Search Results - EGA European Genome-Phenome Archive

Targeted sequencing (paired) of HR genes in primary and metastatic patient-derived xenografts (PDXs) of colorectal cancer (CRC)

Chemotherapy is the standard-of-care treatment for metastatic colorectal cancer (mCRC) and benefits some patients, but what distinguishes responders from non-responders is unclear. In this study, we leveraged a comprehensive collection of 69 molecularly annotated patient-derived xenografts to uncover functional predictors of response to 5-FU and irinotecan combination therapy (FOLFIRI) in mCRC. Genetic analyses revealed that treatment sensitivity was marked by genomic scars indicative of BRCAness, suggesting homologous recombination (HR) deficiency as a key determinant. Accordingly, we surveyed a manually curated panel of 44 genes with a documented role in HR for the potential presence of pathogenic mutations. We did not observe a specific enrichment of HR gene mutations based on response to FOLFIRI. This result, combined with the absence of widespread biallelic inactivation of the analyzed genes and the predominance of mutations categorized as variants of unknown significance, suggests that FOLFIRI sensitivity is not primarily governed by underlying mutations in HR genes responsible for mitigating the genotoxic effects of this therapeutic regimen.

Study EGAS50000000075

Mutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma (H021)

Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. Here, we used whole-exome and transcriptome sequencing to identify a KIT exon 11 mutation (c.1733_1735del, p.578_579del) as actionable target in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy. Molecularly guided treatment with imatinib resulted in a dramatic and durable response with remission of nearly all tumor manifestations, indicating a dominant driver function of mutant KIT in this tumor. This observation highlights the potential of unbiased genomic profiling for uncovering the vulnerabilities of individual malignancies, particularly in rare and unclassifiable tumors, and underscores that KIT exon 11 mutations represent tractable therapeutic targets across different histologies.H021

Study EGAS00001001845

Analytical study of protein function and RNA expression involved in predicting treatment efficacy and adverse event development in lung cancer radiotherapy.

The purpose of this study is to elucidate the functions of DNA repair proteins and RNA expression that are involved in the therapeutic efficacy and adverse events of radiotherapy for lung cancer at our hospital. In particular, this is an exploratory study to identify proteins and RNAs involved in the expression of proteins that are likely to be involved in the prediction of radiotherapy response and adverse events.

Study JGAS000545

Spatial transcriptomics analysis of HPV-dependent and HPV-independent vulval squamous cell carcinoma

In this study we have used sequencing-based spatial transcriptomics (ST) optimised for FFPE tissue to investigate gene expression in a cohort of HPVi and HPVd VSCC, including assessment of pre-invasive LS, HSIL and DVIN and associated inflammation. Our data indicate significant differences in gene expression between VSCC of different aetiologies, with marked differences in immune-related gene expression both within the invasive disease and in peri-tumoural inflammatory areas.

Study EGAS00001007981

Research Program on Genes, Environment and Health (RPGEH)

The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) is a resource developed to facilitate research on genetic and environmental factors on common diseases and healthy aging. The RPGEH resource links biospecimens, health surveys, and comprehensive electronic medical records on broadly consented adult members of Kaiser Permanente Medical Care Plan, Northern California Region (KPNC). KPNC is an integrated health care delivery system with a membership of approximately 3.3 million people in northern California. The membership of KPNC is representative of the general population in the 14 county area in which facilities are located, although extremes of income are underrepresented. At the end of 2013, the RPGEH resource included: (1) demographic and behavioral surveys from over 430,000 participants; (2) biospecimens (DNA, serum, plasma, and/or saliva) from over 204,000 participants, including over 13,000 pregnant women; (3) genome-wide genotype data (70 billion SNP genotypes) on over 100,000 participants, including the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort; and (4) the longitudinal electronic medical records of the participants. The RPGEH was developed beginning in 2005 at the Division of Research of Kaiser Permanente Northern California by Catherine Schaefer (Director), Neil Risch (Co-Director), Lisa Croen, Eric Jorgenson, Lawrence Kushi, Charles Quesenberry, Sarah Rowell, Carol Somkin, Stephen Van den Eeden, Larry Walter, and Rachel Whitmer. Funding of the RPGEH was provided to C. Schaefer (PI) and N. Risch (co-PI) by the Wayne and Gladys Valley Foundation, The Ellison Medical Foundation, the Robert Wood Johnson Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Regional Community Benefit Programs. The GERA cohort was funded by a grant from NIH to RPGEH and UCSF (RC2 AG036607; C. Schaefer and N. Risch, PIs). At the time of the award of the RC2 project in late 2009, the RPGEH had established a cohort of about 140,000 individuals who had answered a detailed survey, provided saliva samples for extraction of DNA, and given broad consent for the use of their data in studies of health and disease. Survey and Cohort Recruitment. Initially, the RPGEH developed electronic disease registries to enable identification of phenotypes, using algorithms applied to EMR data. In 2007, the RPGEH mailed a four page survey to 1.9 million adult (≥ 18 years old) members of KPNC who had been members for two years or more, to obtain data on demographic and behavioral factors complementary to the clinical data in the EMR. The survey materials included a cover letter introducing the RPGEH, a two page list of Frequently Asked Questions, and the survey, which included questions on demographic factors such as education, race-ethnicity, income and marital status, dietary factors, physical activity, smoking, and alcohol consumption, as well as reproductive history and reproductive health. Members whose electronic medical records indicated a preference for written communications in Chinese or Spanish received survey materials both in English and a Chinese or Spanish translation. Approximately 400,000 completed surveys were returned. Saliva Sample Collection. Beginning in July 2008, respondents to the survey were asked to sign and return a consent form and authorization for use and disclosure of protected health information. The consent form authorized broad use of biospecimens, survey data, and data from participants' electronic health records for use in studies of genetic and environmental influences on health and disease. Respondents who returned completed consent forms were mailed (Oragene) saliva collection kits; more than 132,000 saliva samples were collected in two years. Completed saliva kits were scanned and archived in a temporary biorepository at the KPNC Division of Research. In late 2009, the RPGEH began collection of saliva samples from the California Men's Health Study (CMHS), a cohort that had been previously assembled in 2002-2003 and had been excluded from the RPGEH survey mailing with the intent of later adding CMHS participants to the assembled RPGEH cohort. The CMHS was developed to facilitate research on prostate cancer and other conditions in older men; the study protocol is described in Enger, et al., 2006. It enrolled and surveyed more than 40,000 men in KPNC, ages 45-69 years, who were members of KPNC during 2002-2003. CMHS men completed two mailed surveys with demographic and behavioral data similar to that of the RPGEH. The data on analogous variables were reconciled and integrated with the data derived from the RPGEH cohort for use in the RPGEH resource. By 2011, RPGEH collected approximately 15,400 saliva samples from men participating in the CMHS. RPGEH Access and Collaborations Website and Procedures. The RPGEH maintains a web portal for inquiries and applications for collaboration and access to data. The url is: https://rpgehportal.kaiser.org/. RPGEH has an application process and an Access Review Committee that reviews applications for collaboration and use. For more information, please contact RPGEH through the website.

