The Role of Glutathione-S-Transferase Gene Mutation in the Development of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a common cause of death in many parts of the world. Many risk factors play a role in the development of HCC. Viral hepatitis and exposure to aflatoxins are two major risk factors. Also genetic polymorphisms in the genes of some detoxifying enzymes may contribute to HCC. Among these enzymes, the glutathione- S-transferases (GSTs) play a vital role in the detoxification of different environmental carcinogens. Genetic polymorphisms in GSTM1 and GSTT1 (that code for the most active GST isoenzymes) have been correlated with altered risk of several cancers and were suggested as risk factors for HCC with contradicting conclusions among authors. Our study was conducted on 11 controls, 10 hepatitis C and 32 HCC patients in whom aflatoxin level and total GST activity were measured by ELISA and GSTM1 and GSTT1 genotypes were studied by PCR. 34.4% of HCC patients were positive for aflatoxin exposure (aflatoxin 3.6ng/ml) compared to 9.5% of the other 2 groups. This difference was significant and the odds ratio for HCC among aflatoxin-exposed individuals was 4.98 (confidence limit: 1.01-25.38). 81.8%, 60.0% and 75.0% of the respective three groups were of the GSTM1 null genotype. The percentages of GSTT1 null genotypes were 72.7%, 30.0% and 53.1%, respectively. The null genotype of either isoenzyme was not a risk factor for HCC. Total GST activity was higher in the HCC and HCV groups than controls, but the genotype was not a factor affecting the total enzyme activity. GST activity can complement routine liver function tests in HCC and many acute and chronic liver diseases. Our pilot study revealed that the collective prevalence of GSTM1 null genotype in the 53 studied Egyptians was 73.6%, and it was 52.8% for the GSTT1 null genotype. These two figures were higher than what were reported in other ethnic groups which were also quite variable from one-region to another. The PCR method adopted was reliable and yielded clear-cut, reproducible GST genotypes and can, thus, be recommended if larger scale studies are planned among Egyptians.