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Background  Epigenetic changes during ageing and their relationship with cancer are under the focus of intense research.  RASSF1A  and  NORE1A  are novel genes acting in concert in the proapoptotic pathway of the RAS signalling. While  NORE1A  has not been previously investigated in the human liver, recent reports have suggested that  RASSF1A  is frequently epigenetically methylated not only in HCC but also in the cirrhotic liver.    Methods  To address whether epigenetic changes take place in connection to age and/or to the underlying disease, we investigated  RASSF1A  and  NORE1A  gene promoter methylation by conventional methylation specific PCR and Real-Time MSP in a series of hepatitic and non-hepatitic livers harboring regenerative/hyperplastic (cirrhosis/focal nodular hyperplasia), dysplastic (large regenerative, low and high grade dysplastic nodules) and neoplastic (hepatocellular adenoma and carcinoma) growths.    Results  In the hepatitic liver (chronic hepatitic/cirrhosis, hepatocellular nodules and HCC) we found widespread  RASSF1A  gene promoter methylation with a methylation index that increased from regenerative conditions (cirrhosis) to hepatocellular nodules (p < 0.01) to HCC (p < 0.001). In the non-hepatitic liver a consistent pattern of gene methylation was also found in both lesional (focal nodular hyperplasia and hepatocellular adenoma) and non-lesional tissue. Specifically, hepatocellular adenomas (HA) showed a methylation index significantly higher than that detected in focal nodular hyperplasia (FNH) (p < 0.01) and in non-lesional tissue (p < 0.001). In non-lesional liver also the methylation index gradually increased by ageing (p = 0.002), suggesting a progressive spreading of methylated cells over time. As opposed to  RASSF1A  gene promoter methylation,  NORE1A  gene was never found epigenetically alterated in both hepatitic and non-hepatitic liver.    Conclusion  We have shown that in non-lesional, regenerative and neoplastic liver the  RASSF1A  gene is increasingly methylated, that this condition takes place as an age-related phenomenon and that the early setting and spreading over time of an epigenetically methylated hepatocyte subpopulation, might be related to liver tumorigenesis.

Quantitative evaluation of RASSF1Amethylation in the non-lesional, regenerative and neoplastic liver