title: An integrative characterization of recurrent molecular aberrations in glioblastoma genomes.
abstract: Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Decades of investigations and the recent effort of the Cancer Genome Atlas (TCGA) project have mapped many molecular alterations in GBM cells. Alterations on DNAs may dysregulate gene expressions and drive malignancy of tumors. It is thus important to uncover causal and statistical dependency between 'effector' molecular aberrations and 'target' gene expressions in GBMs. A rich collection of prior studies attempted to combine copy number variation (CNV) and mRNA expression data. However, systematic methods to integrate multiple types of cancer genomic data-gene mutations, single nucleotide polymorphisms, CNVs, DNA methylations, mRNA and microRNA expressions and clinical information-are relatively scarce. We proposed an algorithm to build 'association modules' linking effector molecular aberrations and target gene expressions and applied the module-finding algorithm to the integrated TCGA GBM data sets. The inferred association modules were validated by six tests using external information and datasets of central nervous system tumors: (i) indication of prognostic effects among patients; (ii) coherence of target gene expressions; (iii) retention of effector-target associations in external data sets; (iv) recurrence of effector molecular aberrations in GBM; (v) functional enrichment of target genes; and (vi) co-citations between effectors and targets. Modules associated with well-known molecular aberrations of GBM-such as chromosome 7 amplifications, chromosome 10 deletions, EGFR and NF1 mutations-passed the majority of the validation tests. Furthermore, several modules associated with less well-reported molecular aberrations-such as chromosome 11 CNVs, CD40, PLXNB1 and GSTM1 methylations, and mir-21 expressions-were also validated by external information. In particular, modules constituting trans-acting effects with chromosome 11 CNVs and cis-acting effects with chromosome 10 CNVs manifested strong negative and positive associations with survival times in brain tumors. By aligning the information of association modules with the established GBM subclasses based on transcription or methylation levels, we found each subclass possessed multiple concurrent molecular aberrations. Furthermore, the joint molecular characteristics derived from 16 association modules had prognostic power not explained away by the strong biomarker of CpG island methylator phenotypes. Functional and survival analyses indicated that immune/inflammatory responses and epithelial-mesenchymal transitions were among the most important determining processes of prognosis. Finally, we demonstrated that certain molecular aberrations uniquely recurred in GBM but were relatively rare in non-GBM glioma cells. These results justify the utility of an integrative analysis on cancer genomes and provide testable characterizations of driver aberration events in GBM.
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan, ROC and Institute of Information Science, Academia Sinica, Taipei, Taiwan, ROC.
authors.forename: Nardnisa
authors.initials: N
authors.lastname: Sintupisut
authors.forename: Pei-Ling
authors.initials: PL
authors.lastname: Liu
authors.forename: Chen-Hsiang
authors.initials: CH
authors.lastname: Yeang
mesh_terms: D000465:Algorithms; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D058750:Epithelial-Mesenchymal Transition; D016514:Genes, Neurofibromatosis 1; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D005909:Glioblastoma / Q000145:classification / Q000235:genetics* / Q000401:mortality; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D009154:Mutation; D011379:Prognosis; D054840:Retinol-Binding Proteins, Cellular / Q000235:genetics; D016019:Survival Analysis; D014158:Transcription, Genetic
chemical_list: D035683:MicroRNAs; C518456:RBP1 protein, human; D054840:Retinol-Binding Proteins, Cellular
references.citation: Cell. 2010 Dec 10;143(6):1005-17
references.pmid: 21129771
references.citation: Carcinogenesis. 1997 Jul;18(7):1431-3
references.pmid: 9230293
references.citation: Nature. 2010 Jan 21;463(7279):318-25
references.pmid: 20032975
references.citation: Nat Genet. 2003 Jun;34(2):166-76
references.pmid: 12740579
references.citation: Cancer Res. 2009 Dec 1;69(23):9065-72
references.pmid: 19920198
references.citation: PLoS One. 2009 Nov 13;4(11):e7752
references.pmid: 19915670
