Hepatocellular Carcinoma Displays Distinct DNA Methylation Signatures with Potential as Clinical Predictors 英文参考文献.docVIP

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Hepatocellular Carcinoma Displays Distinct DNA Methylation Signatures with Potential as Clinical Predictors 英文参考文献.doc

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Hepatocellular Carcinoma Displays Distinct DNA Methylation Signatures with Potential as Clinical Predictors 英文参考文献

HepatocellularCarcinomaDisplaysDistinctDNA MethylationSignatureswithPotentialasClinical Predictors HectorHernandez-Vargas1.,Marie-PierreLambert1.,FlorenceLeCalvez-Kelm2,Ge′raldineGouysse3, SandrineMcKay-Chopin2,SeanV.Tavtigian2,Jean-YvesScoazec3,ZdenkoHerceg1* 1Epigenetics Group, International Agency for Research on Cancer (IARC), Lyon, France, 2Genetic Cancer Susceptibility Group, International Agency for Research on Cancer(IARC),Lyon,France,3Serviced’AnatomiePathologique,EdouardHerriotHospitalLyon,Lyon,France Abstract Background:Hepatocellularcarcinoma(HCC)ischaracterizedbylatedetectionandfastprogression,anditisbelievedthat epigeneticdisruptionmaybethecauseofitsmolecularandclinicopathologicalheterogeneity.Abetterunderstandingof the global deregulation of methylation states and how they correlate with disease progression will aid in the design of strategiesforearlierdetectionandbettertherapeuticdecisions. Methods and Findings: We characterized the changes in promoter methylation in a series of 30 HCC tumors and their respectivesurroundingtissueandidentifiedmethylationsignaturesassociatedwithmajorriskfactorsandclinicalcorrelates. Awidepanelof cancer-relatedgenepromoters wasanalyzed usingIllumina beadarray technology, andCpG siteswere thenselectedaccordingtotheirabilitytoclassifyclinicopathologicalparameters.AnindependentseriesofHCCtumorsand matchedsurroundingtissuewasusedforvalidationofthesignatures.Wewereabletodevelopandvalidateasignatureof methylation in HCC. This signature distinguished HCC from surrounding tissue and from other tumor types, and was independent ofrisk factors. However, aberrant methylationof anindependent subset of promoterswas associated with tumor progression and etiological risk factors (HBV or HCV infection and alcohol consumption). Interestingly, distinct methylationofanindependentpanelofgenepromoterswasstronglycorrelatedwithsurvivalaftercancertherapy. Conclusion: Our study shows that HCC tumors exhibit specific DNA methylation signatur