Study phs000788

NHLBI Cleveland Family Study (CFS) Candidate Gene Association Resource (CARe)

The Cleveland Family Study is the largest family-based study of sleep apnea world-wide, consisting of 2284 individuals (46% African American) from 361 families studied on up to 4 occasions over a period of 16 years. The study was begun in 1990 with the initial aims of quantifying the familial aggregation of sleep apnea. NIH renewals provided expansion of the original cohort (including increased minority recruitment) and longitudinal follow-up, with the last exam occurring in February 2006. Index probands (n=275) were recruited from 3 area hospital sleep labs if they had a confirmed diagnosis of sleep apnea and at least 2 first-degree relatives available to be studied. In the first 5 years of the study, neighborhood control probands (n=87) with at least 2 living relatives available for study were selected at random from a list provided by the index family and also studied. All available first degree relatives and spouses of the case and control probands also were recruited. Second-degree relatives, including half-sibs, aunts, uncles and grandparents, were also included if they lived near the first degree relatives (cases or controls), or if the family had been found to have two or more relatives with sleep apnea. Blood was sampled and DNA isolated for participants seen in the last two exam cycles (n=1447). The sample, which is enriched with individuals with sleep apnea, also contains a high prevalence of individuals with sleep apnea-related traits, including: obesity, impaired glucose tolerance, and HTN. Phenotyping data have been collected over 4 exam cycles, each occurring ~every 4 years. The last three exams targeted all subjects who had been studied at earlier exams, as well as new minority families and family members of previously studied probands who had been unavailable at prior exams. Data from one, two, three and four visits are available for 412, 630, 329 and 67, participants, respectively. In the first 3 exams, participants underwent overnight in-home sleep studies, allowing determination of the number and duration of hypopneas and apneas, sleep period, heart rate, and oxygen saturation levels; anthropometry (weight, height, and waist, hip, and neck circumferences); resting blood pressure; spirometry; standardized questionnaire evaluation of symptoms, medications, sleep patterns, quality of life, daytime sleepiness measures and health history; venipuncture and measurement of total and HDL cholesterol. The 4th exam (2001-2006) was designed to collect more detailed measurements of sleep, metabolic and CVD phenotypes and included measurement of state-of-the-art polysomnography, with both collection of blood and measurement of blood pressure before and after sleep, and anthropometry, upper airway assessments, spirometry, exhaled nitric oxide, and ECG performed the morning after the sleep study. Data have been collected by trained research assistants or GCRC nurses following written Manuals of Procedures who were certified following standard approaches for each study procedure. Ongoing data quality, with assessment of within or between individual drift, has been monitored on an ongoing basis, using statistical techniques as well as regular re-certification procedures. Between and within scorer reliabilities for key sleep apnea indices have been excellent, with intra-class correlation coefficients (ICCs) exceeding 0.92 for the apnea-hypopnea index (AHI). Sleep staging, assessed with epoch specific comparisons, also demonstrate excellent reliability for stage identification (kappas>0.82). There has been no evidence of significant time trends-between or within scorers- for the AHI variables. We also have evaluated the night-to-night variability of the AHI and other sleep variables in 91 subjects, with each measurement made 1-3 months apart. There is high night to night consistency for the AHI (ICC: 0.80), the arousal index (0.76), and the % sleep time in slow-wave sleep (0.73). We have demonstrated the comparability of the apnea estimates (AHI) determined from limited channel studies obtained at in-home settings with in full in-laboratory polysomnography. In addition to our published validation study, we more recently compared the AHI in 169 Cleveland Family Study participants undergoing both assessments (in-home and in-laboratory) within one week apart. These showed excellent levels of agreement (ICC=0.83), demonstrating the feasibility of examining data from either in-home or in-laboratory studies for apnea phenotyping. Data collected in the GCRC were obtained, when possible, with comparable, if not identical techniques, as were the same measures collected at prior exams performed in the participants' homes. To address the comparability of data collected over different exams, we calculated the crude age-adjusted correlations ~3 year within individual correlations between measures made in the most recent GCRC exam with measures made in a prior exam and demonstrated excellent levels of agreement for BMI (r=.91); waist circumference (0.91); FVC (0.88); and FEV1 (0.86). As expected due to higher biological and measurement variability, 149 somewhat lower 3-year correlations were demonstrated for SBP (0.56); Diastolic BP (0.48); AHI (0.62); and nocturnal oxygen desaturation (0.60). NHLBI Candidate-gene Association Resource. The NHLBI initiated the Candidate gene Association Resource (CARe) to create a shared genotype/phenotype resource for analyses of the association of genotypes with phenotypes relevant to the mission of the NHLBI. The resource comprises nine cohort studies funded by the NHLBI: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), Cleveland Family Study (CFS), Coronary Artery Risk Development in Young Adults (CARDIA), Cooperative Study of Sickle Cell Disease (CSSCD), Framingham Heart Study (FHS), Jackson Heart Study (JHS), Multi-Ethnic Study of Atherosclerosis (MESA), and the Sleep Heart Health Study (SHHS). A database of genotype and phenotype data will be created that includes records for approximately 50,000 study participants with approximately 50,000 SNPs from more than 1,200 selected candidate genes. In addition, a genome wide association study using a 1,000K SNP Chip will be conducted on approximately 9,500 African American participants drawn from the 50,000 participants in the nine cohorts. Some relevant CARe publications CARe Study: PMID 20400780 CVD Chip Design: PMID 18974833

Study phs000284

Trial of Late Surfactant for Prevention of Bronchopulmonary Dysplasia: A Study in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide (TOLSURF-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.Objectives: To assess whether late surfactant treatment in extremely low gestational age newborn (ELGAN, ≤28 week gestation) infants requiring ventilation at 7-14 days safely improves survival without bronchopulmonary dysplasia.Background: Bronchopulmonary dysplasia (BPD) is the most common form of chronic lung disease in children with an estimated 15,000 new cases annually in the United States. BPD affects infants born prematurely, is a major contributor to the cost of prematurity each year, and is associated with long-term pulmonary disability, neurodevelopmental abnormalities and death.Increases in the survival of ELGAN infants have resulted in another form of BPD, which is characterized by impaired alveolar and microvascular development with excess tone and reactivity of airway smooth muscle. Despite treatments to enhance lung maturation, premature infants often need prolonged intubation and mechanical ventilation and/or oxygen support. When mechanical ventilation is required longer than 7 days, BPD results in 70% of surviving ELGAN infants. Most of these infants experience clinical episodes of increased requirement for ventilatory support that are associated with dysfunctional surfactant, which is primarily due to low surfactant protein B (SP-B). In pilot studies of late surfactant treatment in premature infants, there was short-term improvement in SP-B content. These prior studies provided the rationale for a larger clinical trial for later doses of surfactant treatment to prevent episodes of respiratory decompensation and BPD. Participants: 511 infants were eligible for randomization of the 2693 infants screened. Of the 511 infants eligible for randomization, there were 252 infants allocated to the treatment arm and 259 infants allocated to the placebo arm.Design: The study was designed to assess the effect of late doses of surfactant on survival without BPD at 36 weeks post menstrual age (PMA) in ELGAN infants who required intubation and mechanical ventilation between 7 and 14 days of age and were receiving Inhaled nitric oxide (iNO). Infants were stratified within clinical centers and gestational age groups and randomized to treatment with calfactant, a natural surfactant extracted from bovine lung lavage fluid, or a sham procedure.All infants received iNO according to the protocol used in the Nitric Oxide Chronic Lung Disease (NOCLD) trial. A masked syringe containing either a standard dose of calfactant for the treatment group, or air for the placebo group, was administered to the infant behind a screen by staff not involved in providing the infant's clinical care. Monitor and ventilator alarms were turned off during dosing to avoid unblinding of clinical staff. To accommodate research staff availability and infant instability, the dosing interval was not strictly set but could be repeated every 24 – 72 hours up to 5 doses if the infant still required intubation. Dosing could be discontinued by physician request or parental withdrawal from the study. Due to parental preference, the first infant in a multiple birth was randomized according to the randomization schedule and subsequent infants were assigned to the same treatment group. Follow-up to assess pulmonary and neurologic development continued until 2 years of age, with treatment group blinding maintained. The primary outcome was survival without BPD at 36 weeks PMA. Secondary outcomes included BPD at 40 weeks PMA, pulmonary outcome at 12–24 months of age, and neurodevelopmental outcome at 2 years of age. Conclusions: There were no significant differences observed between the treatment group and the control group for survival without BPD at 36 weeks or 40 weeks.

