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000127757 0247_ $$2doi$$a10.1093/hmg/ddt599
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000127757 0247_ $$2ISSN$$a1460-2083
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000127757 1001_ $$0P:(DE-HGF)0$$aKuhmann, Christine$$b0$$eFirst author
000127757 245__ $$aAltered regulation of DNA ligase IV activity by aberrant promoter DNA methylation and gene amplification in colorectal cancer.
000127757 260__ $$aOxford$$bOxford Univ. Press$$c2014
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000127757 520__ $$aColorectal cancer (CRC) presents as a very heterogeneous disease which cannot sufficiently be characterized with the currently known genetic and epigenetic markers. To identify new markers for CRC we scrutinized the methylation status of 231 DNA repair-related genes by methyl-CpG immunoprecipitation followed by global methylation profiling on a CpG island microarray, as altered expression of these genes could drive genomic and chromosomal instability observed in these tumors. We show for the first time hypermethylation of MMP9, DNMT3A and LIG4 in CRC which was confirmed in two CRC patient groups with different ethnicity. DNA ligase IV (LIG4) showed strong differential promoter methylation (up to 60%) which coincided with downregulation of mRNA in 51% of cases. This functional association of LIG4 methylation and gene expression was supported by LIG4 re-expression in 5-aza-2'-deoxycytidine-treated colon cancer cell lines, and reduced ligase IV amounts and end-joining activity in extracts of tumors with hypermethylation. Methylation of LIG4 was not associated with other genetic and epigenetic markers of CRC in our study. As LIG4 is located on chromosome 13 which is frequently amplified in CRC, two loci were tested for gene amplification in a subset of 47 cases. Comparison of amplification, methylation and expression data revealed that, in 30% of samples, the LIG4 gene was amplified and methylated, but expression was not changed. In conclusion, hypermethylation of the LIG4 promoter is a new mechanism to control ligase IV expression. It may represent a new epigenetic marker for CRC independent of known markers.
000127757 536__ $$0G:(DE-HGF)POF3-313$$a313 - Cancer risk factors and prevention (POF3-313)$$cPOF3-313$$fPOF III$$x0
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000127757 650_7 $$2NLM Chemicals$$aBiomarkers, Tumor
000127757 650_7 $$2NLM Chemicals$$aLIG4 protein, human
000127757 650_7 $$2NLM Chemicals$$aRNA, Messenger
000127757 650_7 $$0EC 2.1.1.37$$2NLM Chemicals$$aDNA (Cytosine-5-)-Methyltransferase
000127757 650_7 $$0EC 2.1.1.37$$2NLM Chemicals$$aDNA methyltransferase 3A
000127757 650_7 $$0EC 3.4.24.35$$2NLM Chemicals$$aMMP9 protein, human
000127757 650_7 $$0EC 3.4.24.35$$2NLM Chemicals$$aMatrix Metalloproteinase 9
000127757 650_7 $$0EC 6.5.1.-$$2NLM Chemicals$$aDNA Ligases
000127757 650_7 $$0EC 6.5.1.1$$2NLM Chemicals$$aDNA Ligase ATP
000127757 7001_ $$aLi, Carmen$$b1
000127757 7001_ $$0P:(DE-HGF)0$$aKloor, Matthias$$b2
000127757 7001_ $$0P:(DE-He78)131e5921fcfccbf0f978d4426f1a615b$$aSalou, Mariam$$b3$$udkfz
000127757 7001_ $$0P:(DE-He78)c566ec22a882273029b7cbe4ef700428$$aWeigel, Christoph$$b4$$udkfz
000127757 7001_ $$aSchmidt, Christopher R$$b5
000127757 7001_ $$aNg, Linda W C$$b6
000127757 7001_ $$aTsui, Wendy W Y$$b7
000127757 7001_ $$aLeung, Suet Y$$b8
000127757 7001_ $$aYuen, Siu T$$b9
000127757 7001_ $$0P:(DE-He78)ecb33fb615e08035fdcefcaebfdff8f0$$aBecker, Natalia$$b10$$udkfz
000127757 7001_ $$0P:(DE-He78)ff4024f7bc236e7897d9c18ee19c451f$$aWeichenhan, Dieter$$b11$$udkfz
000127757 7001_ $$0P:(DE-He78)4301875630bc997edf491c694ae1f8a9$$aPlass, Christoph$$b12$$udkfz
000127757 7001_ $$0P:(DE-He78)141ce740f5d881812d2675147b72ecaf$$aSchmezer, Peter$$b13$$udkfz
000127757 7001_ $$aChan, Tsun L$$b14
000127757 7001_ $$0P:(DE-He78)37610ef78c733753f0836ce0e41b9fda$$aPopanda, Odilia$$b15$$eLast author$$udkfz
000127757 773__ $$0PERI:(DE-600)1474816-2$$a10.1093/hmg/ddt599$$gVol. 23, no. 8, p. 2043 - 2054$$n8$$p2043 - 2054$$tHuman molecular genetics$$v23$$x1460-2083$$y2014
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