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000120090 1001_ $$0P:(DE-HGF)0$$aGoeppert, Benjamin$$b0
000120090 245__ $$aGlobal alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathway.
000120090 260__ $$aNew York [u.a.]$$bWiley Interscience$$c2014
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000120090 520__ $$aThe molecular mechanisms underlying the genesis of cholangiocarcinomas (CCs) are poorly understood. Epigenetic changes such as aberrant hypermethylation and subsequent atypical gene expression are characteristic features of most human cancers. In CC, data regarding global methylation changes are lacking so far. We performed a genome-wide analysis for aberrant promoter methylation in human CCs. We profiled 10 intrahepatic and 8 extrahepatic CCs in comparison to non-neoplastic biliary tissue specimens, using methyl-CpG immunoprecipitation (MCIp) combined with whole-genome CpG island arrays. DNA methylation was confirmed by quantitative mass spectrometric analysis and functional relevance of promoter hypermethylation was shown in demethylation experiments of two CC cell lines using 5-aza-2'deoxycytidine (DAC) treatment. Immunohistochemical staining of tissue microarrays (TMAs) from 223 biliary tract cancers (BTCs) was used to analyze candidate gene expression at the protein level. Differentially methylated, promoter-associated regions were nonrandomly distributed and enriched for genes involved in cancer-related pathways including Wnt, transforming growth factor beta (TGF-β), and PI3K signaling pathways. In CC cell lines, silencing of genes involved in Wnt signaling, such as SOX17, WNT3A, DKK2, SFRP1, SFRP2, and SFRP4 was reversed after DAC administration. Candidate protein SFRP2 was substantially down-regulated in neoplastic tissues of all BTC subtypes as compared to normal tissues. A significant inverse correlation of SFRP2 protein expression and pT status was found in BTC patients.We provide a comprehensive analysis to define the genome-wide methylation landscape of human CC. Several candidate genes of cancer-relevant signaling pathways were identified, and closer analysis of selected Wnt pathway genes confirmed the relevance of this pathway in CC. The presented global methylation data are the basis for future studies on epigenetic changes in cholangiocarcinogenesis.
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000120090 650_7 $$2NLM Chemicals$$aDNA, Neoplasm
000120090 650_7 $$2NLM Chemicals$$aMembrane Proteins
000120090 650_7 $$2NLM Chemicals$$aSFRP2 protein, human
000120090 650_7 $$2NLM Chemicals$$aWnt Proteins
000120090 7001_ $$0P:(DE-HGF)0$$aKonermann, Carolin$$b1
000120090 7001_ $$0P:(DE-HGF)0$$aSchmidt, Christopher Roman$$b2
000120090 7001_ $$0P:(DE-He78)3493620cedb8f0b17c9e1b424c0e21db$$aBogatyrova, Olga$$b3$$udkfz
000120090 7001_ $$0P:(DE-HGF)0$$aGeiselhart, Lea$$b4
000120090 7001_ $$0P:(DE-HGF)0$$aErnst, Christina$$b5
000120090 7001_ $$0P:(DE-HGF)0$$aGu, Lei$$b6
000120090 7001_ $$0P:(DE-He78)ecb33fb615e08035fdcefcaebfdff8f0$$aBecker, Natalia$$b7$$udkfz
000120090 7001_ $$0P:(DE-HGF)0$$aZucknick, Manuela$$b8
000120090 7001_ $$aMehrabi, Arianeb$$b9
000120090 7001_ $$aHafezi, Mohammadreza$$b10
000120090 7001_ $$aKlauschen, Frederick$$b11
000120090 7001_ $$aStenzinger, Albrecht$$b12
000120090 7001_ $$aWarth, Arne$$b13
000120090 7001_ $$aBreuhahn, Kai$$b14
000120090 7001_ $$0P:(DE-HGF)0$$aRenner, Marcus$$b15
000120090 7001_ $$aWeichert, Wilko$$b16
000120090 7001_ $$aSchirmacher, Peter$$b17
000120090 7001_ $$0P:(DE-He78)4301875630bc997edf491c694ae1f8a9$$aPlass, Christoph$$b18$$eLast author$$udkfz
000120090 7001_ $$0P:(DE-He78)ff4024f7bc236e7897d9c18ee19c451f$$aWeichenhan, Dieter$$b19$$eLast author$$udkfz
000120090 773__ $$0PERI:(DE-600)1472120-x$$a10.1002/hep.26721$$gVol. 59, no. 2, p. 544 - 554$$n2$$p544 - 554$$tHepatology$$v59$$x0270-9139$$y2014
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