Study phs003899

WES_of_adult_intellectual_disabilities_with_co_morbid_psychiatric_disorders

ost adults with intellectual disabilities (ID) do not undergo genetic diagnostic investigation as part of their clinical care and have 'missed the boat' with regard to the WES and WGS genetic testing that is now being provided for children with ID. There is a dramatically increased risk of psychistric disorders in adults with ID, e.g. the risk of psychoses is 10X higher than in the general population. It remains an open question as to how much of adult ID is genetic in origin and how similar the genetic forms of adult ID are to those being diagnosed in children, in part due to survivor bias. There is also the opportunity to identify adults with treatable forms of ID, of which over 80 have been described, thus improving their clinical management. Furthermore, analysis of medical records of adults with genetic forms of ID can help to characterise the 'natural history' of individual disorders, resulting in more accurate prognoses for diagnosed children and identifying opportunities for improved management and possibly therapeutic intervention (e.g. optimal anti-epileptic therapy). Here we propose to exome sequence (to ~50X coverage) 200 adults with ID and co-morbid psychiatric disorders. This cohort has previously been assayed with chromosomal microarrays (Wolfe et al 2017 EJHG, 25, 66–72) identifying a diagnostic yield of ~11% which is comparable to the CNV diagnostic yield in various child ID cohorts (10-15%). The authors observed no substantive biases in diagnostic yield between different psychiatric diagnostic classes. The WES data will be analysed using the diagnostic workflows developed in the DDD study to ensure comparability between child and adult ID datasets. This study is intended as a pilot study to demonstrate the value of WES in adults with ID. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

Study EGAS00001002962

High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform

Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that are essential for the stability as well as the complete replication of the human genome. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length in clinics and research laboratories due to the lack of accurate and high-throughput telomere length measurement method. Here, we describe a novel workflow to capture and analyze telomeres accurately at the single-nucleotide resolution. By using newly designed telobaits that are complementary to the single-stranded G-rich 3’ telomeric overhangs, we can specifically and efficiently capture full-length telomeres and subject them to single-molecule real-time (SMRT) sequencing. We show that the telomere length can be measured at nucleotide resolution using the PacBio high fidelity (HiFi) sequencing platform, which provides the necessary accuracy and throughput to uncover the steady-state telomere length distribution in human culture cell lines as well as clinical patient samples. This new method is a valuable tool not only in population-wide epidemiology studies but also for the longitudinal assessment of telomere attrition in individuals. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that is dispersed throughout the telomere repeat region. Importantly, the unique distribution pattern and sequence of TVSs in individuals may be used as a fingerprint for sample identification. In addition, the presence of TVSs disrupts the continuity of the canonical (5’-TTAGGG-3’)n telomere repeats, which could affect the binding of shelterin complexes at the chromosomal ends. Therefore, TVSs may act as a form of genetic polymorphisms that impairs telomere protection. Together with the absolute telomere length in each individual, TVSs may have profound implications in human aging and diseases.

Study EGAS00001006103

High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform, P49-P104 and run1 replicates

Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that are essential for the stability as well as the complete replication of the human genome. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length in clinics and research laboratories due to the lack of accurate and high-throughput telomere length measurement method. Here, we describe a novel workflow to capture and analyze telomeres accurately at the single-nucleotide resolution. By using newly designed telobaits that are complementary to the single-stranded G-rich 3’ telomeric overhangs, we can specifically and efficiently capture full-length telomeres and subject them to single-molecule real-time (SMRT) sequencing. We show that the telomere length can be measured at nucleotide resolution using the PacBio high fidelity (HiFi) sequencing platform, which provides the necessary accuracy and throughput to uncover the steady-state telomere length distribution in human culture cell lines as well as clinical patient samples. This new method is a valuable tool not only in population-wide epidemiology studies but also for the longitudinal assessment of telomere attrition in individuals. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that is dispersed throughout the telomere repeat region. Importantly, the unique distribution pattern and sequence of TVSs in individuals may be used as a fingerprint for sample identification. In addition, the presence of TVSs disrupts the continuity of the canonical (5’-TTAGGG-3’)n telomere repeats, which could affect the binding of shelterin complexes at the chromosomal ends. Therefore, TVSs may act as a form of genetic polymorphisms that impairs telomere protection. Together with the absolute telomere length in each individual, TVSs may have profound implications in human aging and diseases.

Study EGAS00001006595

BCR-ABL is enriched in S- and G2-cell cycle phases

To address the unusually long duration of imatinib therapy for chronic myelogenous leukemia, we sought to understand the expression of BCR-ABL gene expression with different phases of the cell cycle. A precedent for dynamic fusion oncoprotein expression already exists for the pediatric solid tumor, rhabdomyosarcoma. Quantitative immunocytochemistry was conducted to compare the expression of BCR-ABL with markers of each cell cycle phase: CDK6 for G1, CDK2 for S, phospho-CDC2 for G2, and phospho-HH3 for M phase. BCR-ABL expression was most strongly correlated with the G2 and S cell cycle phases. Low BCR-ABL expression only coincided with high cell cycle marker expression for the G1. BCR-ABL was rarely if at all expressed in M. Our results suggest a possible explanation for the prolonged nature of imatinib therapy, which may be only effective on S- and G2-phase actively replicating leukemia cells.

