Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer related death worldwide with a poor prognosis. Alcoholic liver disease accounts for approximately one-third of all HCC cases. Current evidence proved that aberrant over-expression of TNFRSF12A correlates with the severity of disease, making it a likely indicator of disease a more aggressive and worse prognosis outcome. Emerging studies have confirmed that epigenetic changes are critical events in the development and progression of liver cancer. The study to investigate the mechanisms by which alcohol abuse mediated changes in the methylation level of TNFRSF12A affect the occurrence, development and prognosis of HCC were under warranted. Thus, in this study we mined two publicly available datasets to detect the association between DNA methylation level of CpG sites in gene TNFRSF12A and the development of HCC in those with alcohol abuse history. Finally, we discovered that the hypomethylation of two methylation sites—cg00510447 and cg26808293—could identify HCC from other non-HCC liver diseases. Also, hypomethylation of these two sites could identify alcoholic cirrhosis from other non-hepatocellular carcinoma liver diseases. Most important, the prognostic analysis revealed that the hypomethylation of cg00510447 and cg26808293 in HCC patients with alcohol abuse history could predict poor prognosis. Further stratified analyses by gender discovered that in male HCC patients with alcohol abuse history, hypomethylation of cg26808293 signified poor prognosis. The further mechanism analysis revealed that the DNA methyltransferases DNMT3L might regulate TNFRSF12A methylation and affect the occurrence, development and prognosis of HCC, especially in patients with a history of alcohol abuse. These findings provide new insights into the role of epigenetic mechanisms in the transformation of alcoholic liver disease into HCC.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer deaths in the world (Forner et al, 2012)
We found a higher expression of TNFRSF12A have worse prognosis in HCC patients with a history of alcohol abuse
Further analysis revealed both the cg00510447 and cg26808293 sites in the TNFRSF12A gene were significantly hypomethylated in HCC patients than normal tissues, these were observed in cases of alcoholic hepatitis
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer deaths in the world (Forner et al, 2012). Because even cessation of alcohol consumption, alcoholic liver disease patients still could develop HCC within 1–10 years (Donato et al, 2002). This suggests that alcohol consumption could synergistic with other risk factors for HCC development. The interaction between global hypomethylation and regional hypermethylation of genes promotes the progression of liver cancer. DNA hypermethylation induced inactivation of E-cadherin and hypomethylation up-regulated the expression of vimentin, which interact with each other to promote the occurrence and development of liver cancer with poor prognosis (Kitamura et al, 2011)
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