Journal Article

DKFZ-2017-03779

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Altered regulation of DNA ligase IV activity by aberrant promoter DNA methylation and gene amplification in colorectal cancer.

Kuhmann, C. (First author)DKFZ* ; Li, C. ; Kloor, M.DKFZ* ; Salou, M.DKFZ* ; Weigel, C.DKFZ* ; Schmidt, C. R. ; Ng, L. W. C. ; Tsui, W. W. Y. ; Leung, S. Y. ; Yuen, S. T. ; Becker, N.DKFZ* ; Weichenhan, D.DKFZ* ; Plass, C.DKFZ* ; Schmezer, P.DKFZ* ; Chan, T. L. ; Popanda, O. (Last author)DKFZ*

2014
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/hmg/ddt599

Abstract: Colorectal 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.

Keyword(s): Biomarkers, Tumor ; LIG4 protein, human ; RNA, Messenger ; DNA (Cytosine-5-)-Methyltransferase ; DNA methyltransferase 3A ; MMP9 protein, human ; Matrix Metalloproteinase 9 ; DNA Ligases ; DNA Ligase ATP

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Contributing Institute(s):

1. Epigenomik und Krebsrisikofaktoren (C010)
2. Biostatistik (C060)
3. Gentherapie von Tumoren (G105)

Research Program(s):

1. 313 - Cancer risk factors and prevention (POF3-313) (POF3-313)

Appears in the scientific report 2014

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Database coverage:
; Allianz-Lizenz / DFG ; BIOSIS Previews ; Current Contents - Life Sciences ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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