Study EGAS00001006769

Brain Arteriovenous Malformation Genetics Study

The Predictors of Spontaneous Cerebral AVM Hemorrhage study was designed to identify genetic markers that predict adverse outcomes in brain arteriovenous malformation (BAVM) patients, examine race-ethnicity influences on BAVM hemorrhage risk, and use genome-wide association analysis to identify novel genetic predictors of AVM and hemorrhage using the Affymetrix GeneChip. We performed the first genome-wide association study (GWAS) (PMID: 26818729) of sporadic BAVM to investigate association of common single nucleotide polymorphisms (SNPs) with risk of sporadic BAVM in the international, multicenter Genetics of Arteriovenous Malformation (GEN-AVM) consortium. The study included a Caucasian discovery cohort of 515 BAVM cases and 1,191 controls genotyped using Affymetrix genome-wide SNP arrays. The Phase 1 discovery cohort comprised of 338 BAVM cases (154 male) and 504 controls genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. The molecular data (individual genetic data) for the Phase 1 discovery cohort 338 BAVM cases (self-reported Caucasian) recruited at University of California, San Francisco, or Kaiser Permanente of Northern California (KPNC) are included in the dbGaP Study Report: Brain Arteriovenous Malformation Genetics Study, with the additional BAVM case phenotypic and sample attribute characteristics: sex, race, age at BAVM diagnosis, hemorrhagic presentation, BAVM size. Written informed consent was obtained from all participants and the study was approved by the respective Institutional Review Boards. The molecular dataset for this study in dbGaP is based on the genotypes obtained for the initial set of 906,600 SNPs for cases and controls called together using Birdseed v2 algorithm in Affymetrix Genotyping Console Software. The final QC'd dataset includes 717,335 markers as SNPs with MAF<0.01 or deviating from Hardy-Weinberg equilibrium (P<0.00001) in controls were excluded. After QC, the average genotyping call rate was 99%. The discovery phase GWAS identified 57 top BAVM-associated SNPs which were tested in a replication cohort including 608 BAVM cases and 744 controls. The molecular dataset for these 338 BAVM cases was also included in a report investigating common and rare genome-wide copy number variation for association with BAVM (PMID: 24098321), which included a total sample size of 371 sporadic Caucasian BAVM cases and 563 Caucasian controls. This study identified a CNV region on 1p36.13 (NBPF1 locus) that was significantly enriched with duplications in BAVM cases compared to controls, although this association did not replicate in an independent cohort of 184 sporadic BAVM cases and 182 controls. This resource will help researchers to better understand the genetic risk factors for BAVM and/or hemorrhage. These data may be applied to examine the genetic contributions to arteriovenous malformation, stroke, and related vascular disorders and may help generate hypotheses regarding the genetics of cerebrovascular disease.

Study phs002069

Center for Sub-Cellular Genomics

A cell is a highly complex system with distributed molecular physiologies in structured sub-cellular compartments whose interplay with the nuclear genome determine the functional characteristics of the cell. A classic example of distributed genomic processes is found in neurons. Learning and memory require modulation of individual synapses through RNA localization, localized translation, and localized metabolites, such as those from dendritic mitochondria. Dendrites of neurons integrate distributed synaptic signals into both electrical and nuclear transcriptional response. Dysfunction of these distributed genomic functions in neurons can result in a broad spectrum of neuropsychiatric diseases such as bipolar and depressive disorders, autism, among others. The Center for Sub-Cellular Genomics' (CSG) mission is to develop new technologies to enable the dissection of complex genomic interactions within a single cell. New technologies include methods to target DNA and RNA sampling at sub-cellular resolution in live cells; high-throughput isolation and microfluidics chemistry for sub-cellular fractions; sub-cellular resolution mass-spectrometry; and computational tools for analysis of sub-cellular genomics data. The new technologies developed by CSG will enable the broader genomics community to associate sub-cellular processes to cell function and dysfunction. These technologies will be utilized in the center to generate a comprehensive atlas of genomic signatures of sub-cellular compartments in the mammalian neuron system. The technologies and neuron-focused data obtained here will be relevant to neurodegenerative and neuropsychiatric diseases including schizophrenia, depression, autism spectrum disorder, traumatic brain injury, and Alzheimer's.

Study phs002120

GWAS for Membranous Nephropathy

Primary membranous nephropathy (MN) is a rare autoimmune cause of kidney failure. This dataset is from a genome-wide association study (GWAS) designed to identify novel genetic risk loci for MN. The provided cohort (named as European-1 Cohort) is composed of 611 cases of primary MN and 1,246 healthy controls of European ancestry. This cohort was used in the GWAS meta-analysis, as described in the manuscript entitled "Genetic architecture of membranous nephropathy and its potential diagnostic implications" (Nature Communications 2020, in press).The genome-wide summary statistics, including trans-ethnic meta-analysis across 8 GWAS cohorts of European and East Asian ancestry and ethnicity specific meta-analyses, are freely available for download on the Kiryluk lab website: http://www.columbiamedicine.org/divisions/kiryluk/resources.php.

Study phs001984

Epidemiologic Architecture for Genes Linked to Environment (EAGLE) MetaboChip Study

The Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study is a study site of the larger Population Architecture using Genomics and Epidemiology (PAGE) I study.  EAGLE accessed two data resources during the course of study: the National Health and Nutrition Examination Surveys (NHANES) and BioVU, the Vanderbilt University Medical Center biorepository linked to de-identified electronic health records.The EAGLE MetaboChip Study, also known as EAGLE BioVU in the literature, is a data resource of Illumina MetaboChip genotypes for ~15,000 DNA samples from African American/Black, Hispanic, and Asian patients in BioVU (PMID: 26201699). Several EAGLE BioVU and PAGE I study phenotypes were extracted using structured and unstructured data available in de-identified electronic health records linked to the DNA samples. 

Study phs002767

Center for Common Disease Genomics (CCDG) - Cardiovascular: BioImage Cohort

The genetic basis of cardiovascular disease in individuals of non-European ancestry remains largely unknown. Availability of ethnically diverse study populations is essential to fully investigate the underlying causes of disease. The BioImage Study enrolled adults aged 55-80 in a prospective observational study. Subjects had no prior history of cardiovascular disease, but were identified to be at intermediate to high risk for atherosclerotic cardiovascular events (PMID: 25790876). The recruiting target was a cohort with similar demographics to the US population in terms of race and ethnicity. Produced as part of the NHGRI Centers for Common Disease Genomics, this study contains whole genome sequence data and variant calls from 922 African American participants of the BioImage Study.

Study phs002325

NCT03343197: Clinical Biomarker Data

Patients with IDH1-mutated low-grade glioma were treated with AG-120 (ivosidenib), AG-881 (vorasidenib), or Placebo for 28 days before surgical resection. A portion of the surgical sample was submitted for exome capture-based transcriptome sequencing (Personalis ACE Whole Transcriptome). Following surgery, subjects had the option to continue (or initiate) treatment with AG-120 or AG-881.This dataset comprises next-generation sequencing data from biopsies obtained in the clinical trial: NCT03343197 (Study of AG-120 and AG-881 in Subjects with Low Grade Glioma).

Study phs003148

Segmental Overgrowth/Vascular Anomalies/Dermatologic Disorders

This study was designed to determine the molecular etiology of disorders characterized by segmental overgrowth, vascular anomalies, or dermatologic conditions that are part of the diagnostic criteria for Proteus syndrome or PIK3CA-related overgrowth spectrum (PROS). Somatic variants in AKT1 or PIK3CA have been identified as causative for Proteus syndrome and PROS respectively, and this study aimed to determine the extent of allelic and genetic heterogeneity in individuals who fully met the diagnostic criteria, had some aspects of, or had isolated manifestations of either syndrome.

