15174 results for "cancer studies using rna-seq"

in 24.87 milliseconds.

• ATRX mutant neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal differentiation.

  Mutations and structural alterations of the SWI/SNF-like chromatin remodeler ATRX have been reported at high frequency in a number of adult and pediatric tumors1. However, the consequences of ATRX (Alpha Thalassemia/Mental Retardation, X-linked) mutations in cancer and their underlying epigenetic sensitivities remain ill defined. Particularly intriguing are the large N-terminal deletions of ATRX in neuroblastoma that generate in-frame fusion (IFF) proteins1–3 devoid of key chromatin interaction domains. Here we demonstrate that neuroblastoma cells harbouring ATRX IFFs have distinct gene expression programs compared to neuroblastoma cells that are wild type for ATRX. This is due in part to H3K27me3-mediated silencing of REST (RE1 Silencing Transcription Factor) target genes involved in neuronal differentiation. In turn, we find that ATRX IFF cells display exquisite sensitivity to EZH2 inhibition in both adherent and tumorsphere conditions, due in part to derepression of neurogenesis genes, including REST targets. Examination of the epigenomic landscape of a pediatric neuroblastoma tumor harboring an ATRX IFF revealed that H3K27me3 occupies a subset of REST target genes that are transcriptionally silenced, and are sensitive to EZH2 inhibition in our cell-based assays. Thus, our study greatly advances our understanding of indolent neuroblastoma and identifies EZH2 inhibition as a potential therapy for patients with ATRX mutant disease. Further, these studies may be applicable to other ATRX mutant pediatric malignancies, particularly those carrying similar structural alterations of ATRX.

  Study EGAS00001002507

• Assessing Neural Mechanisms of Injury in Inborn Errors of Urea Metabolism Using Structural MRI, Functional MRI, and Magnetic Resonance Spectroscopy

  Urea cycle disorders represent a group of rare inborn errors of metabolism that lead to accumulation of ammonia, a toxic product of protein metabolism. Individuals with urea cycle disorders cannot metabolize the ammonia that accumulates due to enzyme deficiency. The symptoms of these disorders may present at birth, childhood or adulthood (milder deficiencies). There are currently eight enzyme deficiencies that constitute the range of inborn errors of ureagenesis. This project will focus on the most common enzyme disorder of the urea cycle, ornithine transcarbamylase deficiency, inherited as an X-linked trait. This project will study cognitive and motor dysfunction in patients who are female carriers of ornithine transcarbamylase deficiency (OTCD) or are males with late onset presentation of OTCD, utilizing state of the art MRI (magnetic resonance imaging), a non -invasive technique. This project seeks to improve our understanding of the underlying neural mechanisms that contribute to metabolic, cognitive, sensory and motor abnormalities in urea cycle disorders, which although individually rare, collectively constitute a major cause of neonatal encephalopathy, leading to significant morbidity and mortality. As a result of this study, a greater understanding of the anatomic, cognitive, motor, and biochemical underpinnings of neurologic damage attributable to this metabolic disorder will be gained. Experimental approaches will combine sensory, cognitive and motor testing with structural, functional and molecular magnetic resonance imaging to study symptomatic and asymptomatic heterozygous female carriers of X-linked ornithine transcarbamylase deficiency (OTCD), and late onset hemizygous males. Participants to be included in the studies will range from ages 18-60 years and will be compared to an age-matched typically developed (TD) comparison group. For our research, we use anatomic MRI, functional Magnetic Resonance Imaging (fMRI), and magnetic resonance spectroscopy (MRS) to monitor brain activity. The technique of fMRI provides detailed maps of the brain areas underlying human mental activities. By using fMRI, we are able to observe how the brain is functioning while a person is performing a specific task, such as reading. We can not only observe differences in the structure of the brain, but can also measure differences in brain function and activity as well. This information will ultimately be used to provide a basis for designing more effective interventions and methods for early identification of learning disabilities in patients with OTCD and related disorders. We will also use MRS to study various brain chemicals such as glutamine using the non-invasive MRI imaging techniques.

