Search Results - EGA European Genome-Phenome Archive

Age related Macular Degeneration (AMD) - Michigan, Mayo, AREDS, Pennsylvania (MMAP) Cohort Study: Association and Sequencing Studies

Age-related Macular Degeneration (AMD) is a leading cause of incurable blindness in people over the age of 65. AMD is a late-onset multi-factorial neurodegenerative disease and its pathogenesis involves interaction of genetic and environmental factors. Several chromosomal regions have been associated with AMD susceptibility through linkage analysis (Swaroop et al., 2009). More recent studies provide strong evidence that variants within the CFH gene cluster on chromosome 1 and at/near LOC387715/ARMS2 on chromosome 10 are strongly associated with the disease. Variants at other genes including C2/BF, C3, CFI and APOE4, also contribute to AMD susceptibility. Our primary goals are to identify genetic variants and haplotypes that are associated with AMD. The underlying hypothesis is that DNA variation(s) in multiple genetic susceptibility loci will predispose individuals to AMD pathogenesis, and comparison of DNA of cases and controls should identify these susceptibility variants. Our studies are focused on the genetic analysis of advanced AMD and should provide novel insights into disease diagnosis, progression and pathology. We have assembled a collaborative group of researchers from the University of Michigan, Mayo Clinic, University of Pennsylvania, and the AREDS group including National Eye Institute intramural investigators, who collected clinical data and DNA from a large number of patients affected with AMD and from unaffected controls. The primary source of funding was National Eye Institute. Study 1: To identify genetic variants and haplotypes that are associated with AMD, we submitted and obtained usable genotyping data on 2185 patients and 1155 controls from the Center for Inherited Disease Research (CIDR). Study 2: To identify rare coding variants associated with a large increase in risk of AMD, 10 candidate loci spanning 57 genes were sequenced in 2,335 cases and 789 controls. Probes were designed to capture 96.5% of the coding sequence and 35% of total locus sequence, generating an average 123Mb of on-target sequence per individual at 127x average depth. Substudies: phs000182 AMD-MMAP Cohort Study: A Joint Genome-Wide Asscociation Study phs000246 Fuchs' Corneal Dystrophy GWAS phs000457 MMAP Methylation in AMD phs000685 Age-Related Macular Degeneration Targeted Sequencing Study

Study phs000684

Single-Cell Mitochondrial Mutation Lineage Tracing of Non-Dysplastic and Dysplastic Barrett's Esophagus

This study addresses a critical knowledge gap in understanding Barrett's esophagus (BE), a common metaplastic condition and precursor to esophageal adenocarcinoma, by identifying lineage connections and cell states underlying its development and malignant transformation. We collected biopsies from 13 Barrett's esophagus patients undergoing routine surveillance endoscopy, sampling metaplastic tissue alongside normal squamous esophagus and gastric cardia tissues when clinically appropriate. Our novel approach integrated single-cell RNA sequencing of nearly 180,000 cells with mitochondrial DNA mutation analysis for lineage tracing, coupled with spatial transcriptomics and comprehensive whole-exome sequencing. For one patient with high-grade dysplasia, we performed detailed whole-exome sequencing analysis at 100x coverage on dissociated Barrett's esophagus cells alongside matched normal esophagus and gastric cardia tissues. This genomic profiling revealed critical genetic drivers of malignant transformation, including a truncating mutation in the mutation cluster region of APC (a negative WNT regulator), mutations in the tumor suppressor genes CDKN2A and TP53, and significant copy number alterations including loss of CDKN2A on chromosome 9. These genetic alterations corresponded with the transcriptional changes observed in our single-cell data, particularly WNT pathway dysregulation and the expansion of LGR5-expressing stem cells, providing molecular evidence for how single clones can initiate the dysplastic transformation. Data deposited in dbGaP consist specifically of the whole-exome sequencing raw files, processed variant calls, and copy number analyses from the single patient with high-grade dysplasia and matched normal esophagus and stomach control tissue. Whole exome sequencing was performed on an Illumina NovaSeq 6000. Sequencing data was preprocessed following the Genome Analysis Toolkit's (GATK) Best Practices. Sequencing data was analyzed with Mutect2 (GATK, v4.2.5.0) to identify short somatic mutations including single-nucleotide polymorphisms and insertions and deletions. The Barrett's esophagus sample was run with the two matched normals, as well as the publicly available germline resource somatic-hg38_af-only-gnomad.hg38.vcf.gz (GATK). Somatic variant calls were filtered using FilterMutectCalls (GATK) and loaded into the Integrative Genomics Viewer (v2.12.3) for identification of high-quality variants in known esophageal adenocarcinoma regulators. Copy number alterations in the Barrett's esophagus sample were estimated using CNVkit (v0.9.9). CNV, Mutect2, and SVC analyses will be made available through dbGAP. Copy number alterations in the Barrett's esophagus sample were estimated using CNVkit (v0.9.9) with the default run settings; a pooled reference was generated from the normal esophagus and stomach samples. Copy number results were plotted directly within CNVkit using the function scatter.