Study phs002006

UW TAN Study of Metastatic Urothelial Carcinoma

Patients with metastatic urothelial carcinoma treated at our institution, who elected to undergo rapid autopsy at the time of death, are included in this study. These patients agreed to submit their tissue (normal samples for germline analysis [kidney or liver] as well as primary and metastatic tumor sites [urothelial carcinoma]) and the time of autopsy. Each patient signed consent to allow study of these tissues including histologic, sequencing (DNA/RNA), and implantation in to animals as able for future study.

Study phs001797

A Large-Scale, Consortium-Based Genomewide Association Study of Asthma

We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma.

Study EGAS00000000077

WES sequencing of metastatic colorectal cancer patient-derived xenografts with known response to irinotecan.

Chemotherapy is the standard-of-care treatment for metastatic colorectal cancer (mCRC) and benefits some patients, but what distinguishes responders from non-responders is unclear. In this study, we expand a pre-existing collection (https://doi.org/10.1158/2159-8290.CD-24-0556) of molecularly annotated patient-derived xenografts to uncover functional predictors of response to 5-FU and irinotecan combination therapy (FOLFIRI) in mCRC. We complemented previous mutational profiles with whole exome sequencing for 46 xenografts with known response to irinotecan.

Study EGAS50000001484

Bulk RNA sequencing of metastatic colorectal cancer patient-derived xenografts with known response to irinotecan

Chemotherapy is the standard-of-care treatment for metastatic colorectal cancer (mCRC) and benefits some patients, but what distinguishes responders from non-responders is unclear. In this study, we expand a pre-existing collection (https://doi.org/10.1158/2159-8290.CD-24-0556) of molecularly annotated patient-derived xenografts to uncover functional predictors of response to 5-FU and irinotecan combination therapy (FOLFIRI) in mCRC. We complemented previous expression profiles with bulk RNAseq for 38 xenografts with known response to irinotecan.

Study EGAS50000001485

Transcriptome HCCO Hypoxia and Doxorubicin resistance

We hypothesized that HCCO-intrinsic determinants of response to hypoxia or doxorubicin could be reflected in the gene expression profiles of the HCCOs. Therefore, we selected for comparative transcriptomic analysis two sets of 4 HCCO lines that were severely (hypoxia-sensitive) or barely affected (hypoxia-resistant) by hypoxia in an ATP-based proliferation assay or two sets of 4 HCCO lines whose doxorubicin response curves were clearly separated both under normoxic and hypoxic culture conditions for comparative transcriptomic analysis.

Study EGAS50000000042

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

Cell motility and migration as determinants of stem cell efficacy

Limited stem cell migration capacities and undirected homing hamper their therapeutic efficacy. We report here the novel technology to isolate stem cell subpopulations with high migration potential. Hereby, we identified podoplanin-dependent stem cell mobility as important mechanism for their in vivo homing capacities and therapeutic efficacy as validated in preclinical models of Alzheimer´s disease and mouse glioma. In vivo applications of highly migrating stem cells resulted in remarkable improvement of targeted homing and engraftment rates. Moreover, animals receiving highly migrating stem cells showed higher recovery rates compared to unselected stem cells. This novel technology provides useful tool to improve therapeutic efficacy of stem cells and give insights into stem cell subpopulations heterogeneity with the potential of general applicability for cellular therapies.

Study EGAS00001002478

Targeting PTPRK-RSPO3 colon tumours promotesdifferentiation and loss of stem-cell function

Colorectal cancer remains a major unmet medical need, promptinglarge-scale genomics efforts in the field to identify moleculardrivers for which targeted therapies might be developed. Wepreviously reported the identification of recurrent translocationsin R-spondin proteins present in a subset of colorectal tumours.Here we show that targeting RSPO3 in PTPRK-RSPO3-fusion positivehuman tumour xenografts inhibits tumour growth andpromotes differentiation. Notably, genes expressed in the stem-cellcompartment of the intestine were among those most sensitive toanti-RSPO3 treatment. This observation, combined with functionalassays, suggests that a stem-cell compartment drives PTPRK-RSPO3colorectal tumour growth and indicates that the therapeutictargeting of stem-cell properties within tumours may be a clinicallyrelevant approach for the treatment of colorectal tumors.

Study EGAS00001001462

Sampling of multi-centric lower grade glioma influences management and provides insight into gliomagenesis

Rare multicentric lower-grade gliomas (LGG) represent a unique opportunity to study the heterogeneity between distinct tumor foci in a single patient, and to infer their origins and parallel patterns of evolution. In this study, we integrate clinical features, histology and immunohistochemistry for 4 patients with multicentric LGG, arising both synchronously and metachronously. For 3 patients we analyze the phylogeny of the lesions using exome sequencing, including one case with a total of 8 samples from the two lesions. We show that each tumor in multicentric LGG cases may arise independently or may diverge very early in their development, presenting as genetically and histologically distinct tumors suggesting that comprehensive sampling of these lesions can significantly alter diagnosis and management.

Study EGAS00001002495

Pilot_experiment_on_functional_genomics_in_osteoarthritis_RNA

The aim of this work is to apply an integrated systems approach to understand the biological underpinnings of large joint (hip and knee) osteoarthritis which culminates in the need for total joint replacement (TJR). In this pilot we will assess the feasibility of the approach in the relevant tissue. We will obtain diseased and non-diseased tissue (cartilage and endochondral bone) following TJR, coupled with a blood sample, from 12 patients. We will characterise the 12 pairs of diseased and non-diseased tissue samples in terms of transcription (RNASeq) The pilot will help assess the feasibility of isolating sufficient levels of starting material for the different approaches, and will instigate the development of analytical approaches to synthesising the resulting data.

Study EGAS00001001203

Heterogeneous endocrine cell composition defines human islet functional phenotypes

Phenotyping and genotyping initiatives within the Integrated Islet Distribution Program (IIDP), the largest source of human islets for research in the U.S., provide standardized assessment of islet preparations distributed to researchers, enabling the integration of multiple data types. Data from islets of the first 299 organ donors without diabetes, analyzed using this pipeline, highlights substantial heterogeneity in islet cell composition associated with hormone secretory traits, sex, reported race and ethnicity, genetically predicted ancestry, and genetic risk for type 2 diabetes (T2D). While α and β cell composition influenced insulin and glucagon secretory traits, the abundance of δ cells showed the strongest association with insulin secretion and was also associated with the genetic risk score (GRS) for T2D. These findings have important implications for understanding mechanisms underlying diabetes heterogeneity and islet dysfunction and may provide insight into strategies for personalized medicine and β cell replacement therapy.

