12515 results for ""non-traditional+communal+storytelling+approach"+novel+segment+noted+in+critical+commentary"

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• Mechanisms of Risk for Sulfonamide Hypersensitivity

  Hypersensitivity (HS) reactions to sulfonamide antibiotics occur uncommonly, but with potentially severe clinical manifestations. A familial predisposition to sulfonamide HS is suspected, but robust predictive genetic risk factors have yet to be identified. Strongly linked genetic polymorphisms have been used clinically as screening tests for other HS reactions prior to administration of high-risk drugs. The purpose of this study was to evaluate for genetic risk of sulfonamide HS in the immunocompetent population using genome-wide association. Ninety-one patients with symptoms after trimethoprim-sulfamethoxazole (TMP-SMX) attributable to "probable" drug HS based on medical record review and the Naranjo Adverse Drug Reaction Probability Scale, and 184 age- and sex-matched patients who tolerated a therapeutic course of TMP-SMX, were included in a genome-wide association study using both common and rare variant techniques. Additionally, two subgroups of HS patients with a more refined clinical phenotype (fever and rash; or fever, rash and eosinophilia) were evaluated separately. For the full dataset, no single nucleotide polymorphisms were suggestive of or reached genome-wide significance in the common variant analysis, nor was any genetic locus significant in the rare variant analysis. A single, possible gene locus association (COL12A1) was identified in the rare variant analysis for patients with both fever and rash, but the sample size was very small in this subgroup (n=16), and this may be a false positive finding. No other significant associations were found for the subgroups. No convincing genetic risk factors for sulfonamide HS were identified in this population. These negative findings may be due to challenges in accurately confirming the phenotype in exanthematous drug eruptions, or to unidentified gene-environment interactions influencing sulfonamide HS. Reprinted under PLOS ONE's open access license, CC-BY (http://www.plos.org/open-access).

  Study phs001124

• Genomic Profiling of Pediatric B-cell Acute Lymphoblastic Leukemia

  Pediatric leukemia is the most common type of childhood cancer and, despite tremendous progress in treatment, remains the second leading cause of cancer deaths in children. B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of pediatric leukemia. Recent studies using transcriptional profiling of large cohorts of pediatric B-ALL have shown that patients can be grouped into transcriptional subtypes that are often defined by specific driver mutations. Interestingly, many of these mutational subtypes are defined by gene fusions or rearrangements that drive altered expression of transcription factors (ETV6-RUNX1, PAX5, DUX4, TCF3-PBX1, ZNF384) or in chromatin regulatory machinery (KMT2A), suggesting that transcriptional dysregulation is a major driver of B-ALL. While the transcriptional distinctions are clear, the relationship between patients in terms of their chromatin regulatory landscape remains unclear. To address this, we profiled gene expression, open chromatin, and 3D genome folding in patient derived B-ALL samples. We identified that at the level of 3D genome organization, many chromatin interactions and looping events are shared across mutational subtypes, suggesting that shared transcriptional programs, in addition to group specific driver mutations, possibly regulate the chromatin landscape in B-ALL. Using RNA-seq and ATAC-seq data, we were able to identify "latent" signatures of expression related to non-mutant transcription factors (TFs) that also contribute to expression heterogeneity across TF subtypes. These are related to patient specific patterns of 3D genome folding, and in some cases, are predictive of disease outcomes. This study helps shed light on the chromatin landscape in B-ALL and furthers our understanding of the interactions between diverse mutant TFs that drive B-ALL and non-mutant TFs that help shape the B-ALL chromatin landscape.

