ABSTRACT
Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.
Subject(s)
DNA Mutational Analysis , Genome, Human/genetics , Medulloblastoma/classification , Medulloblastoma/genetics , Whole Genome Sequencing , Carcinogenesis/genetics , Carrier Proteins/genetics , Cohort Studies , DNA Methylation , Datasets as Topic , Epistasis, Genetic , Genomics , Humans , Molecular Targeted Therapy , Muscle Proteins/genetics , Mutation , Oncogenes/genetics , Transcription Factors/genetics , Wnt Proteins/geneticsABSTRACT
The One Touch Pipeline (OTP) is an automation platform managing Next-Generation Sequencing (NGS) data and calling bioinformatic pipelines for processing these data. OTP handles the complete digital process from import of raw sequence data via alignment of sequencing reads to identify genomic events in an automated and scalable way. Three major goals are pursued: firstly, reduction of human resources required for data management by introducing automated processes. Secondly, reduction of time until the sequences can be analyzed by bioinformatic experts, by executing all operations more reliably and quickly. Thirdly, storing all information in one system with secure web access and search capabilities. From software architecture perspective, OTP is both information center and workflow management system. As a workflow management system, OTP call several NGS pipelines that can easily be adapted and extended according to new requirements. As an information center, it comprises a database for metadata information as well as a structured file system. Based on complete and consistent information, data management and bioinformatic pipelines within OTP are executed automatically with all steps book-kept in a database.
Subject(s)
Database Management Systems , Databases, Genetic , Genomics , High-Throughput Nucleotide Sequencing , Sequence Analysis, DNA , Automation , User-Computer InterfaceABSTRACT
Methane (CH(4)) formation under aerobic conditions has been intensely debated, especially since the discovery of CH(4) generation by both dried plant material and living plants. In this study we test the hypothesis that non-microbial CH(4) formation also occurs in soils. All lyophilised soil samples investigated under aerobic conditions released CH(4) at temperatures ranging from 30 to 70°C exceeding that allowing normal enzymatic activity to proceed. No emissions were observed for single mineral soil components such as quartz sand, clay mineral and iron oxide. Methane release rates from the soils investigated were found to increase both with increasing temperature and higher organic carbon content. Addition of water to dried soils increased CH(4) release rates up to 8-fold those observed with the dried material. Our results suggest the existence of a chemical process in soils that produces CH(4) under aerobic conditions, a finding which has not been hitherto reported.
Subject(s)
Methane/chemistry , Soil/chemistry , Water/chemistry , Aerobiosis , Carbon/chemistry , Kinetics , Lignin/chemistry , Minerals/chemistry , Pectins/chemistryABSTRACT
The possibility of methane formation in an oxidative environment has been intensely debated, especially since the discovery of methane generation by living plants. However, recent studies with animal tissue suggested that under specific conditions aerobic methane formation is also possible. Here, we investigated the generation of methane in an abiotic model system using bioavailable substances. We show formation of methane in a highly oxidative media, using ascorbic acid, ferrihydrite and hydrogen peroxide as reagents. Methane production was shown to be related to reagent ratio, reaction volume and pH. A 2:1 ratio of hydrogen peroxide to ascorbic acid, catalytic amounts of ferrihydrite and acidic conditions (pH 3) enhanced formation of methane. We further show that gaseous oxygen has a strong influence with higher levels found to inhibit methane formation. This study is a first step towards providing an insight for the reaction mechanism of methane formation that would be applicable to aerobic environments.