Study EGAS50000000697

Study for establishment for effective screening and diagnosis of Lynch syndrome

The purpose of this study is to establish efficient diagnostic procedure of the Lynch syndrome in Japan and to determine the MMR gene mutation spectrum and clinicopathologic characteristics.The person who is suspected Lynch Syndrome and gives informed consent for participation in this study .To carry out the project ?Construction of clinical and genetic integral information database to help Lynch syndrome management?, the following three are required. 1) screening for Lynch syndrome-suspected cases, 2) genetic testing to define Lynch syndrome, 3) integration of detailed clinical data of Lynch syndrome, and 4) The case which has not been diagnosed Lynch syndrome, is investigated causing gene.

Study JGAS000638

CONSERTING: integrating copy number analysis with structural variation detection

We developed Copy Number Segmentation by Regression Tree in Next Generation Sequencing (CONSERTING), a novel algorithm for detecting somatic copy number alteration (CNA) using whole-genome sequencing (WGS) data. CONSERTING performs iterative analysis of segmentation by read depth change and localized structural variation detection to achieve high accuracy and sensitivity. Analysis of 43 pediatric and adult cancer genomes revealed novel oncogenic CNAs, complex re-arrangements and subclonal CNAs missed by alternative approaches. This study contains all data for "CONSERTING: an accurate method for detecting somatic DNA copy number alterations in whole genome sequencing data", which was previously split between EGAS00001001202 and EGAS00001001050.

Study EGAS00001001202

Genome-wide genetic and epigenetic dataset of pancreatic acinar cell carcinomas

Pancreatic acinar cell carcinoma (ACC) is an aggressive exocrine tumor with largely unknown biology. To identify potential targets for personalized treatment, integrative genome- and epigenome-wide analyses were performed. The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures suggesting defective DNA repair. In contrast to pancreatic ductal adenocarcinoma, no recurrent point mutations are known. The tumor suppressors ID3, ARID1A, APC, and CDKN2A are frequently impaired also on the protein level and thus potentially affect ACC tumorigenesis. Consequently, this work identifies potential novel therapeutic targets in ACC for drugs recently approved for precision cancer therapy.

Study EGAS00001002533

Drug screening of patient-derived organoids from colorectal peritoneal metastases

Colorectal cancer (CRC) patients with peritoneal metastases (CRPM) have limited treatment options and the lowest CRC survival rates. We trialed the possibility of organoid directed precision treatment for CRPM patients. CRPM organoids (peritonoids) isolated from patients underwent next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing. Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for 2 patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications. In conclusion, our approach is feasible, reproducible and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.

Study phs002023

DAC for human-derived clonal organoid studies

This is the DAC for human-derived clonal organoid culture studies. It includes the study to investigate the clonal evolution of metastatic CRC at the single-cell level, where we performed WGS in 58 clonal organoids and 18 fresh-frozen (FT) bulk-tissue samples from surgically resected primary and metastatic tumors before and after anticancer therapies in 6 patients. This approach enabled detailed phylogenetic reconstruction of individual clones. We discovered the timing and burden of treatment-related mutations as well as the heterogeneous evolution in driver mutations and genomic rearrangements in late-stage clonal evolution under anticancer therapies in metastatic CRC.

Dac EGAC50000000628

The genomic landscape of lung adenocarcinoma in East Asians

We performed exome sequencing of 210 and transcriptome sequencing of 181 LUADs of Chinese patients. For more details, please see publication "Genomic landscape of lung adenocarcinoma in East Asians" by Chen J. et. al. in Nature Genetics 2020. https://www.nature.com/articles/s41588-019-0569-6.

Study EGAS00001002941

Plasma sequencing data for ctDNA monitoring for NSCLC in TRACERx

Ultrasensitive circulating tumour DNA (ctDNA) detection can stratify clinical risk in early-stage non-small cell lung cancer (NSCLC). Here, we applied a whole-genome, tumour-informed approach to study ctDNA in more than 400 NSCLC of the TRACERx project. This study captures the plasma sequencing data from the project.

Study EGAS50000001767

Hereditary Cancer Diagnostics with I2HCP gene panel

Germline blood DNA sequencing data generated in routine diagnostics of hereditary cancer using the I2HCP gene panel (~135 genes). There are 130 samples sequenced in a MiSeq machine and 108 sequenced in a HiSeq machine. There is a partial overlap between those two sets, meaning that some samples were sequenced in both machines. There is a strong enrichment in samples with copy-number variants (CNV), both single- and multi-exon, since this dataset was compiled for a benchmarking effort of CNV calling tools for genetic diagnostics.

Dataset EGAD00001006171

PD-associated regulatory variants in human dopaminergic neurons reveals modulators of SCARB2 and BAG3 expression

SNPs have been associated with the risk of Parkinson’s disease but not in regulatory regions. While those potentially disrupt TFBS altering gene expression and contributing to cis-regulatory variation. To study changes in A and B compartment interactions and in topologically associated domains (TADs), we sequenced: - 3D chromatin contact using LowC, 6 samples. 3 replicates for each condition: smNPC (controls) cells and differentiated neurons after 30 days. Resulting paired-end are provided as BAM files. In order to confirm the predicted impact of the PD-associated allele of rs144814361 on BAG3 promoter, we proceeded with genome editing of the TH-REP1 cell line by using prime editing to insert the “T” allele at the position chr10:119651405 in the BAG3 promoter. - Chromatin accessibility using ATAC-seq, 9 samples of derived cell line TH-REP1. 3 replicates for each condition: 1) iPSC Wild Type 2) SNP-BAG3 variant in iPSC 3) SNP-BAG3 variant in smNPC. BAG3 variant: heterozygous for the SNP variant: rs144814361 (chr10 119651405) Resulting sequencing are provided as paired-end FASTQ files.

Dataset EGAD50000002258

Whole exome and transcriptome analysis of UV-exposed epidermis and carcinoma in situ reveals early drivers of carcinogenesis

Squamous cell carcinoma in situ (SCCIS) is a prevalent precancerous lesion that can progress to cutaneous squamous cell carcinoma (cSCC). Although SCCIS is common, its pathogenesis remains poorly understood. To better understand SCCIS development, we performed laser-captured microdissection of human SCCIS and adjacent epidermis to isolate genomic DNA and RNA for next generation sequencing. Whole exome sequencing (WES) identified UV-signature mutations in multiple genes including Notch 1-3 (GeneID:4851, GeneID:4853, GeneID:4854) in the epidermis and SCCIS and oncogenic TP53 (GeneID:7157) mutations in SCCIS. Novel gene families, including SCHLAFEN genes, contained UV/oxidative-signature disruptive (UVD) epidermal mutations that manifested positive selection in SCCIS. The frequency and distribution of NOTCH and TP53 mutations indicate that NOTCH mutations may precede TP53 mutations. RNA sequencing identified 1166 differentially expressed genes; the top 5 enriched GO biological processes included: 1) immune response, 2) epidermal development, 3) protein phosphorylation, 4) regulation of catalytic activity, and 5) cytoskeletal regulation. The NEURL1 ubiquitin ligase, which targets Notch ligands for degradation, was upregulated in SCCIS. Neuralized 1 protein was found to be elevated in SCCIS suggesting that increased levels could represent a novel mechanism for downregulating Notch during UV-induced carcinogenesis. The data from DNA and RNA sequencing of epidermis and SCCIS provide insights regarding SCCIS formation.

