Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns 英文参考文献.docVIP

Sprouletal.GenomeBiology2012,13:R84 /2012/13/10/R84 RESEARCH OpenAccess Tissueoforigindeterminescancer-associated CpGislandpromoterhypermethylationpatterns DuncanSproul1,2,RobertRKitchen1,3,ColmENestor1,2,JMichaelDixon1,AndrewHSims1,DavidJHarrison1,4, BernardHRamsahoye1,5 andRichardRMeehan1,2* Abstract Background:AberrantCpGislandpromoterDNAhypermethylationisfrequentlyobservedincancerandis believedtocontributetotumorprogressionbysilencingtheexpressionoftumorsuppressorgenes.Previously,we observedthatpromoterhypermethylationinbreastcancerreflectscelllineageratherthantumorprogressionand occursatgenesthatarealreadyrepressedinalineage-specificmanner.Toinvestigatethegeneralityofour observationweanalyzedthemethylationprofilesof1,154cancersfrom7differenttissuetypes. Results:Wefindthat1,009genesarepronetohypermethylationinthese7typesofcancer.Nearlyhalfofthese genesvariedintheirsusceptibilitytohypermethylationbetweendifferentcancertypes.Weshowthatthe expressionstatusofhypermethylationpronegenesintheoriginatortissuedeterminestheirpropensitytobecome hypermethylatedincancer;specifically,genesthatarenormallyrepressedinatissueareproneto hypermethylationincancersderivedfromthattissue.Wealsoshowthatthepromoterregionsof hypermethylation-pronegenesaredepletedofrepetitiveelementsandthatDNAsequencearoundthesame promotersisevolutionarilyconserved.Weproposethatthesetwocharacteristicsreflecttissue-specificgene promoterarchitectureregulatingtheexpressionofthesehypermethylationpronegenesinnormaltissues. Conclusions:Asaberrantlyhypermethylatedgenesarealreadyrepressedinpre-canceroustissue,wesuggestthat theirhypermethylationdoesnotdirectlycontributetocancerdevelopmentviasilencing.Insteadaberrant hypermethylationreflectsdevelopmentalhistoryandtheperturbationofepigeneticmechanismsmaintainingthese repressedpromotersinahypomethylatedstateinnormalcells. Background CGI hypermethylator phenotype (termed CIMP) has Aberrant DNAhypermethylation ofCpGisland (CGI) beendescribedwherehundredsofCGIsbeco