  Study phs001108

• Genome-Wide Association Study of HCC in Non-Asian USA Population

  This GWAS of HCC relied on existing biological and data resources from 7 USA sites and one Canadian site which allows for the integration of genetic and environmental data. Total of 2199 case patients and 1103 non cancer controls were genotyped. Case patients are defined as patients with pathological or radiological diagnosis of HCC with and without chronic hepatitis C virus infection. Study was restricted to Caucasian population without prior infection with chronic HBV infection. All DNA samples were extracted from peripheral blood. Study population of the participated sites are: Site-1: University of Texas MD Anderson Cancer Center A hospital based-case-control study was initiated at UT MD Anderson Cancer Center in 2000 and approved by the Institutional Review Board of The University of Texas M. D. Anderson Cancer Center. Study design was previously described in detailed (1-3). Written informed consent for an interview and for a biological sample was obtained from each participant. At time of diagnosis prior to treatment exposure. Case patients were recruited from the population of patients with newly diagnosed HCC who were evaluated and treated at the institution's gastrointestinal medical and surgical oncology outpatient clinics. Inclusion criteria were as follows: a pathologically confirmed diagnosis of HCC, U.S. residency, and the ability to communicate in English. Patients with concurrent or past history of other types of cancers were excluded. Control subjects were healthy spouses of patients with cancers other than liver, gastrointestinal, lung, or head and neck (smoking-related cancers) undergoing treatment at our institution. Eligibility criteria for control subjects were the same as those for patients, except that control subjects could not have ever had cancer. A short, structured questionnaire was used to screen potential control subjects on the basis of eligibility criteria. Control subjects and patients were recruited simultaneously. Case patients and control subjects were interviewed by well-trained interviewers who followed a written protocol to guide ascertainment and reduce surveillance, interviewer, and recall bias. No proxy interviews were conducted. The interviewers used a structured and validated questionnaire to collect information about demographic characteristics and potential risk factors for HCC such as personal smoking history, alcohol use, medical history, occupational history, and family history of cancer. Blood samples from cases and controls were tested for HBV and HCV. HCV antibodies, hepatitis B surface antigen, and antibodies to hepatitis B core antigen were detected by use of a third-generation enzyme-linked immunosorbent assay (ELISA) (Abbott Laboratories, North Chicago, IL). Important clinical information were retrieved from patients' medical records. Total of 1188 case patients and 278 controls from MD Anderson study were genotyped. Site-2: Mayo Clinic Case patients and controls included in the study from Mayo clinic were recruited as part of Mayo International Hepatobiliary Neoplasia Register and Biorepository. Only USA patients and controls were participated. All cases and controls signed informed consent indicating their willingness to participate in genetic studies. Epidemiological and clinical data were collected from participants and retrieved from medical records. Total of 522 HCC case patients and 182 controls were genotyped in this study. Site-3: Toronto University Molecular Epidemiology of Hepatobiliary Tumors (HBT study, CAPCR 09-0289) is a hospital-based study that includes 1710 patients diagnosed with liver, bile duct or gallbladder adenocarcinoma (Hepatocellular carcinoma - HCC; cholangiocarcinoma - CCA; and gall bladder adenocarcinoma -GBCa) recruited at University Health Network (UHN) between 2009 and 2018. HBT study is a prospective study of cancer patients that collects self-reported demographic and epidemiological data, medical records/clinical information and blood samples for research purposes. Eligible patients recruited between 2009 and March 15 2016 were selected to participate in the Genome-Wide Association Study in Patients with Hepatocellular Carcinoma (GWAS in HCC, CAPCR 15-9943-CE), a sub-study of the HBT study. Eligible prospective patients recruited after March 15 2016 signed the Addendum to the HBT consent form and became eligible to participate in the GWAS in HCC study. Total of 271 cases and 21 controls were genotyped from Toronto University Site-4: University of Pittsburgh The design of the study has been described previously (4-6). Briefly, this population-based study enrolled 120 HCC patients and 230 matched controls from black, Hispanic, and non-Hispanic white residents of Los Angeles County who were between 18 and 74 years of age at diagnosis from January 1995 through December 2001. HCC Cases were identified through the Los Angeles County Cancer Surveillance Program. We sought to recruit up to two control subjects per case from the neighborhoods where HCC patients resided at the time of diagnosis, who were matched to the index case by sex, age (within 5 years), and race (Hispanic white, non-Hispanic white, black). Blood samples (plasma and buffy coat), medical and lifestyle factors were collected from all consenting participants. Total of 65 cases and 60 controls were genotyped in this study Site-5: South Western Dallas Under IRB approval, HCC Cases and controls were prospectively collected since 2015 from the outpatient Liver clinics from Parkland Health and Hospital System and UT Southwestern Medical Center, two large health systems in Dallas TX. A Total of 31 cases and 29 controls were genotyped from site 5. Site-6: Columbia University HCC patients from Columbia are those recruited as part of the Herbert Irving Comprehensive Cancer Center Database Shared Resource which seeks to recruit all cancer patients for potential future studies. The PI is Dr. Katherine Crew AAAL5871. This resource collects sociodemographic, lifestyle and clinical data on patients as well as a blood sample. Those who indicated on their consent form that they would participate in genetic studies were included. Total of 79 case patients with HCC were genotyped from Columbia University. Site-7: University of Michigan The study population included from University of Michigan were included from a prospective study of with chronic HCV infection recruited in Ann Arbor Patients who had under- gone liver transplantation, known coinfection with HIV, life expectancy <12 months due to extra-hepatic illnesses, or were receiving HCV treatment at enrolment, were excluded. Protocol, surveys, and data forms were developed where each enrolled patient completed the same questionnaire All patients provided written informed consent before enrolment in the study. The study was approved by the institutional review board or ethics committee at the University of Michigan. Detailed study description was previously published (7). Total of 44 cases and 347 controls were genotyped Site-8: Veteran Administration Medical Center in Houston This research including written informed consent form was jointly approved by Institutional Review Boards for the Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, Texas. Study details have been previously published (8). Briefly, we prospectively recruited consecutive HCV-infected veterans prior to their previously scheduled HCV clinic visit at a large tertiary care VA medical center between May 1, 2009 and December 31, 2012. Patients completed a research assistant (RA) administered survey interrogating medical and risk factor history including lifetime alcohol use, had anthropometric measurements taken, and completed a fasting venipuncture for performance of the FibroSure-ActiTest as a measure of hepatic pathology. We restricted our current analysis to individuals who were: (1) White male veterans between 18 and 70 years; (2) had no history of HCC, liver transplant, decompensated liver disease including ascites, dementia, or psychosis; (3) were serologically-confirmed to have chronic HCV and to be negative for both HIV and active HBV infection; (4) were not currently receiving anti-HCV pharmacotherapy; and (5) had FibroSURE testing shown F3/F4 fibrosis consistent with cirrhosis.

