Analysis Of GSTM1, GSTT1, MDM2 And p53 Polymorphisms And Hepatitis C Virus Genetic Variability In Brazilian Patients With And Without Hepatocellular Carcinoma

Oscar ARA┌JO, Oswaldo Cruz Foundation, Brazil

1 Oswaldo Cruz Institute, Laboratory of Molecular Virology, Rio de Janeiro, Brazil.
2 Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Hepatology Division, Rio de Janeiro, Brazil.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Liver cirrhosis promoted by chronic hepatitis C virus (HCV) infection is the major risk factor for developing HCC in Brazil, accounting for over 50% of cases. The development of HCV-induced HCC is a multistep process affected by both genetic and virological factors. The aim of this study is to analyze the association of genetic polymorphisms in GSTM1 and GSTT1 (null genotypes), p53 (Pro72Arg), and MDM2 (SNP309 T/G) genes, as well as the occurrence of the R70Q core mutation in HCV genotype 1b strains, with the severity of liver disease in Brazilian patients. The genetic polymorphisms for each gene were detected by PCR-RFLP, and HCV genotypes were determined by core region nucleotide sequencing followed by phylogenetic analysis. At this moment, 145 HCV positive patients (44 with HCC, 63 with cirrhosis, and 38 with chronic hepatitis) were analyzed. The proportion of null genotype for GSTT1 was higher among patients with HCC (22.7%) or cirrhosis (22.2%) than chronic hepatitis (7.9%). The occurrence of both null genotypes for GSTM1 and GSTT1 was 11.4%, 4.8% and 2.6% in patients with HCC, cirrhosis and chronic hepatitis, respectively. Simultaneous occurrence of MDM2 G/G and p53 Pro/Pro genotypes was only observed among HCC patients (n=2, 5,7%). Furthermore, the HCV 1b-R70Q mutation was found in 6 (46.2%) and 9 (56.3%) patients with HCC and cirrhosis, respectively, but in only one (9.1%) of those with chronic hepatitis. These preliminary results showed that the highest frequencies of GSTM1 plus GSTT1 null genotypes, MDM2 G/G plus p53 Pro/Pro genotypes, as well as HCV 1b-R70Q mutation, were found in patients with advanced liver disease. Genetic and virological factors may be predictors of disease progression and useful for the early HCC detection in HCV chronic patients.
Financial support: CNPq, FAPERJ and FIOCRUZ.