Study phs003949

Medulloblastoma exome sequence analysis

Medulloblastomas are the most common malignant brain tumors in children. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles. Here, we utilized whole exome hybrid capture and Illumina sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, to our knowledge novel findings in medulloblastoma and all cancer. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma. "Reprinted from 'MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATION', with permission from Nature"

Study phs000504

Genomic Predictors of Response to Immune Checkpoint Therapy

Immune checkpoint therapies, including monoclonal antibodies to programmed cell death-1 (PD-1) and cytotoxic % lymphocyte associated protein-4 (CTLA-4), yield durable clinical responses across many tumor types, including metastatic melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, predictors of response to these therapies in RCC are still unknown. Genomic characterization of large clinical cohorts of patients treated with anti-CTLA-4 and anti-PD-1 agents in melanoma and NSCLC have suggested that high mutational burden, high neoantigen burden, and high expression of certain genes in pre-treatment tumors may be associated with patient response to these therapies. In this study, we sought to investigate genomic predictors of response to anti-PD1 therapy in metastatic RCC in two independent clinical cohorts using whole exome and whole transcriptome sequencing.

Study phs001493

MP2PRT: Identification of Genetic Changes Associated with Relapse and/or Adaptive Resistance in Patients Registered as Favorable Histology Wilms Tumor on AREN03B2

The Molecular Profiling to Predict Response to Treatment (MP2PRT) program is part of the NCI's Cancer Moonshot Initiative. The aim of this program is the retrospective characterization and analysis of biospecimens collected from completed NCI-sponsored trials of the National Clinical Trials Network and the NCI Community Oncology Research Program. This study, titled "Identification of Genetic Changes Associated with Relapse and/or Adaptive Resistance in Patients Registered as Favorable Histology Wilms Tumor on AREN03B2", performs genomic characterization (WGS 30X, Total RNAseq, miRNAseq) on a discovery set of 70 trio cases (normal tissue, tumor tissue at time of diagnosis, tumor tissue at time of relapse) from patients who relapsed with Favorable Histology Wilms Tumor. Prioritized findings from the discovery set will be validated using Targeted Sequencing in an independent validation set of 47 relapse samples.

Study phs001965

NHLBI TOPMed: Genetic Study of Atherosclerosis Risk (GeneSTAR)

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

Study phs001218

DEPArray-based sorting of pure carcinoma and stromal populations from formalin-fixed paraffin-embedded (FFPE) tissues followed by shallow whole genome sequencing

To overcome the challenges of low DNA yields, degraded DNA by formalin fixation and diluted signal of genomic aberrations by non-carcinoma components in the heterogeneous FFPE samples, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from 9 primary and metastatic breast cancer and 3 primary ovarian high-grade serous carcinomas. This was followed by downstream shallow whole genome sequencing (WGS) for copy number landscape profiling for 10 samples. Seven out of 10 samples (even some with low tumour content or of old age) produced good quality genomic data, detecting sCNA in all carcinoma population samples but not in the stromal populations.