  Study phs001744

• CRCbiome: Gut metagenome of Norwegian screening participants using FIT sampling

  The study aims to characterize the gut metagenome of Norwegian screening participants and assess the ability of the gut metagenome to identify those at need for colonoscopy. Background: Colorectal cancer (CRC) screening reduces CRC incidence and mortality. However, current screening methods are either hampered by invasiveness or suboptimal performance, limiting their effectiveness as primary screening methods. To aid in the development of a non-invasive screening test with improved sensitivity and specificity, we have initiated a prospective biomarker study (CRCbiome), nested within a large randomized CRC screening trial in Norway. We aim to develop a microbiome-based classification algorithm to identify advanced colorectal lesions in screening participants testing positive for an immunochemical fecal occult blood test (FIT). We will also examine interactions with host factors, diet, lifestyle and prescription drugs. The prospective nature of the study also enables the analysis of changes in the gut microbiome following the removal of precancerous lesions. Methods: The CRCbiome study recruits participants enrolled in the Bowel Cancer Screening in Norway (BCSN) study, a randomized trial initiated in 2012 comparing once-only sigmoidoscopy to repeated biennial FIT, where women and men aged 50–74 years at study entry are invited to participate. Since 2017, participants randomized to FIT screening with a positive test result have been invited to join the CRCbiome study. Self-reported diet, lifestyle and demographic data are collected prior to colonoscopy after the positive FIT-test (baseline). Screening data, including colonoscopy findings are obtained from the BCSN database. Fecal samples for gut microbiome analyses are collected both before and 2 and 12 months after colonoscopy. Samples are analyzed using metagenome sequencing, with taxonomy profiles, and gene and pathway content as primary measures. CRCbiome data will also be linked to national registries to obtain information on prescription histories and cancer relevant outcomes occurring during the 10 year follow-up period. Discussion: The CRCbiome study will increase our understanding of how the gut microbiome, in combination with lifestyle and environmental factors, influences the early stages of colorectal carcinogenesis. This knowledge will be crucial to develop microbiome-based screening tools for CRC. By evaluating biomarker performance in a screening setting, using samples from the target population, the generalizability of the findings to future screening cohorts is likely to be high.