  Study phs003226

• Puerto Rico Heart Health Program (PRHHP-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 investigate morbidity and mortality from Coronary Heart Disease (CHD) in Puerto Rican rural and urban men. The objectives of the study were: (1) to identify factors related to the development of CHD, (2) compare the etiology of disease in rural versus urban men, and (3) determine the prevalence and incidence of CHD and other cardiovascular diseases in Puerto Rican males.Background: As Puerto Rico became more industrialized in the 1940s and 1950s, mortality rates for CHD increased. Since many factors related to CHD can be relatively homogenous within a population, two contrasting subgroups were selected for study in Puerto Rico: a rural population of men from a mountainous community and an urban population selected from San Juan. The NHLBI initiated the Puerto Rico Heart Health Program in May, 1965 as a prospective study of lifestyle, environmental and biological factors in the progression of cardiovascular disease in Puerto Rican men.Participants: A total of 9,824 (2,976 rural, 6,848 urban) men, age 45 to 64 were examined at the baseline exam.Design: The examination consisted of standardized questionnaires to determine education, occupation, smoking habits, and physical activity. Trained interviewers conducted a nutritional survey through a 24 hour diet recall. Subjects were also examined to determine prevalent cardiovascular, cerebrovascular and peripheral vascular abnormalities. The examination included vital capacity, a 12-lead ECG, and laboratory tests for hematocrit, glucose, serum cholesterol, serum glycercides and lipoprotein electrophoresis. A medical history was also obtained. Three additional exams, approximately three years apart, were conducted and morbidity and mortality follow-up concluded in 1980.

  Study phs003930

• Molecular evolution of metastatic clear cell renal cell carcinoma progressing under tyrosine kinase inhibitor therapy (HIPO-045)

  Background:Acquired resistance to targeted drugs is largely due to intra-tumor molecular heterogeneity and clonal selection. Objective:The objective of this study was to determine molecular alterations and mediating resistant mechanisms and to suggest additional treatment options.Design, Setting, and Participants:Four patients were enrolled into the MORE (Molecular Renal Cancer Evolution) trial. We investigated the mutational spectra of metastatic clear cell renal cell carcinoma (ccRCC) at baseline and compared them to those upon clonal evolution at progression on systemic therapy with tyrosine kinase inhibitors.Outcome Measurements:DNA was isolated from tumor tissues after surgery, metastasis biopsies after progression on sunitinib or axitinib, and subjected to whole-exome sequencing (WES). In addition, the exomes of circulating tumor DNA (ctDNA) from two patients were sequenced at baseline and at progression.Results and Limitations:Our data provide evidence for clonal evolution and various acquired resistance mechanisms of ccRCC with subclonal mutations in FLT4, MTOR, ITGA3/5, SETD2, and VHL on metastatic progression. The limited number of shared mutations in tissue and plasma biopsies indicates that both sources provide complementary information, possibly due to mutations present in metastatic lesions which were not amenable to tissue sampling but are represented in the ctDNA. Conclusion:Acquired resistance to targeted therapies in metastatic ccRCC is due to intra-tumor heterogeneity and clonal evolution. Larger patient cohorts have to be studied to estimate the benefit of WES from biopsies and ctDNA for therapy decision in metastatic ccRCC.Patient Summary:We analyzed the molecular profiles of ccRCC patients in primary tissues and metastatic tissues upon progression on tyrosine kinase inhibitor therapy. Clinically relevant mutations upon progression were detected in the metastatic sites of all of four patients, suggesting that it might be possible to derive therapies based on sequencing the metastases.?HIPO-045

  Study EGAS00001001861

• Molecular_diagnosis_of_albinism

  Albinism is genetically heterogeneous rare genetic condition affecting 1:17000 in the Western world (but more frequent in Africa) whose main feature is a profound visual impairment, characterised by foveal hypoplasia, abnormal chiasmatic connections, nystagmus and photofobia. All these features result in severly altered visual acuity (<0,1), absent depth perception and poor night vision. People with albinism are primarily visually handicapped. In addition, for some types of albinism, the visual phenotype can be presented with partial or total hypopigmentation, hence resulting in a secondary phenotype which can lead to skin cancer if skin is not adequately protected. Recently a new syndrome has been described, FHONDA, with the same visual abnormalities of albinism but without pigment alteration. The traditional classification differentiates Oculoculatenous albinism (OCA), where hypopigmentation involves hair, skin and eyes versus Ocular Albinism (OA), where hypopigmentation only affects the eyes. These are non-sydrimic types of albinism. Some syndromic forms (Hermansky-Pudlak=HPS, Chediak-Higashi=CHS) affect cells beyond pigment cells, present in the lungs, immune system, platelets and intestines, resulting in more severe phenotypes that can be fatal. Mutations in at least 19 genes are assocaited with the corresponding types of albinism. Most hospitals will only diagnose the most frequent cases using traditional Sanger, MLPA approaches. Some will use CGH arrays. We aim to diagnose all cases of albinism through the Albinochip proposal, which combines a Sequenom first step of known mutations combined with subsequent NGS approaches. In some cases we fail to find a second mutation, these are good candidates for further full exome analyses. 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 EGAS00001002068