references.citation: Clin Dev Immunol. 2011;2011:732413
references.pmid: 22190972
references.citation: Bioinformatics. 2011 Jul 1;27(13):i401-9
references.pmid: 21685098
references.citation: Nature. 2001 Feb 8;409(6821):685-90
references.pmid: 11217851
references.citation: Carcinogenesis. 2010 Oct;31(10):1770-7
references.pmid: 20668009
references.citation: Mol Syst Biol. 2011 Apr 26;7:486
references.pmid: 21525872
references.citation: Stat Appl Genet Mol Biol. 2008;7(1):Article3
references.pmid: 18241193
references.citation: Clin Med Insights Oncol. 2011;5:265-314
references.pmid: 22084619
references.citation: Cancer Res. 2005 Oct 1;65(19):8679-89
references.pmid: 16204036
references.citation: J Neuroinflammation. 2011 Mar 16;8:25
references.pmid: 21410936
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Nucleic Acids Res. 2005 Jan 1;33(Database issue):D428-32
references.pmid: 15608231
references.citation: Cancer Res. 2004 Sep 15;64(18):6503-10
references.pmid: 15374961
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Cancer Cell. 2010 Jan 19;17(1):98-110
references.pmid: 20129251
references.citation: Cancer Res. 2002 Nov 1;62(21):6205-10
references.pmid: 12414648
references.citation: Cancer Cell. 2010 May 18;17(5):510-22
references.pmid: 20399149
references.citation: Cancer Res. 1991 Apr 15;51(8):2164-72
references.pmid: 2009534
references.citation: Bioinformatics. 2010 Jun 15;26(12):i237-45
references.pmid: 20529912
references.citation: J Neurosci Res. 2010 Nov 15;88(15):3243-56
references.pmid: 20882566
references.citation: Bioinformatics. 2005 Nov 1;21(21):4026-32
references.pmid: 16159925
references.citation: Science. 2008 Sep 26;321(5897):1807-12
references.pmid: 18772396
references.citation: BMC Genomics. 2006 Jul 25;7:187
references.pmid: 16869964
references.citation: J Clin Oncol. 2008 Jun 20;26(18):3015-24
references.pmid: 18565887
references.citation: Oncogene. 2009 Jul 30;28(30):2697-709
references.pmid: 19483722
references.citation: BMC Syst Biol. 2011 Nov 04;5:186
references.pmid: 22051105
references.citation: PLoS One. 2010 Feb 12;5(2):e8918
references.pmid: 20169195
references.citation: Cancer Res. 2007 Oct 1;67(19):8994-9000
references.pmid: 17908999
references.citation: Mol Biol Rep. 2012 Sep;39(9):8695-9
references.pmid: 22699883
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14062-7
references.pmid: 16968785
references.citation: Genome Res. 2009 Sep;19(9):1639-45
references.pmid: 19541911
references.citation: Nucleic Acids Res. 2003 Jan 1;31(1):374-8
references.pmid: 12520026
references.citation: Nat Genet. 2005 Apr;37(4):382-90
references.pmid: 15778709
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4834-9
references.pmid: 19261849
references.citation: J Neuroimmunol. 2010 May;222(1-2):62-9
references.pmid: 20303602
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Nature. 2009 Nov 5;462(7269):108-12
references.pmid: 19847166
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D674-9
references.pmid: 18832364
references.citation: BMC Bioinformatics. 2010 Oct 06;11:495
references.pmid: 20925909
references.citation: Nat Genet. 2008 May;40(5):499-507
references.pmid: 18443585
references.citation: Nucleic Acids Res. 2009 Aug;37(15):5057-70
references.pmid: 19542187
references.citation: J Clin Neurosci. 2010 Dec;17(12):1543-7
references.pmid: 20822910
references.citation: Genes Chromosomes Cancer. 1998 Mar;21(3):195-206
references.pmid: 9523194
references.citation: Nat Methods. 2012 Feb 12;9(4):351-5
references.pmid: 22327835
references.citation: Nature. 2008 Oct 23;455(7216):1061-8
references.pmid: 18772890
references.citation: PLoS Genet. 2009 Oct;5(10):e1000692
references.pmid: 19834560
references.citation: Nat Med. 2007 Jan;13(1):84-8
references.pmid: 17159987
references.citation: Mol Cancer. 2008 Jan 14;7:6
references.pmid: 18194544
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5
references.pmid: 12883005
references.citation: Cancer Cell. 2006 Mar;9(3):157-73
references.pmid: 16530701
references.citation: Mol Biol Rep. 2013 Feb;40(2):1641-50
references.pmid: 23079710
references.citation: Genome Biol. 2007;8(10):R214
references.pmid: 17922911
references.citation: Nat Genet. 2005 Jul;37(7):710-7
references.pmid: 15965475
references.citation: Neurosurg Rev. 2004 Jan;27(1):58-64
references.pmid: 12845540
references.citation: PLoS One. 2011;6(8):e23423
references.pmid: 21853131
references.citation: Genome Biol. 2005;6(7):R62
references.pmid: 15998451