Study EGAS50000001328

ENOC WGS for the study Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes

For ENOC cohorts, OvCaRe cases were reviewed, including frozen material, by at least two expert gynecopathologists prior to inclusion in the sequencing cohort who provided the confirmation on final selected cohort. Frozen H&E from Tokyo were also used for evaluation along with representative H&E photos and review done at the Jikei School of Medicine. For ENOC, DAH985 and DG1288 are recurrent and both were treated with chemotherapy after their first surgery. DAH123 is a untreated sample, metastasis from an primary endometrial tumour. All HGSC, GCT, CCOC and the rest ENOC tumours are primary tumour samples. Library construction and sequencing Frozen specimens with >50% tumour cellularity (based on initial slide review) were used for cryosectioning and subsequent nucleic acid extraction. Patient tumour and normal blood samples derived from primary, untreated fresh frozen tumour specimens harvested at diagnosis during standard of care debulking surgery. Germline DNA was provided from peripheral blood buffy coat on all specimens except 13 from Tokyo, where non-cancer frozen tissue was used as a germline source. DNA extraction from both matched normal (blood) and tumour samples (frozen tissue) were performed using the QIAamp Blood and Tissue DNA kit (Qiagen) and quantified using a Qbit fluorometer and reagents (high-sensitivity assay). Three lanes of Illumina HiSeq 2500 v4 chemistry for normal samples and five lanes for tumour samples were obtained. The PCR-free protocol was adopted to eliminate the PCR-induced bias and improve coverage across the genome.

Dataset EGAD00001003266

Assessment of Health-related Quality of Life in Rare Kidney Stones

The purpose of this study is to learn about Health-related Quality Of Life (HRQoL) in patients enrolled in the Rare Kidney Stone Consortium (RKSC) registries. Quality of life studies look at different aspects of both physical and mental components of people's lives. HRQoL data for people affected by kidney stones are not currently available for people followed over time. All participants enrolled in the RKSC registries will be invited, via email or postal mail, to participate in this study. Health-related quality of life in people with rare kidney stones enrolled in the RKSC registries will be measured. Instruments used in this study are the SF-10 for pediatric participants and SF-36v2 for adult participants. The surveys will be completed online. Participants without a computer or internet access will participate using a paper version of the survey. These surveys will be done at enrollment and annually thereafter. The SF-36v2 includes 36 questions and is estimated to take 15 minutes for its completion, while the SF-10 includes 10 questions and could be completed in 5 minutes. The research questions are: Assessment of HRQoL in patients with rare kidney stones. Comparison of HRQoL results between rare kidney stone formers, general population and other populations with relevant chronic diseases. Comparison of HRQoL results in the same populations affected by different stones and analyzed with attention to the effects of various factors included in the disease registry, such as stone activity, burden of urologic interventions, medication and other treatments. Evaluation of HRQoL and its trends over time in patients undergoing treatment for rare kidney stones. About this study: The plan is to have 400 participants from all four registries take part in this multi-center study. The assessment of your HRQoL will be done annually for 5 years.

Study phs001770

A Phase 2 Study of Tipifarnib in Large Granular Lymphocyte (LGL) Leukemia

LGL leukemia can be divided into three subsets including the following: αβ or γδT-LGL and NK-LGL leukemia. All three subtypes will be enrolled using a two-stage design. The primary endpoint of the study is assessment of overall clinical response. Correlative laboratory studies will be performed aimed at determining the mechanism of response to treatment. Thirteen participants will be accrued in the first stage at a dose of 300 mg BID administered intermittently every other week (i.e., 7 days on and 7 days off). If there are two or more responders, the protocol will be extended to a second stage of the study and accrual will be extended to 25 evaluable participants. Allowing for 10% rate of ineligibility due to unexpected events and dropout, we will accrue 14 patients in the first stage and 27 patients in total. Participants that withdraw from the study for reason unrelated to toxicity, will be replaced. There are two potential stopping rules for toxicity. If 3 or more participants out of the 13 enrolled in the first stage experiences grade IV neurotoxicity, the study will be stopped due to excessive toxicity. Dose reductions have been incorporated for hematologic toxicity. Treatment of T and NK LGL leukemia with immunosuppressive agents such as low-dose methotrexate generally require from four to six months for a clinical response and sometimes much longer. Therefore, in participants who show clinical improvement with less than grade three toxicity, tipifarnib treatment will be continued for as many as four additional months (12 months total). After the first 8 months, response will be assessed. The protocol treatment will be discontinued in participants with progression of disease. A long-term follow up will be performed for five years in patients that receive a complete clinical response. The long-term follow up will consist of vital signs, weight, CBCs, serum chemistries, and physical examination at six month intervals.

Study phs000594

15176 results for "cancer studies using rna-seq"

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