Entropy Measures Quantify Global Splicing Disorders in Cancer 英文参考文献.docVIP

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Entropy Measures Quantify Global Splicing Disorders in Cancer 英文参考文献.doc

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Entropy Measures Quantify Global Splicing Disorders in Cancer 英文参考文献

EntropyMeasuresQuantifyGlobalSplicingDisordersin Cancer WilliamRitchie1,SamuelGranjeaud1,DenisPuthier1,DanielGautheret2* 1Universite′ delaMe′diterrane′e, INSERMERM206,TechnologiesAvance′espourleGe′nomeetlaClinique,Marseille,France,2Universite′ Paris-Sud11,CNRSUMR8621, InstitutdeGe′ne′tiqueetMicrobiologie,Orsay,France Abstract Mostmammaliangenesareabletoexpressseveralsplicevariantsinaphenomenonknownasalternativesplicing.Serious alterations of alternative splicing occur in cancer tissues, leading to expression of multiple aberrant splice forms. Most studies of alternative splicing defects have focused on the identification of cancer-specific splice variants as potential therapeutictargets.Here,weexamineinsteadthebulkofnon-specifictranscriptisoformsandanalyzetheirlevelofdisorder usingameasureofuncertaintycalledShannon’sentropy.Wecompareisoformexpressionentropyinnormalandcancer tissuesfromthesameanatomicalsitefordifferentclassesoftranscriptvariations:alternativesplicing,polyadenylation,and transcription initiation. Whereas alternative initiation and polyadenylation show no significant gain or loss of entropy between normal and cancer tissues, alternative splicing shows highly significant entropy gains for 13 of the 27 cancers studied.Thisentropygainischaracterizedbyaflatteningintheexpressionprofileofnormalisoformsandiscorrelatedto thelevelofestimatedcellularproliferationinthecancertissue.Interestingly,thegenesthatpresentthehighestentropy gainareenrichedinsplicingfactors.Weprovideherethefirstquantitativeestimateofsplicingdisruptionincancer.The expressionofnormalsplicevariantsiswidelyandsignificantlydisruptedinatleasthalfofthecancersstudied.Wepostulate that suchsplicing disorders may develop in partfrom splicing alteration in key splice factors, which in turnsignificantly impactmultipletargetgenes. Citation:RitchieW,GranjeaudS,PuthierD,GautheretD(2008)EntropyMeasuresQuantifyGlobalSplicingDisordersinCancer.PLoSComputBiol4(3):e1000011. doi:10.1371/journal.pcbi.100