  Study EGAS50000000170

• Mucociliary Clearance Consortium (MCC) Longitudinal Study of Primary Ciliary Dyskinesia: Participants 5-18 Years of Age

  The purpose of this longitudinal study protocol is to define age-related prevalence of phenotypic characteristics and the progression of key features of lung disease in participants with one of these disorders, Primary Ciliary Dyskinesia (PCD). In PCD, the abnormal structure and function of cilia results in impaired clearance of secretions and consequent obstruction and chronic recurrent infection in the airways, sinuses and middle ears. Although it seems likely that the onset of PCD airway disease occurs early in childhood, as has been reported for cystic fibrosis (CF), the clinical course of PCD lung disease is not well defined, nor, is the time course of emergence of specific microbial pathogens, or the age of onset and rate of progression of airway disease and bronchiectasis. This longitudinal study is designed to define the rate of progression of PCD lung function in participants between 5-18 years of age using spirometry which tracks well with lung impairment and prognosis in other disorders of the airways such as cystic fibrosis. This longitudinal protocol will also systematically track other specific outcomes, including pathogens infecting the airways (assessed by respiratory cultures), and age at onset and progression of airway damage and bronchiectasis (assessed by high-resolution computerized tomography, HRCT, of the chest). Blood will be collected for DNA to test for genetic mutations. The blood samples will be processed to establish a cell line (lymphocyte transformation) for a source of DNA for future genetic studies, in participants with disease. For participants unable to provide a blood sample, a buccal sample will be obtained for DNA.

  Study phs000596

• Chromothripsis in Patient WHIM-09

  We are studying the natural history, pathogenesis and treatment of patients with WHIM syndrome, an immunodeficiency disorder characterized by warts, hypogammaglobulinemia, recurrent infections and neutropenia usually due to autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. We have identified a patient born with WHIM syndrome and the WHIM mutation CXCR4R334X who has been disease-free for 20 years and who lacks CXCR4R334X in myeloid cells, the cells that drive disease manifestations. She is a genetic and hematopoietic mosaic, since she still has the mutation in lymphoid cells and non-hematopoietic cells. Cytogenetics and microarray analysis revealed that the mechanism of loss of the mutation was deletion of the mutant allele from one copy of chromosome 2. Whole genome sequencing of patient neutrophil and skin fibroblast genomic DNA revealed that the mechanism of deletion was chromothripsis, a process of chromosome shattering resulting in deletions and rearrangements of the non-deleted chromosomal segments. In the patient, this process evidently occurred in a single hematopoietic stem cell (HSC), resulting in deletion of the disease allele CXCR4R334X and one copy of 163 other genes on chromosome 2. This HSC evidently acquired a growth advantage and repopulated the HSC population and the myeloid lineage. Consistent with this, studies using gene targeted mice in competitive bone marrow transplantation experiments revealed that selective Cxcr4 haploinsufficiency (inactivation of one copy of Cxcr4 and not of any other genes) was sufficient to confer a strong engraftment advantage over bone marrow cells from wild type mice as well as bone marrow cells from a mouse model of WHIM syndrome. These results suggest that CXCR4 knockdown may be a useful strategy to enhance bone marrow engraftment in the absence of toxic bone marrow conditioning regimens.

  Study phs000856

• Gene mutation and rescue in congenital diaphragmatic hernia

  Congenital Diaphragmatic Hernia (CDH) is a common and life-threatening malformation. The most common phenotype is left-sided posterolateral (Bochdalek-type) hernia accompanied by pulmonary hypoplasia. Due to the high mortality, most of the cases have no family history for CDH. The rare presumed Mendelian instances of CDH have the potential to be extremely informative about the molecular mechanisms generating this phenotype. Three multiplex families were deemed meritorious for study by whole exome sequencing: Parents who were 1st cousins gave birth to 2 children with CDH (one of whom also had cleft lip and palate), both now deceased. A DNA sample was available from one child. We proposed to perform a SNP array to identify regions of homozygosity by descent and intersect these regions with variants detected on exome sequencing. This effort has led to the identification of 3 confirmed variants. We are determining which if any are expressed in the primordial developing diaphragm and are also using bioinformatic approaches to determine which of these candidates interact with known CDH genes. This non-consanguineous couple gave birth to 2 affected boys with an identical and lethal CDH phenotype (consisting of diaphragmatic hernia, epigastric hernia, and facial dysmorphism) and one healthy boy. We predicted X-linked inheritance and findings from X chromosome microsatellite marker analysis are consistent with this. Accordingly, we are focusing on sequence variants mapping to the X chromosome. We have identified a single candidate gene and confirmed that the variant follows an X-linked pattern of inheritance in all family members. Expression studies are underway. These affected males are second cousins. By virtue of their position in the pedigree, we predicted an inheritance pattern consistent with X-linked inheritance. Data from WES and microsatellite marker analysis are currently being integrated.

