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      The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma

      research-article
      Author(s): 1 , 2 , 3 , 2 , 2 , 4 , 1 , 2 , 1 , 1 , 2 , 5 , 1 , 1 , 6 , 1 , 1 , 1 , 7 , 7 , 7 , 1 , 8 , 1 , 1 , 1 , 9 , 5 , 5 , 5 , 5 , 2 , 6 , 6 , 6 , 10 , 11 , 12 , 13 , 13 , 13 , 6 , 6 , 6 , 4 , 14 , 14 , 1 , # , 2 , 3 , #
      Publication date (Electronic):
      Journal: Nature genetics

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          Abstract

          Pediatric high-grade glioma (HGG) is a devastating disease with a two-year survival of less than 20% 1 . We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs) by whole genome, whole exome, and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPG (32%), in addition to the previously reported frequent somatic mutations in histone H3, TP53 and ATRX in both DIPG and NBS-HGGs 2- 5 . Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, 2, or 3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase/RAS/PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59%, respectively, of pediatric HGGs, including DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.

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          Is Open Access

          Fast and accurate short read alignment with Burrows–Wheeler transform

          Heng Li, Richard Durbin (2009)
          Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ∼10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: http://maq.sourceforge.net Contact: rd@sanger.ac.uk
          Article 0 comments Cited 11135 times – based on 0 reviews     Review now
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            Comprehensive genomic characterization defines human glioblastoma genes and core pathways

            (2008)
            Human cancer cells typically harbor multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multidimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here, we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas (GBM), the most common type of adult brain cancer, and nucleotide sequence aberrations in 91 of the 206 GBMs. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the PI3 kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of GBM. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
            Article 0 comments Cited 917 times – based on 0 reviews     Review now
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              Consed: a graphical tool for sequence finishing.

              D. Gordon, C Abajian, P. Green (1998)
              Sequencing of large clones or small genomes is generally done by the shotgun approach (Anderson et al. 1982). This has two phases: (1) a shotgun phase in which a number of reads are generated from random subclones and assembled into contigs, followed by (2) a directed, or finishing phase in which the assembly is inspected for correctness and for various kinds of data anomalies (such as contaminant reads, unremoved vector sequence, and chimeric or deleted reads), additional data are collected to close gaps and resolve low quality regions, and editing is performed to correct assembly or base-calling errors. Finishing is currently a bottleneck in large-scale sequencing efforts, and throughput gains will depend both on reducing the need for human intervention and making it as efficient as possible. We have developed a finishing tool, consed, which attempts to implement these principles. A distinguishing feature relative to other programs is the use of error probabilities from our programs phred and phrap as an objective criterion to guide the entire finishing process. More information is available at http:// www.genome.washington.edu/consed/consed. html.
              Article 0 comments Cited 802 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9216904
                Journal ID (pubmed-jr-id): 2419
                Journal ID (nlm-ta): Nat Genet
                Journal ID (iso-abbrev): Nat. Genet.
                Title: Nature genetics
                ISSN (Print): 1061-4036
                ISSN (Electronic): 1546-1718
                Publication date Nihms-submitted: 28 May 2014
                Publication date (Electronic): 06 April 2014
                Publication date (Print): May 2014
                Publication date PMC-release: 01 November 2014
                Volume: 46
                Issue: 5
                Pages: 444-450
                Affiliations
                [1 ]Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105
                [2 ]Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105
                [3 ]Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163
                [4 ]Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105
                [5 ]Department of Pediatric Cancer Genome Project, St. Jude Children’s Research Hospital, Memphis, TN 38105
                [6 ]The Genome Institute, Washington University, 633108
                [7 ]Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN 38105
                [8 ]Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105
                [9 ]Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263
                [10 ]Division of Molecular Pathology, Institute for Cancer Research, London, UK SM2 5NG
                [11 ]Division of Cancer Therapeutics, Institute for Cancer Research, London, UK SM2 5NG
                [12 ]Department of Surgery, St. Jude Children’s Research Hospital, Memphis, TN 38105
                [13 ]Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN 38105
                [14 ]Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105
                Author notes
                [# ]To whom Correspondence should be addressed: Suzanne Baker; Suzanne.Baker@ 123456stjude.org ; Jinghui Zhang; Jinghui.Zhang@ 123456stjude.org
                Article
                Manuscript ID: NIHMS573627
                DOI: 10.1038/ng.2938
                PMC ID: 4056452
                PubMed ID: 24705251
                SO-VID: b7e5b617-5b95-4769-853a-4742aa409cc7
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                ScienceOpen disciplines: Genetics
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                ScienceOpen disciplines: Genetics

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