Study phs002019

Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma Pathology

Multiple Myeloma (MM) develops from well-defined precursor stages known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering MM (SMM); however, invasive bone marrow (BM) biopsy limits screening and monitoring strategies for patients. In this study, we enumerated circulating tumor cells (CTCs) from patients with precursor and overt diseases, and developed a novel approach, MinimuMM-seq, which enables detection of translocations and copy number abnormalities through whole-genome sequencing of highly pure CTCs. In a cohort of 51 patients, 24 with paired BM, we applied our method MinimuMM-seq and detected 100% of clinically reported BM biopsy events. The next-generation sequencing (NGS) assay could replace molecular cytogenetics by Fluorescence In Situ Hybridization (FISH) for diagnostic yield and risk classification. In 8 patients we could apply MinimuMM-seq on serially collected samples to track and monitor major clones in peripheral blood. We describe clonal evolution and shifting dynamics of subclones over time, as well as in between blood and marrow compartments. All whole-genome sequencing (WGS) data generated in this study will be made accessible through dbGaP.

Study phs003084

Reference Exome Data for a Northern Brazilian population

Whole exome sequencing (WES) is a popular technology widely used in the diagnosis of rare genetic diseases and provides useful variant data for analysis of complex diseases. However, there is not always adequate population-specific reference data available to assist clinical geneticists in assigning a diagnostic variant to a specific clinical condition. Here we provide a catalogue of variants called after sequencing the exomes of 45 babies from the State of Rio Grande do Nord in Brazil. Sequence data were processed using an ‘intersect-then-combine’ (ITC) approach, using GATK and SAMtools to call variants. A total of 612,761 variants were identified in at least one individual in this Brazilian Cohort, including 559,448 single nucleotide variants (SNVs) and 53,313 insertion/deletions. Of these, 58,111 overlapped with nonsynonymous (nsSNVs) or splice site (ssSNVs) SNVs in dbNSFP. As an aid to clinical diagnosis of rare diseases, we used the American College of Medicine Genetics and Genomics (ACMG) guidelines to assign pathogenic/likely pathogenic status to 439 (0.755%) of the 58,111 nsSNVs and ssSNVs. Our data set provides a useful reference point for diagnosis of rare diseases in Brazil.

Study EGAS00001004112

Patient-tailored design for selective co-inhibition of leukemic cell subpopulations

The extensive primary and secondary drug resistance in many cancer types requires rational approaches to design personalized and selective combinatorial therapies that do not only show synergistic effect in overall cancer cell killing but also result in minimal toxic side effects on non-malignant cells. To address the combinatorial explosion in the number of relevant combinations, we implemented a machine learning approach that prioritizes patient-customized drug combinations with a desired synergy-efficacy-toxicity balance by combining single-cell RNA-sequencing with ex vivo single-agent testing in scarce patient-derived primary cells. When applied to two diagnostic and two refractory AML patient cases, each with a different genetic background, our integrated approach accurately predicted patient-specific combinations that were shown to result not only in synergistic cancer cell co-inhibition but were also capable of targeting specific AML cell subpopulations that emerge in differing stages of disease pathogenesis or treatment regimens. Our data-driven approach provides an unbiased means for systematic identification of personalized combinatorial regimens that selectively co-inhibit leukemic cells while avoiding inhibition of non-malignant cells, and highlight the relevance of considering cell heterogeneity for personalized cancer therapy.

Study EGAS00001004614

Search for Susceptibility Genes for Diabetic Nephropathy in Type 1 Diabetes (GoKinD study participants and parents), NIDDK

Genetics of Kidneys in Diabetes (GoKinD) study is an initiative aimed at identifying susceptibility genes for diabetic nephropathy in type 1 diabetes. A large number of individuals with type 1 diabetes were screened to identify two subsets, one with clear-cut kidney disease and another with normal renal status despite long-term diabetes. Those who met additional entry criteria and consented to participate were enrolled. When possible, both parents were also enrolled to form family trios. Altogether, GoKinD includes 3043 participants comprising 931 cases, 944 singletons, 268 pairs of parents of cases, and 316 pairs of parents of control. Accessible as a GAIN database are 905 of the cases, 890 of the controls, 10 pairs of parents of cases and 10 pairs of parents of controls (dbGaP phs000018 Search for Susceptibility Genes for Diabetic Nephropathy in Type 1 Diabetes (GoKinD study participants), GAIN). The other parents and the remaining cases and controls are available by a separate application process through NIDDK. Interested investigators may request the DNA collection and corresponding clinical data for GoKinD participants using the instructions and application form available at http://www.niddkrepository.org or by contacting the Juvenile Diabetes Research Foundation.

Study phs000088

CIDR: Genome Wide Association Study in Familial Parkinson Disease (PD)

This proposal brings together the two largest NIH funded genetic studies focused on the identification of novel genes that influence the risk of PD. These two studies, PROGENI (PI: Tatiana Foroud; R01NS037167) and GenePD (PI: Richard Myers; R01NS036711) have been evaluating and recruiting families with two or more PD affected members for more than 8 years and represent the largest such cohorts world-wide. The combined sample has more than 1,000 PD families. Each study has used rigorous clinical criteria to assess their study participants. Unlike previous genome wide association studies (GWAS) in PD, all the PD cases in this proposal have a positive family history of disease. In the vast majority of these families, the index PD case has at least one sibling with the disease. Thus, the sample is unique for having substantial evidence for a genetic contribution to disease. The control group for this study consists of samples previously collected and maintained by the NINDS Repository. Genome-wide, single nucleotide polymorphism (SNP) genotyping services were provided by the Center for Inherited Disease Research (CIDR). Data analyses will focus on the identification of SNPs associated with PD susceptibility and the age of onset of disease.

Study phs000126

Search for Susceptibility Genes for Diabetic Nephropathy in Type 1 Diabetes (GoKinD study participants), GAIN

Genetics of Kidneys in Diabetes (GoKinD) study is an initiative aimed at identifying susceptibility genes for diabetic nephropathy in type 1 diabetes. A large number of individuals with type 1 diabetes were screened to identify two subsets, one with clear-cut kidney disease and another with normal renal status despite long-term diabetes. Those who met additional entry criteria and consented to participate were enrolled. When possible, both parents were also enrolled to form family trios. Altogether, GoKinD includes 3043 participants comprising 931 cases, 944 singletons, 268 pairs of parents of cases, and 316 pairs of parents of control. Accessible as a GAIN database are 905 of the cases, 890 of the controls, 10 pairs of parents of cases and 10 pairs of parents of controls. The other parents and the remaining cases and controls are available by a separate application process through NIDDK (dbGaP phs000088 Search for Susceptibility Genes for Diabetic Nephropathy in Type 1 Diabetes (GoKinD study participants and parents), NIDDK). Interested investigators may request the DNA collection and corresponding clinical data for GoKinD participants using the instructions and application form available at Juvenile Diabetes Research Foundation. Consent groups and participant set Diabetic complications only (DCO): 1825 (904 cases, 881 controls, 40 others)