  Study phs000485

• Center Common Disease Genomics [CCDG] - Cardiovascular: Partners Biobank

  This study is a part of NHGRI's Center for Common Disease Genomics, a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will perform whole genome sequencing of 140K individuals and whole exome sequencing of 225K individuals over the course of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation, congestive heart failure and type 2 diabetes. CAD is the leading cause of death in the world and common variant association studies show that our understanding of the underlying molecular mechanisms is incomplete (e.g, >2/3 of the 63 common variants previously mapped for CAD do not directly relate to known risk factors). CAD is representative of a class of common diseases with onset at middle age. When CAD occurs early in life, there is a stronger inherited component. In addition, there is empirical evidence that a burden of rare coding alleles in individual genes contribute to risk for CAD. Source: https://ccdg.rutgers.edu/sites/default/files/CCDG_CVD_EOCAD_STROKE_FINAL.pdf For this study, The Broad Institute of MIT and Harvard generated genetic data for ~13,500 individuals from the Partners Biobank, including using whole exome sequencing and whole genome genotyping (Infinium Global Screening Array), with 550 samples from patients with myocardial infarction, a type of EOCAD. Partners Biobank, launched in 2010, is a biobank composed of samples from Partners hospitals, including Massachusetts General Hospital and Brigham and Women's Hospital. The Biobank has enrolled >100K individuals to study how genes, lifestyle, and other factors affect people's health and contribute to disease.

  Study phs002018

• UK10K NEURO FSZ

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. These Finnish schizophrenia samples have been collected from a population cohort using national registers. The entire sample collection consists of 2756 individuals from 458 families of whom 931 are diagnosed with schizophrenia spectrum disorder, each family having at least two affected siblings. 170 families originate from an internal isolate (Kuusamo) with a three-fold lifetime risk for the trait. The genealogy of the internal isolate is well documented and the individuals form a “megapedigree” reaching to the 17th Century. All diagnoses are based on DSM-IV and for a large fraction of cases there is cognitive data. For further details/descriptions with regard to this data set please contact Tiina Paunio (tiina.paunio@thl.fi)

  Study EGAS00001000118

• The Immune Microenvironment, Genome–Wide Copy Number Aberrations and Survival in Mesothelioma

  IntroductionResults of recent clinical studies of immune checkpoint inhibitors in malignant pleural mesothelioma (MPM) have dampened initial enthusiasm. However, the immune environment and targets of these treatments such as program cell death protein 1 (PD-1) and its ligand PD-L1 have not been well characterised in MPM. Using a large cohort of patients, we investigated PD-L1 expression, immune infiltrates and genome-wide copy number status and correlated them to clinicopathological features.Patients and methodsTissue microarrays were constructed and stained with PD-L1(clone E1L3N, CST), CD4, CD8 and FOXP3 antibodies. PD-L1 positivity was defined as ≥5% membranous staining regardless of intensity and PD-L1+hi as ≥50%. Genomic DNA from a representative subset of 113 patients was used for genome-wide copy number analysis. The percent genome alteration (PGA) was computed as a proxy for genomic instability, and statistical analyses were used to relate copy number aberrations (CNA) to other variables.ResultsAmongst 329 patients evaluated, PD-L1+ was detected in 130/311 (41.7%), but PD-L1+hi was only seen in 30/311 (9.6%). PD-L1+ correlated with non–epithelioid histology and increased infiltration with CD4+, CD8+ and FOXP3+ lymphocytes. PD-L1+hi expression correlated with worse prognosis (HR = 2.37; 95%CI= 1.57-3.56; P < 0.001) on univariate analysis, but not in multivariate analysis. Higher PGA was associated with epithelioid histology and poorer survival (HR = 1.59; 95%CI= 1.01-2.5; P = 0.04), but not PD-L1 expression.ConclusionPD-L1 expression was associated with non-epithelioid MPM, poor clinical outcome and increased immunological infiltrates. Increased genomic instability did not correlate with PD-L1 expression, but was associated with poorer survival.

  Study EGAS00001002323