title: Distinct DNA methylation patterns in cirrhotic liver and hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Ole
authors.initials: O
authors.lastname: Ammerpohl
authors.forename: Johann
authors.initials: J
authors.lastname: Pratschke
authors.forename: Clemens
authors.initials: C
authors.lastname: Schafmayer
authors.forename: Andrea
authors.initials: A
authors.lastname: Haake
authors.forename: Wladimir
authors.initials: W
authors.lastname: Faber
authors.forename: Oliver
authors.initials: O
authors.lastname: von Kampen
authors.forename: Mario
authors.initials: M
authors.lastname: Brosch
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.forename: Witigo
authors.initials: W
authors.lastname: von Schönfels
authors.forename: Katharina
authors.initials: K
authors.lastname: Balschun
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.forename: Alexander
authors.initials: A
authors.lastname: Arlt
authors.forename: Bodo
authors.initials: B
authors.lastname: Schniewind
authors.forename: Jonas
authors.initials: J
authors.lastname: Grauholm
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
authors.forename: Peter
authors.initials: P
authors.lastname: Neuhaus
authors.forename: Felix
authors.initials: F
authors.lastname: Stickel
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Thomas
authors.initials: T
authors.lastname: Becker
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism; D044127:Epigenesis, Genetic; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics*; D063146:Polycomb-Group Proteins; D025341:Principal Component Analysis / Q000379:methods; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics; D015203:Reproducibility of Results
chemical_list: D063146:Polycomb-Group Proteins; D012097:Repressor Proteins