Frequent and Distinct Aberrations of DNA Methylation Patterns in Fibrolamellar Carcinoma of the Liver 英文参考文献.docVIP

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Frequent and Distinct Aberrations of DNA Methylation Patterns in Fibrolamellar Carcinoma of the Liver 英文参考文献.doc

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Frequent and Distinct Aberrations of DNA Methylation Patterns in Fibrolamellar Carcinoma of the Liver 英文参考文献

FrequentandDistinctAberrationsofDNAMethylation PatternsinFibrolamellarCarcinomaoftheLiver WolfgangTra¨nkenschuh1,FlorianPuls1,MatthiasChristgen1,CordAlbat1,AlbertHeim2 ,Jeanette Poczkaj1,PeerFleming1¤,HansKreipe1,UlrichLehmann1* 1InstituteofPathology,MedizinischeHochschuleHannover,Hannover,Germany,2InstituteofVirology,MedizinischeHochschuleHannover,Hannover,Germany Abstract Background:GenesilencingduetoaberrantDNAmethylationisafrequenteventinhepatocellularcarcinoma(HCC)and also in hepatocellularadenoma(HCA).However, verylittle is knownaboutepigenetic defectsin fibrolamellarcarcinoma (FLC),ararevariantofhepatocellularcarcinomathatdisplaysdistinctclinicalandmorphologicalfeatures. Methodology/PrincipalFindings:WeanalyzedthemethylationstatusoftheAPC,CDH1,cyclinD2,GSTp1,hsa-mir-9-1,hsa- mir-9-2,andRASSF1Ageneinaseriesof15FLCandpairednormallivertissuespecimensbyquantitativehigh-resolution pyrosequencing. Results were compared with common HCC arising in non-cirrhotic liver (n=10). Frequent aberrant hypermethylationwasfoundforthecyclinD2(19%)andtheRASSF1A(38%)geneaswellasforthemicroRNAgenesmir-9-1 (13%)andmir-9-2(33%).IncontrasttocommonHCCtheAPCandCDH1(E-cadherin)geneswerefounddevoidofanyDNA methylationinFLC,whereastheGSTp1geneshowedcomparableDNAmethylationintumorandsurroundingtissueata moderate level. Changes in global DNA methylation level were measured by analyzing methylation status of the highly repetitive LINE-1 sequences. No evidence of global hypomethylation could be found in FLCs, whereas HCCs without cirrhosisshowedasignificantreductioninglobalmethylationlevelasdescribedpreviously. Conclusions: FLCs display frequent and distinct gene-specific hypermethylation in the absence of significant global hypomethylationindicatingthatthesetwoepigeneticaberrationsareinducedbydifferentpathwaysandthatfull-blown malignancycandevelopintheabsenceofgloballossofDNAmethylation.OnlyquantitativeDNAmethylationdetection methodologywasabletoidentifythesedifferences. Citation:Tra¨nkens