Study phs000018

DEMENTIA-SEQ: WGS in Lewy Body Dementia and Frontotemporal Dementia

Lewy body dementia, amyotrophic lateral sclerosis/frontotemporal dementia, and multiple system atrophy are age-related, neurodegenerative syndromes that are poorly understood. Delineating the genetic risk that is driving the pathophysiology of these neurological diseases is fundamental for understanding disease mechanisms and for developing disease-modifying treatments. In version 1 of the study/dbGaP deposition, we performed a whole-genome sequencing study consisting of 7,403 total samples, including 2,633 genomes from patients with Lewy body dementia, 2,641 frontotemporal dementia patients, and 1,980 neurologically healthy controls. Of these, 6,907 were uploaded to dbGaP as the basis of the DementiaSeq, phs001963 dataset. The data relating to these samples are available on dbGaP. In version 2 of this study/dbGaP deposition, we made much of these data available on Anvil. More specifically, data for 6,254 of these samples were also uploaded to the ALS Compute platform on AnVIL. The data for the remaining 653 samples are only available on dbGaP. The dbGaP/AnVIL Table lists the availability of dbGaP and AnVIL for each individual sample: phd008475.In version 3 of the study/dbGaP deposition, we added whole-genome sequence data generated using DNA samples obtained from 683 patients diagnosed with multiple system atrophy.

Study phs001963

Identification of biomarkers of response to preoperative talazoparib monotherapy in treatment naïve gBRCA+ breast cancers

Germline mutations in BRCA1 or BRCA2 exist in ~2-7% of breast cancer patients, which has led to the approval of PARP inhibitors in the advanced setting. We have previously reported a phase II neoadjuvant trial of single agent talazoparib for patients with germline BRCA pathogenic variants with a pathologic complete response (pCR) rate of 53%. As nearly half of the patients treated did not have pCR, better strategies are needed to overcome treatment resistance. To this end, we conducted multi-omic analysis of 13 treatment naïve breast cancer tumors from patients that went on to receive single-agent neoadjuvant talazoparib. We looked for biomarkers that were predictive of response (assessed by residual cancer burden) after 6 months of therapy. We found that all resistant tumors exhibited either the loss of SHLD2, expression of a hypoxia signature, or expression of a stem cell signature. These results indicate that the deep analysis of pre-treatment tumors can identify biomarkers that are predictive of response to talazoparib and potentially other PARP inhibitors, and provides a framework that will allow for better selection of patients for treatment, as well as a roadmap for the development of novel combination therapies to prevent emergence of resistance.

Study EGAS00001005676

Chromatin immunoprecipitation linked to next-generation whole genome sequencing (ChIP-Seq) for H3K36me3 in paediatric high grade glioma cell lines KKNS4 and SF188 with and without a G34V mutation in H3F3A

Glioblastomas of children and young adults have a median survival of only 12-15months and are clinically and biologically distinct from histologically similar cancers in older adults1. They are defined by highly specific mutations in the gene encoding the histone H3.3 variant H3F3A2, occurring either at or close to key residues marked by methylation for regulation of transcription – K27 and G34. We performed chromatin immunoprecipitation linked to next-generation whole genome sequencing (ChIP-Seq) for H3K36me3 in order to test the hypothesis that, rather than total H3K36me3, the G34V mutation may instead result in differential binding of the trimethyl mark throughout the genome. Compared with H3F3A wild-type SF188 paediatric GBM cells, H3K36me3 was found to be significantly differentially bound in KNS42 cells at 5130 distinct regions of the genome corresponding to 156 genes. Concurrent whole genome DNA sequencing demonstrated that this was not confounded by copy number alterations. The cerebral hemispheric-specific G34 mutation drives a distinct expression signature through differential genomic binding of the K36 trimethylation mark (H3K36me3). The transcriptional program induced recapitulates that of the developing forebrain, and involves numerous markers of stem cell maintenance, cell fate decisions and self-renewal. Critically, H3F3A G34 mutations cause profound upregulation of MYCN, a potent oncogene which is causative of glioblastomas when expressed in the correct developmental context. This driving aberration is selectively targetable in this patient population by inhibiting kinases responsible for stabilisation of the protein.

Study EGAS00001001437

Combination of ribociclib and gemcitabine for the treatment of medulloblastoma

Group 3 (G3) medulloblastoma (MB) is one of the deadliest forms of the disease for which novel treatment is desperately needed. Here we evaluate ribociclib, a highly selective CDK4/6 inhibitor, with gemcitabine in mouse and human G3 MBs. Ribociclib CNS penetration was assessed by in vivo microdialysis and by immunohistochemistry and gene expression studies. Survival studies to determine the efficacy of ribociclib and gemcitabine combination were performed on mice orthotopically implanted with luciferase labelled mouse and human G3 MB. Pharmacokinetic-pharmacodynamic outcomes and univariable survival models were analyzed to estimate survival. Gene activity inference using NetBID and tumor differentiation analysis investigated the effects of the combination after short and long-term treatments. Tumors from mice treated with oral ribociclib displayed inhibited RB phosphorylation, downregulated E2F target genes, and decreased proliferation. Treatment of mice with the combination of ribociclib and gemcitabine was well tolerated, slowed tumor progression and metastatic spread, and increased survival. Molecular analysis of treated versus untreated tumors showed a significant decrease in the activity and expression of genes involved in cell cycle progression and DNA damage response, and an increase in activity and expression of genes implicated in neuronal identity and neuronal differentiation. Ribociclib is CNS-penetrant. When administered/combined with gemcitabine in orthotopic G3 MB models resulted in improved survival. Our findings, with both mouse and human patient-derived-orthotopic xenograft models, suggest that this combination therapy has promise for children with G3 MB and may represent an effective treatment strategy for other CNS malignancies.

Study EGAS00001006001

Developing Allelic Imbalance Analysis from Single-Nucleus RNA-Seq Data

Single-cell RNA-seq (scRNA-seq) is emerging as a powerful tool for understanding gene function across diverse cells. Recently, this has included the use of allele-specific expression (ASE) analysis to better understand how variation in the human genome affects RNA expression at the single-cell level. We reasoned that, because intronic reads are more prevalent in single-nucleus RNA-Seq (snRNA-Seq) and introns are under lower purifying selection, and are thus enriched for genetic variants, that snRNA-seq should facilitate single-cell analysis of ASE. Here we demonstrate how experimental and computational choices can improve the results of allelic imbalance analysis. We explore how experimental choices, such as RNA source, read length, sequencing depth, genotyping, etc., impact the power of ASE-based methods. We developed a new suite of computational tools to process and analyze scRNA-seq and snRNA-seq for ASE. As hypothesized, we extracted more ASE information from reads in intronic regions than those in exonic regions and show how read length can be set to increase power. Additionally, hybrid selection improved our power to detect allelic imbalance in genes of interest. We also explored methods to recover allele-specific isoform expression levels from both long- and short-read snRNA-seq. Overall, we provide an end-to-end experimental and computational approach for future studies.

Study phs003749

17488 results for "free coins in fc 26 Visit Buyfc26coins.com for latest FC 26 coins news..Y2KA"

in 46.75 milliseconds.