Frequent Alteration of MLL3 Frameshift Mutations in Microsatellite Deficient Colorectal Cancer 英文参考文献.docVIP

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Frequent Alteration of MLL3 Frameshift Mutations in Microsatellite Deficient Colorectal Cancer 英文参考文献.doc

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Frequent Alteration of MLL3 Frameshift Mutations in Microsatellite Deficient Colorectal Cancer 英文参考文献

FrequentAlterationofMLL3FrameshiftMutationsin MicrosatelliteDeficientColorectalCancer YoshiyukiWatanabe1,2*.,RyanJ.Castoro1.,HyunSooKim1,BrittanyNorth1,RitsukoOikawa2 ,Tetsuya Hiraishi2,SairaS.Ahmed1,WoonbokChung1,Mee-YonCho3,MinoruToyota4,FumioItoh2,MarcosR.H. Estecio1,LanlanShen1,JaroslavJelinek1,Jean-PierreJ.Issa1 1Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America, 2Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan, 3Department of Pathology, Yonsei University WonjuCollegeofMedicine,Wonju,Korea,4DepartmentofBiochemistry,SapporoMedicalUniversity,Sapporo,Hokkaido,Japan Abstract Background:MLL3isahistone3-lysine4methyltransferasewithtumor-suppressorpropertiesthatbelongstoafamilyof chromatinregulatorgenespotentiallyalteredinneoplasia.MutationsinMLL3werefoundinawholegenomeanalysisof colorectalcancerbuthavenotbeenconfirmedbyaseparatestudy. Methods and Results: We analyzed mutations of coding region and promoter methylation in MLL3 using 126 cases of colorectalcancer.WefoundtwoisoformsofMLL3andDNAsequencingrevealedframeshiftandothermutationsaffecting both isoforms of MLL3 in colorectal cancer cells and 19 of 134 (14%) primary colorectal samples analyzed. Moreover, frameshiftmutationsweremorecommonincaseswithmicrosatelliteinstability(31%)bothinCRCcelllinesandprimary tumors.ThelargestisoformofMLL3istranscribedfromaCpGisland-associatedpromoterthathashighlyhomologywitha pseudo-gene on chromosome 22 (psiTPTE22). Using an assay which measured both loci simultaneously we found prominentagerelatedmethylationinnormalcolon(from21%inindividualslessthan25yearsoldto56%inindividuals olderthan70,R=0.88,p,0.001)andfrequenthypermethylation(83%)inbothCRCcelllinesandprimarytumors.Wenext studiedthetwolociseparatelyandfoundthatageandcancerrelatedmethylationwassolelyapropertyofthepseudogene CpGislandandthattheMLL3lociwasunmeth