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Variable DNA methylation patterns associated with progression of disease in hepatocellular carcinomas

Published on:2016-11-28   Views:183


Hepatocellular carcinoma (HCC) mostcommonly arises from chronic inflammation due to viral infection, as a resultof genetic and epigenetic abnormalities. A global picture of epigenetic changesin HCC is lacking. We used methylated CpG island amplification microarrays(MCAMs) to study 6458 CpG islands in HCC and adjacent preneoplastic tissues[chronic hepatitis (CH) or liver cirrhosis (LC)] in comparison with normalliver tissues where neither viral infection nor hepatitis has existed. MCAMidentified 719 (11%) prominent genes of hypermethylation in HCCs. HCCs arisingfrom LC had significantly more methylation than those arising from CH (1249genes or 19% versus 444 genes or 7%, P < 0.05). There were four patterns ofaberrant methylation: Type I (4%, e.g. matrix metalloproteinase 14) shows asubstantially high methylation level in adjacent tissue and does not increasefurther in cancer. Type II (55%, e.g. RASSF1A) shows progressively increasingmethylation from adjacent tissue to HCC. Type III (4%, e.g. GNA14) showsdecreased methylation in adjacent tissue but either similar or increasedmethylation in HCC. Type IV (37%, e.g. CDKN2A) shows low levels of methylationin normal tissue and adjacent tissue but high levels in HCC. These DNAmethylation changes were confirmed by quantitative pyrosequencing methylationanalysis in representative 24 genes and were analyzed for correlation withclinicopathological parameters in 38 patients. Intriguingly, methylation in theType IV genes is characteristic of moderately/poorly differentiated cancer. Ourglobal epigenome analysis reveals distinct patterns of methylation that areprobably to represent different pathophysiologic processes in HCCs.