Automated Network Analysis Identifies Core Pathways in Glioblastoma 英文参考文献.docVIP

AutomatedNetworkAnalysisIdentifiesCorePathwaysin Glioblastoma EthanCerami1,2*,EmekDemir1,NikolausSchultz1,BarryS.Taylor1,ChrisSander1 1Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America, 2Tri-Institutional Training Program in ComputationalBiologyandMedicine,NewYork,NewYork,UnitedStatesofAmerica Abstract Background:Glioblastomamultiforme(GBM)isthemostcommonandaggressivetypeofbraintumorinhumansandthe firstcancerwithcomprehensivegenomicprofilesmappedbyTheCancerGenomeAtlas(TCGA)project.Acentralchallenge inlarge-scalegenomeprojects,suchastheTCGAGBMproject,istheabilitytodistinguishcancer-causing‘‘driver’’mutations frompassivelyselected‘‘passenger’’mutations. Principal Findings: In contrast to a purely frequency based approach to identifying driver mutations in cancer, we propose anautomated network-based approach foridentifying candidate oncogenic processes anddriver genes. The approach is based on the hypothesis that cellular networks contain functional modules, and that tumors target specific modules critical to their growth. Key elements in the approach include combined analysis of sequence mutations and DNA copy number alterations; use of a unified molecular interaction network consisting of both protein-protein interactions and signaling pathways; and identification and statistical assessment of network modules, i.e. cohesive groups of genes ofinterest with ahigher density of interactions within groups than between groups. Conclusions:WeconfirmandextendtheobservationthatGBMalterationstendtooccurwithinspecificfunctionalmodules, inspiteofconsiderablepatient-to-patientvariation,andthattwoofthelargestmodulesinvolvesignalingviap53,Rb,PI3K and receptor protein kinases. We also identify new candidate drivers in GBM, including AGAP2/CENTG1, a putative oncogeneandanactivatorofthePI3Kpathway;and,threeadditionalsignificantlyalteredmodules,includingoneinvolved in microtubule organization. To facilitate the app