations have been identified. However how this relates to the overall liver is not known and therefore by taking geographically disparate biospies, we aim to correlate our findings and make conclusions as to the characteristics of the overall genomic landscape.

  Study EGAS00001004329

• Identification of Somatic Changes in Tumors from Fanconi Anemia Patients

  This study focused on the identification of genomic signatures present in tumors from Fanconi anemia patients. Fanconi anemia is a rare hereditary disease caused by defects in DNA interstrand crosslink repair. The primary patient phenotypes are bone marrow failure and cancer predisposition. We concentrated on squamous cell carcinomas and used whole genome Illumina sequencing (22 tumor samples and 12 normal samples) , whole exome sequencing (37 tumor samples and 33 normal samples), PacBio long-read whole-genome (nine tumor and four normal samples),10X linked-read whole-genome sequencing, 10x single-cell/nuclei 3’ RNA sequencing (three tumor samples), 10x Visium spatial transcriptomics (one tumor sample), EPIC 850K methylation array (six samples), and bulk RNAseq (six tumor samples) to identify somatic changes present in tumors. The study aimed to identify changes that drive tumorigenesis in Fanconi anemia, give insight into the early development and aggressive nature of these tumors, and suggest therapeutic avenues for these patients. Another goal was to compare the genomic changes identified in tumors from Fanconi anemia patients with sporadic head and neck cancers. This study demonstrated that the tumors from Fanconi anemia individuals are generally not driven by HPV. Instead, they acquire mutations in the p53 tumor suppressor. The main characteristic of the tumors is the presence of a high number of structural variants in the form of small deletions, unbalanced translocations, and fold-back inversions, which often form complex rearrangements. These rearrangements result in amplifications and deletions of a multitude of oncogenes and tumor suppressors, respectively. The study also shows that lack of the Fanconi anemia DNA repair pathway leads to an epithelial-to-mesenchymal transition in a mouse model and in human samples that may influence the behavior of tumors in Fanconi anemia. Finally, comparing genomic changes in Fanconi anemia and sporadic tumors of the head and neck, we propose that the structural variants present in sporadic cancer result in a functional deficiency of the Fanconi anemia DNA repair pathway.

  Study phs002652

• Carcinoma of the oral tongue (OTSCC) genomic landscape characterisation

  Carcinoma of the oral tongue (OTSCC) is the most common malignancy of the oral cavity, characterized by frequent recurrence and poor survival. The last three decades has witnessed a change in the OTSCC epidemiological profile, with increasing incidence in younger patients, females and never-smokers. Here, we sought to characterize the OTSCC genomic landscape and to determine factors that may delineate the genetic basis of this disease, inform prognosis and identify targets for therapeutic intervention.

  Study EGAS00001001329

• Induction of fetal meiotic oocytes from embryonic stem cells in cynomolgus monkeys

  Human in vitro oogenesis provides a framework for clarifying the mechanism of human oogenesis. To create its benchmark, it is vital to promote in vitro oogenesis using a model physiologically close to humans. Here, we establish a foundation for in vitro oogenesis in cynomolgus (cy) monkeys: cy female embryonic stem cells harboring one active and one inactive X chromosome (Xa and Xi, respectively) differentiate robustly into primordial germ cell-like cells, which in xenogeneic reconstituted ovaries develop efficiently into oogonia and, remarkably, further into meiotic oocytes at the zygotene stage. This differentiation entails a comprehensive epigenetic reprogramming, including Xi reprogramming, yet, as partly observed in vivo, Xa and Xi remain epigenetically asymmetric with incomplete Xi reactivation. In humans and monkeys, the Xi epigenome in pluripotent stem cells functions as an Xi-reprogramming determinant. We further show that developmental-pathway over-activations with suboptimal up-regulation of relevant meiotic genes impede in vitro meiotic progression. Cy in vitro oogenesis exhibits critical homology with the human system, including with respect to bottlenecks, providing a salient model for advancing human in vitro oogenesis.