• Genetic characterization of B-cell prolymphocytic leukemia: a hierarchical prognostic model involving MYC and TP53 abnormalities - WXS

  B-PLL is a rare disease, whose molecular pathology is largely unknown. We report here the cytogenetic and molecular findings in a large series of 34 B-PLL. Karyotype (K) was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. The most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (62%), 17p deletion including TP53 gene (38%), trisomy 18/18q (30%), 13q14 deletion (29%), trisomy 3 (24%), trisomy 12 (24%) and 8p deletion (23%). Whole-Exome Sequencing performed in 16 patients revealed recurrent mutations in TP53 (6/16, 38%), MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2) and BCLAF1 (n=2). The main group of patients (21/34, 62%) had a t(MYC) associated with a higher percentage of prolymphocytes (p=0.03), CD38 expression (p<0.001), lower K complexity (p=0.0004), mutations in MYC and in genes involved in RNA metabolism and chromatin remodeling. Principal component analysis of gene expression data showed that patients with t(MYC) clustered together. A second group with MYC gain (5/34, 15%), was associated with HCK≥5 (p=0,01) and trisomy 3 (p=0,008). Altogether, 26/34 patients (76%) had a MYC activation, translocation or gain, that were mutually exclusive. We identified 3 distinct cytogenetic prognostic groups (p=0.0006): lower risk: absence of MYC activation (median not reached); intermediate risk: MYC activation without del17p (125 months); high risk: MYC activation + del17p (11 months). Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification.

  Study EGAS00001003275

• Genetic characterization of B-cell prolymphocytic leukemia: a hierarchical prognostic model involving MYC and TP53 abnormalities - RNA-seq

  B-cell prolymphocytic leukemia (B-PLL) is a rare disease, whose molecular pathology is largely unknown. We report here the cytogenetic and molecular findings in a large series of 34 B-PLL. Karyotype (K) was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. The most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (62%), 17p deletion including TP53 gene (38%), trisomy 18/18q (30%), 13q14 deletion (29%), trisomy 3 (24%), trisomy 12 (24%) and 8p deletion (23%). Whole-Exome Sequencing performed in 16 patients revealed recurrent mutations in TP53 (6/16, 38%), MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2) and BCLAF1 (n=2). The main group of patients (21/34, 62%) had a t(MYC) associated with a higher percentage of prolymphocytes (p=0.03), CD38 expression (p<0.001), lower K complexity (p=0.0004), mutations in MYC and in genes involved in RNA metabolism and chromatin remodeling. Principal component analysis of gene expression data showed that patients with t(MYC) clustered together. A second group with MYC gain (5/34, 15%), was associated with HCK≥5 (p=0,01) and trisomy 3 (p=0,008). Altogether, 26/34 patients (76%) had a MYC activation, translocation or gain, that were mutually exclusive. We identified 3 distinct cytogenetic prognostic groups (p=0.0006): lower risk: absence of MYC activation (median not reached); intermediate risk: MYC activation without del17p (125 months); high risk: MYC activation + del17p (11 months). Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification.

