Analysis of the Association between CIMP and BRAFV600E in Colorectal Cancer by DNA Methylation Profiling 英文参考文献.docVIP
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Analysis of the Association between CIMP and BRAFV600E in Colorectal Cancer by DNA Methylation Profiling 英文参考文献
AnalysisoftheAssociationbetweenCIMPandBRAFV600E
inColorectalCancerbyDNAMethylationProfiling
ToshinoriHinoue1,2,DanielJ.Weisenberger1,FeiPan1,MihaelaCampan2,MyungjinKim2 ,Joanne
Young3,4,VickiL.Whitehall5,BarbaraA.Leggett5,PeterW.Laird1,2*
1USC Epigenome Center, Keck School of Medicine, University ofSouthern California, Los Angeles, California, United States of America, 2Department of Surgery and
DepartmentofBiochemistryandMolecularBiology,USC/NorrisComprehensiveCancerCenter,KeckSchoolofMedicine,UniversityofSouthernCalifornia,LosAngeles,
California,UnitedStatesofAmerica,3FamilialCancerLaboratory,QueenslandInstituteofMedicalResearch,Herston,Queensland,Australia,4UniversityofQueensland
School ofMedicine,Herston, Queensland, Australia, 5ConjointGastroenterology Laboratory,Clinical ResearchCentre,Royal Brisbane andWomen’s HospitalResearch
Foundation,Herston,Queensland,Australia
Abstract
ACpGislandmethylatorphenotype(CIMP)isdisplayedbyadistinctsubsetofcolorectalcancerswithahighfrequencyof
DNAhypermethylationinaspecificgroupofCpGislands.RecentstudieshaveshownthatanactivatingmutationofBRAF
(BRAFV600E)istightlyassociatedwithCIMP,raisingthequestionofwhetherBRAFV600Eplaysacausalroleinthedevelopment
of CIMP or whether CIMP provides a favorable environment for the acquisition of BRAFV600E. We employed Illumina
GoldenGateDNAmethylationtechnology,whichinterrogates1,505CpGsitesin807differentgenes,tofurtherstudythis
association. We first examined whether expression of BRAFV600E causes DNA hypermethylation by stably expressing
BRAFV600E in the CIMP-negative, BRAF wild-type COLO 320DM colorectal cancer cell line. We determined 100 CIMP-
associatedCpGsitesandexaminedchangesinDNAmethylationineightstablytransfectedclonesovermultiplepassages.
WefoundthatBRAFV600EisnotsufficienttoinduceCIMPinoursystem.Secondly,consideringthealternativepossibility,we
identifiedgeneswhoseDNAhypermethylationwascloselylinkedtoBRAFV600EandCIMPin235primarycolorectaltumors.
Interestingly,genesthatshowedthemost
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