  Study JGAS000573

• single cell RNA-seq and ATAC-seq of human fetal forebrain tissue

  Oligodendrogenesis in the human central nervous system has been mainly observed at the second trimester of gestation, a much later developmental stage compared to mouse. Here we characterize the transcriptomic neural diversity in the human forebrain at post conceptual weeks (PCW) 8 to 10, using single-cell RNA-Seq. We find evidence of the emergence of a first wave of oligodendrocyte lineage cells as early as PCW 8, which we also confirm at the epigenomic level with single-cell ATAC-Seq. Using regulatory network inference, we predict key transcriptional events leading to the specification of oligodendrocyte precursor cells (OPCs). Moreover, by profiling the spatial expression of fifty key genes using In Situ Sequencing (ISS), we identify regions in the human ventral fetal forebrain where oligodendrogenesis first occurs. Our results indicate evolutionary conservation of the first wave of oligodendrogenesis between mouse and human and describe regulatory mechanisms involved in human OPC specification.

  Study EGAS00001006136

• Target resequencing of LQTS-related 100 genes in Japanese patients

  Some of the fatal familial arrhythmias cause sudden death in seemingly healthy individuals. It is not easy to make a pre-symptomatic diagnosis of these diseases using only clinical examinations such as an electrocardiogram. The purpose of this study is to elucidate the cause of lethal arrhythmia and/or the genetic factors that influence its susceptibility, thereby enabling early diagnosis and selection of effective treatment methods, and preventing sudden death. The most important purpose of this study is to identify the sites of genetic abnormalities and disease-related genes in pre-symptomatic cases. If a genetic abnormality is found, it is expected that the functional abnormality can be evaluated and appropriate measures to prevent sudden death can be taken.

  Study JGAS000579

• Exome sequencing of samples taken at multipl time points to monitor therapy response in AML

  As part of our individualized systems medicine program, personalized treatment options are identified and administered to chemorefractory AML patients based on exome sequencing and ex-vivo drug sensitivity and resistance testing data. In this study, we developed this approach further to take into account clonal heterogeneity and analyzed responses of 13 AML patients to chemotherapy and six patients to targeted treatments by using exome and ultra-deep amplicon resequencing. The data submitted includes fastq files from exome sequencing of multiple time-point samples collected from the 13 patients. In this study we identified rare subclonal variants present at diagnosis or later relapse samples and developed a correlation-based method to compare subclonal responses in serial samples across multiple time-points. Significant subclone-specific responses were observed subsequent to chemotherapy and specifically to targeted therapy in five patients.

  Study EGAS00001001948

• Genome-wide Association Study for Non-syndromic Clefts in the African Population: CIDR

  The focus of this project is to identify genetic variants that are associated with orofacial clefts in African populations in sub-Saharan Africa. Most genetic studies of CLP (including the vast majority of GWAS) have been conducted in populations of European origin with only a few focused on Asian or African populations. We choose to study the genetics of these complex traits in African populations because, African populations have the greatest genetic variation amongst the various populations in the world by virtue of being the primary ancestral population to modern humans (Cavalli-Sforza and Feldman, 2003; Ramsay et al., 2011). Therefore, the potential for finding novel loci for CLP is quite high. To date 6 genome wide association studies (GWAS) for cleft lip with or without cleft palate (CL/P) have been conducted and 18 risk loci identified (Birnbaum et al., 2009; Grant et al., 2009 ; Beaty et al., 2010; Mangold et al., 2010; Ludwig et al., 2012; Sun et al., 2015). All these studies have either been conducted in European populations, Asian populations or both. There is currently no published GWAS for clefts in African populations. African populations represent a novel and richly productive populations for genetic and environmental exposure studies for CL/P. Investigating the presence of genetic variants in diverse population groups can identify novel variants and candidate genes that are population specific. Environmental factors may also increase the risks in certain population groups due to genetic susceptibility and/or specific exposures. Understanding the role these susceptibility genes play in the effects of environmental risk factors can inform strategies designed towards reducing the outcome of these complex traits, e.g. through the modification of the environmental influences. The study population comprises a large number of individuals (3205 individuals) from Africa (Ghana, Ethiopia and Nigeria). There are cases, case triads (nuclear families), as well as controls with no history of OFC nor other developmental defects.

