DEFICIENT REPAIR OF DNA LESION O6-METHYLGUANINE IN CIRRHOSIS

Cirrhosis is a risk factor for hepatocellular carcinoma. O6-methylguanine is a promutagenic and potentially carcinogenic DNA lesion produced by environmental alkylating agents. If it is not repaired, DNA replication can lead to a G-to-A transition mutation, which is a known mechanism of oncogene activation. We have found that the activity of the repairing methyltransferase enzyme is significantly lower in cirrhotic tissue than in non-cirrhotic diseased liver or in normal liver. This finding suggests a mechanism for cirrhosis being a risk factor for cancer of the liver: increased cellular proliferation together with persistence of O6-methylguanine might lead to malignant transformation of liver cells through mutation and oncogene activation.