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1.
Nat Genet ; 45(8): 927-32, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23817572

ABSTRACT

Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.


Subject(s)
Astrocytoma/genetics , Brain Neoplasms/genetics , Mutation , Receptor, Fibroblast Growth Factor, Type 1/genetics , Receptor, trkB/genetics , Animals , Astrocytoma/metabolism , Base Sequence , Brain Neoplasms/metabolism , Cell Line , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Chromosome Breakpoints , Chromosomes, Human, Pair 6 , Chromosomes, Human, Pair 9 , Fibroblast Growth Factors/metabolism , Humans , MAP Kinase Signaling System , Mice , Models, Molecular , Oncogene Proteins, Fusion/chemistry , Oncogene Proteins, Fusion/genetics , Protein Conformation , Proto-Oncogene Proteins B-raf/chemistry , Proto-Oncogene Proteins B-raf/genetics , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Receptor, trkB/metabolism
2.
PLoS One ; 8(6): e66621, 2013.
Article in English | MEDLINE | ID: mdl-23776689

ABSTRACT

The emergence of high-throughput, next-generation sequencing technologies has dramatically altered the way we assess genomes in population genetics and in cancer genomics. Currently, there are four commonly used whole-genome sequencing platforms on the market: Illumina's HiSeq2000, Life Technologies' SOLiD 4 and its completely redesigned 5500xl SOLiD, and Complete Genomics' technology. A number of earlier studies have compared a subset of those sequencing platforms or compared those platforms with Sanger sequencing, which is prohibitively expensive for whole genome studies. Here we present a detailed comparison of the performance of all currently available whole genome sequencing platforms, especially regarding their ability to call SNVs and to evenly cover the genome and specific genomic regions. Unlike earlier studies, we base our comparison on four different samples, allowing us to assess the between-sample variation of the platforms. We find a pronounced GC bias in GC-rich regions for Life Technologies' platforms, with Complete Genomics performing best here, while we see the least bias in GC-poor regions for HiSeq2000 and 5500xl. HiSeq2000 gives the most uniform coverage and displays the least sample-to-sample variation. In contrast, Complete Genomics exhibits by far the smallest fraction of bases not covered, while the SOLiD platforms reveal remarkable shortcomings, especially in covering CpG islands. When comparing the performance of the four platforms for calling SNPs, HiSeq2000 and Complete Genomics achieve the highest sensitivity, while the SOLiD platforms show the lowest false positive rate. Finally, we find that integrating sequencing data from different platforms offers the potential to combine the strengths of different technologies. In summary, our results detail the strengths and weaknesses of all four whole-genome sequencing platforms. It indicates application areas that call for a specific sequencing platform and disallow other platforms. This helps to identify the proper sequencing platform for whole genome studies with different application scopes.


Subject(s)
High-Throughput Nucleotide Sequencing/methods , Animals , Genomics/methods , Humans , Sequence Analysis, DNA/methods
3.
Nature ; 488(7409): 100-5, 2012 Aug 02.
Article in English | MEDLINE | ID: mdl-22832583

ABSTRACT

Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.


Subject(s)
Cerebellar Neoplasms/genetics , Genome, Human/genetics , Medulloblastoma/genetics , Aging/genetics , Amino Acid Sequence , Cell Transformation, Neoplastic , Cerebellar Neoplasms/classification , Cerebellar Neoplasms/diagnosis , Cerebellar Neoplasms/pathology , Child , Chromatin/metabolism , Chromosomes, Human/genetics , DEAD-box RNA Helicases/genetics , DNA Helicases/genetics , DNA-Binding Proteins/genetics , Genomics , Hedgehog Proteins/metabolism , High-Throughput Nucleotide Sequencing , Histone Demethylases/genetics , Humans , Medulloblastoma/classification , Medulloblastoma/diagnosis , Medulloblastoma/pathology , Methylation , Mutation/genetics , Mutation Rate , Neoplasm Proteins/genetics , Nuclear Proteins/genetics , Oncogene Proteins, Fusion/genetics , Patched Receptors , Patched-1 Receptor , Phosphoprotein Phosphatases/genetics , Polyploidy , Receptors, Cell Surface/genetics , Sequence Analysis, RNA , Signal Transduction , T-Box Domain Proteins/genetics , Transcription Factors/genetics , Wnt Proteins/metabolism , beta Catenin/genetics
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