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Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma
Author(s) -
Ammerpohl Ole,
Pratschke Johann,
Schafmayer Clemens,
Haake Andrea,
Faber Wladimir,
von Kampen Oliver,
Brosch Mario,
Sipos Bence,
von Schönfels Witigo,
Balschun Katharina,
Röcken Christoph,
Arlt Alexander,
Schniewind Bodo,
Grauholm Jonas,
Kalthoff Holger,
Neuhaus Peter,
Stickel Felix,
Schreiber Stefan,
Becker Thomas,
Siebert Reiner,
Hampe Jochen
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26136
Subject(s) - cpg site , dna methylation , biology , methylation , hepatocellular carcinoma , cirrhosis , cancer research , hccs , epigenetics , microbiology and biotechnology , gene , genetics , medicine , gene expression
Abberrant DNA methylation is one of the hallmarks of cancerogenesis. Our study aims to delineate differential DNA methylation in cirrhosis and hepatic cancerogenesis. Patterns of methylation of 27,578 individual CpG loci in 12 hepatocellular carcinomas (HCCs), 15 cirrhotic controls and 12 normal liver samples were investigated using an array‐based technology. A supervised principal component analysis (PCA) revealed 167 hypomethylated loci and 100 hypermethylated loci in cirrhosis and HCC as compared to normal controls. Thus, these loci show a “cirrhotic” methylation pattern that is maintained in HCC. In pairwise supervised PCAs between normal liver, cirrhosis and HCC, eight loci were significantly changed in all analyses differentiating the three groups ( p < 0.0001). Of these, five loci showed highest methylation levels in HCC and lowest in control tissue ( LOC55908 , CELSR1 , CRMP1 , GNRH2 , ALOX12 and ANGPTL7 ), whereas two loci showed the opposite direction of change ( SPRR3 and TNFSF15 ). Genes hypermethylated between normal liver to cirrhosis, which maintain this methylation pattern during the development of HCC, are depleted for CpG islands, high CpG content promoters and polycomb repressive complex 2 (PRC2) targets in embryonic stem cells. In contrast, genes selectively hypermethylated in HCC as compared to nonmalignant samples showed an enrichment of CpG islands, high CpG content promoters and PRC2 target genes ( p < 0.0001). Cirrhosis and HCC show distinct patterns of differential methylation with regards to promoter structure, PRC2 targets and CpG islands.