  Study EGAS00001003274

• RNA seq on 19 samples of Radiation-Induced Meningiomas

  Purpose: Majority of pediatric cancers require the irradiation of the central nervous system (CNS), and as more patients survive into adulthood from improved oncological therapy the sequelae of brain radiation are increasing in prevalence. Radiation-induced meningiomas (RIMs), one such secondary effect, demonstrate a clinically more aggressive behaviour than sporadic meningiomas (SMs). We aimed to describe the genomic mutational landscape of RIMs.Methods: We analyzed a principal cohort of 18 RIMs, with 31 RIMs overall, from patients who received childhood radiation therapy and 30 SMs, as a comparator population. We performed a multiplatform integrative genomic analysis; including methylation, whole exome and RNA sequencing. Results: RIMs exhibited a five-fold increase in copy number alterations, commonly the loss of chromosome 1p (17/18 RIMs) and 22q (17/18 RIMs), which was significantly more than observed in sporadic meningiomas. Furthermore, RNA sequencing data revealed an NF2 gene fusion event in 35.3% of RIMs. In all 6 cases, there was a complete NF2 exon spliced into a complete exon of a reciprocal gene, suggesting that the breakpoints of genomic rearrangement are intronic. All tumours with the NF2 fusion also possessed monosomy of chromosome 22q, rendering the cells with homozygous disruption of NF2. Clinically, RIMs with the NF2 fusion exhibited ill-defined borders and a tendency to develop in anatomic frontal location. Also, targeted sequencing panel confirmed that RIMs had fewer nonsynonymous NF2 mutations (6.5% vs. 30% in SM) and absence of mutations in TRAF7, SMO, KLF4, PIK3CA and AKT1, genes traditionally involved in SMs.Conclusion: Our study demonstrates that RIMs have distinct genomic drivers of oncogenesis as compared to SMs, specifically NF2 inactivation through fusion event. Radiation therapy possibly triggers genomic structural rearrangements through error-prone repair of double-stranded DNA breaks.

  Study EGAS00001002318

• UK10K NEURO EDINBURGH

  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. This sample set consists of subjects with schizophrenia recruited from psychiatric in-patient and out-patient facilities in Scotland. All diagnoses are based on standard research procedures and family histories are available. Patients have IQ>70 and the cohort includes the following groups: 100 cases with detailed clinical, cognitive and structural and functional neuroimaging phenotypes; 138 familial cases who are the probands of families where DNA has been collected from other affected members; 162 unrelated individuals. In most cases patients and their families may be re contacted to take part in further studies.For further information on this cohort please contact Andrew McIntosh (andrew.mcintosh@ed.ac.uk).

  Study EGAS00001000117

• 18 Whole Exome Sequencing for Radiation Induced-Meningiomas

  Purpose: Majority of pediatric cancers require the irradiation of the central nervous system (CNS), and as more patients survive into adulthood from improved oncological therapy the sequelae of brain radiation are increasing in prevalence. Radiation-induced meningiomas (RIMs), one such secondary effect, demonstrate a clinically more aggressive behaviour than sporadic meningiomas (SMs). We aimed to describe the genomic mutational landscape of RIMs.Methods: We analyzed a principal cohort of 18 RIMs, with 31 RIMs overall, from patients who received childhood radiation therapy and 30 SMs, as a comparator population. We performed a multiplatform integrative genomic analysis; including methylation, whole exome and RNA sequencing. Results: RIMs exhibited a five-fold increase in copy number alterations, commonly the loss of chromosome 1p (17/18 RIMs) and 22q (17/18 RIMs), which was significantly more than observed in sporadic meningiomas. Furthermore, RNA sequencing data revealed an NF2 gene fusion event in 35.3% of RIMs. In all 6 cases, there was a complete NF2 exon spliced into a complete exon of a reciprocal gene, suggesting that the breakpoints of genomic rearrangement are intronic. All tumours with the NF2 fusion also possessed monosomy of chromosome 22q, rendering the cells with homozygous disruption of NF2. Clinically, RIMs with the NF2 fusion exhibited ill-defined borders and a tendency to develop in anatomic frontal location. Also, targeted sequencing panel confirmed that RIMs had fewer nonsynonymous NF2 mutations (6.5% vs. 30% in SM) and absence of mutations in TRAF7, SMO, KLF4, PIK3CA and AKT1, genes traditionally involved in SMs.Conclusion: Our study demonstrates that RIMs have distinct genomic drivers of oncogenesis as compared to SMs, specifically NF2 inactivation through fusion event. Radiation therapy possibly triggers genomic structural rearrangements through error-prone repair of double-stranded DNA breaks.

  Study EGAS00001002317