  Study phs001090

• Genomic Regions Associated with Susceptibility to Barrett's Esophagus and Esophageal Adenocarcinoma in African Americans: The Cross BETRNet Admixture Study

  Differences in rates of diseases between different populations with similar environments are presumed to be secondary to variability in population frequencies of disease causing alleles. Recently admixed populations such as African Americans (AAs) provide a natural opportunity to identify disease-causing variants by examining the ancestry of long chromosomal haplotypes. Admixture mapping approach can be successful in locating genes for diseases such as EAC whose rates varies markedly between the ancestral populations. This is a case only study with 54 African American cases and also on a subset of 28 cases with high genotyping quality. We seek to identify chromosome regions that have excess European ancestry and contrasting it to excess African ancestry.

  Study phs001454

• Phenotype and genotype correlation analysis in tuberous sclerosis complex

  To elucidate the genetic clues of the related clinical manifestations, whole exome sequencing analysis was performed in 163 of the patients with TSC and compared the severity of the symptoms.

  Study JGAS000688

• National Heart Lung and Blood Institute (NHLBI) GO-ESP: Heart Cohorts Component of the Exome Sequencing Project (ARIC)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. HeartGO is a consortium of six well-phenotyped NHLBI cohorts: Atherosclerosis Risk in Communities (ARIC) study, the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Cardiovascular Health Study, the Framingham Heart Study, the Jackson Heart Study, and the Multi-Ethnic Study of Atherosclerosis. Together, these cohorts have provided DNA and phenotype datasets from a diverse cohort of individuals of African-American, Caucasian, Asian, and Hispanic ancestry to be made available for use by qualified investigators in dbGaP. HeartGO investigators will conduct genotype-phenotype analyses for phenotypes related not only to heart disease but with other variables that will be contributed to dbGaP. The HeartGO dataset provides investigators with genotype-phenotype analytic opportunities for traits not only related to heart disease but also associated with ancillary variables that will be contributed to dbGaP, including disease endpoints, risk factors, biomarkers, and subclinical disease measures. The phenotypes planned for investigation as part of the GO-ESP HeartGO project include early-onset myocardial infarction (EOMI), low density lipoprotein (LDL) cholesterol, body mass index/type 2 diabetes (BMI/T2D), blood pressure and ischemic stroke. Results of the proposed analyses as well as relevant replication/follow-up analyses will be reported in peer-reviewed journals. This study phs000398 contains the Atherosclerosis Risk in Communities (ARIC) subset of GO-ESP/Heart-GO. Additional GO-ESP data is also available via dbGaP.

  Study phs000398

• Molecular Profiling of Gallbladder Cancer (MPOG)

  The purpose of this study is to investigate the underlying genetic factors involved in gallbladder cancer.

  Study phs001404

• Whole Exome Sequencing of Congenital Diaphragmatic Hernia Patients and Trios

  Congenital diaphragmatic hernia (CDH) is a common and severe birth defect characterized by structural defects of the diaphragm and by pulmonary hypoplasia. Congenital diaphragmatic hernia patient may present either as an isolated phenotype or together with other congenital anomalies in a complex phenotype. Despite the clinical significance of CDH, the underlying genetic and developmental pathways are incompletely understood. In order to establish a catalog of human genetic variation for this condition, we performed whole exome sequencing (WES) on 275 carefully phenotyped individuals with CDH in the Pediatric Surgical Research Laboratories at the Massachusetts General Hospital (Boston, MA, USA) and Boston Children's Hospital (Boston, MA, USA). The exome data generated are valuable for comparison of candidate genes derived from WES of other CDH cohorts or affected kindreds, and to provide ideal candidates for further functional studies with the ultimate goal of enhancing our understanding of the heterogeneous and, possibly, oligogenic molecular etiology of CDH. While familial clustering has been reported in rare kindreds, the majority of probands with CDH have no family history of CDH leading to the hypothesis that de novo variants are an important and relatively frequent etiological mechanism. In the second version of the study, we performed WES analysis on 87 trios, to assess the contribution of de novo mutations in the etiology of diaphragmatic and pulmonary defects and to identify previously unknown candidate genes. This dbGaP submission includes WES data on: (a) 20 new probands, (b) 9 probands also reported in the previous version (dbGaP accession no. phs000783.v1.p1), (c) 174 unaffected parents, including the parents of 67 previously reported probands. Combined analysis with other available cohorts of congenital diaphragmatic hernia revealed a genome-wide enrichment of likely gene-disrupting de novo variants (i.e., nonsense, frameshift or splice site), and missense de novo variants predicted in silico to be damaging.

  Study phs000783