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Sequencingofthousandsoftumoursampleshasrevealedthelandscapeofsomaticmutationsinprotein-codinggenes1.Mostpreviousstudiesofcancergenomeshaveusedexomesequencingratherthanwhole-genomesequencing(WGS)owingtolowercostsandafocusontheregionsthatareconsideredtobemostfunctionallyrelevant.However,thedecreasingcostsofsequenc-inghaveenabledWGSofthousandsoftumoursbyindividualresearchgroupsandeffortssuchasTCGA(TheCancerGenomeAtlas)andICGC(InternationalCancerGenomeConsortium).Oneofthemostimpor-tantbenefitsofWGSistheidentificationofvariantsinnon-codingregionsofthegenome.Indeed,mostofthevariantsobtainedfromWGSoftumourgenomesliethere(FIG. 1).Thereisanincreasedrealizationoftheimportanceofnon-codingvariantsincancer,andanongoingcollaborationbetweenTCGAandICGC,calledthePan-CancerAnalysisofWholeGenomes(PCAWG)aimstoanalysenon-codingvariantsin~2,500tumourandmatchednormalwholegenomes.Oneofthebiggestchallengesofanalysingnon-codingorcodingvariantsistoidentifydrivermutationsandtodistinguishthemfrompassenger mutations.Thelinkbetweeninheritedgermlinevariantsandcomplexdisorders,includingcancer,hasbeenprobedpreviouslybynumerousgenome-wideassociationstudies(GWASs)usingDNAfromnon-diseasecells(usuallyblood).Thesestudiesimplicatedvariousprotein-codinggenesintumorigenesis(suchasDNArepairandcell-cyclecontrolgenes)2.Importantly,thesestudiesalsorevealedthatmanylocithatareassociatedwithcancersusceptibilitylieinnon-codingregionsofthe genome3,4.InthisReview,wediscussourcurrentunder-standingoftheroleofnon-codingsequencevariantsincancerdevelopmentandgrowth.Wefirstdescribedistinctionsinthenatureofsomaticversusgermlinesequencevariantsandthenprovidebriefoverviewsofthevariousnon-codingannotations.Wethendiscussdiversemolecularmechanismsbywhichsomaticandgermlinevariantsareknowntoleadtotumorigenesis,includingtheirfunctionalinterplay.Finally,tointer-pretnon-codingvariantslinkedtocancer,wedescribehowbioinformaticsandexperimentalapproachescanbeusedtoprioritizethemandvalidatetheirfunc-tionalrelevance.ThroughoutourReview,wefocusontheeffectsofDNAsequencevariantsinnon-codingregions.However,wenotethatbesidessequencealter-ations,otherchangescanoccurinnon-codingregionsofcancergenomes,suchasepigeneticchangesatreg-ulatoryelementsandtranscriptionaldysregulationofnon-codingRNAs(ncRNAs);forfurtherinformationonthesephenomena,thereaderisreferredtoREFS 5–9.GenomicsequencevariantsMostofthegenomeisnon-codingandmostDNAsequencevariantsoccurinnon-codingregions.Hence,thegeneralpropertiesofsequencevariantsareappli-cabletonon-codingvariants.Theyrangefromsinglenucleotidevariants(SNVs)tosmallinsertionsanddele-tionsoflessthan50basepairsinlength(indels),toCorrespondencetoE.K.,M.A.R. andM.G.ekk2003@med.cornell.edu;rubinma@med.cornell.edu;mark.gerstein@yale.eduSeeAuthoraddressesboxfor addresslist.doi:10.1038/nrg.2015.17Publishedonline19Jan2016ExomesequencingSequencingtheprotein-codingportionofthegenomeusingtarget-enrichmentandhigh-throughputsequencingtechnology.DrivermutationsSequencevariantsthatconfer growthadvantageto tumour cells.PassengermutationsSequencevariantsthatdonotcontributetocancer growth.GermlinevariantsHeritablevariantsthataretransmittedtooffspring.Thesevariantsareconstitutional(that is,presentinallcellsofthe body).Roleofnon-codingsequencevariantsincancerEktaKhurana1–4,YaoFu5,DimpleChakravarty2,6,FrancescaDemichelis2,3,7,Mark A. Rubin1,2,6andMarkGerstein8–10Abstract|Patientswithcancercarrysomaticsequencevariantsintheirtumourinadditiontothegermlinevariantsintheirinheritedgenome.Althoughvariantsinprotein-codingregionshavereceivedthemostattention,numerousstudieshavenotedtheimportanceofnon-codingvariantsincancer.Moreover,theoverwhelmingmajorityofvariants,bothsomaticandgermline,occurinnon-codingportionsofthegenome.Wereviewthecurrentunderstandingofnon-codingvariantsincancer,includingthegreatdiversityofthemutationtypes—fromsinglenucleotidevariantstolargegenomicrearrangements—andthewiderangeofmechanismsbywhichtheyaffectgeneexpressiontopromotetumorigenesis,suchasdisruptingtranscriptionfactor-bindingsitesorfunctionsofnon-codingRNAs.Wehighlightspecificcasestudiesofsomaticandgermlinevariants,anddiscusshownon-codingvariantscanbeinterpretedonalarge-scalethroughcomputationalandexperimentalmethods.APPLICATIONSOFNEXT-GENERATIONSEQUENCINGREVIEWSNATUREREVIEWS|GENETICSVOLUME17|FEBRUARY2016|93©2016MacmillanPublishersLimited.AllrightsreservedGenome-wideassociation studies(GWASs).Studiesthatinterrogatemultiplecommongeneticvariantsalongthegenomeinlargecohortsofindividualstoevaluatewhetheranyvariantisassociatedwithaspecific trait.SinglenucleotidevariantsDNAsequencechangesatsinglenucleotides.SomaticvariantsVariantsthatarenotinheritedfromaparentandarenottransmittedtooffspring.PenetranceTheproportionofindividualscarryinganallele(oragenotype)thatalsoexpressthetrait(phenotype)associatedwith it.Chromoplexy(FromtheGreekpleko,meaningtoweave,ortobraid).A classofcomplexsomaticDNArearrangementswherebyabundantDNAdeletionsandintra-andinter-chromosomaltranslocationsthathaveoriginatedinaninterdependentwayoccurwithinas
本文标题:01 Role of non-coding sequence variants in cancer
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