Association of Hepatitis B Virus Pre-S Deletions with the Development of Hepatocellular Carcinoma in Qidong, China

Abstract

Background/AimTo investigate the roles of mutations in pre-S and S regions of hepatitis B virus (HBV) on the progression of hepatocellular carcinoma (HCC) in Qidong, China.MethodsWe conducted an age matched case-control study within a cohort of 2387 male HBV carriers who were recruited from August, 1996. The HBV DNA sequence in pre-S/S regions was successfully determined in 96 HCC cases and 97 control subjects. In addition, a consecutive series of samples from 11 HCC cases were employed to evaluate the pre-S deletion patterns before and after the occurrence of HCC.ResultsAfter adjustment for age, history of cigarette smoking and alcohol consumption, HBeAg positivity, pre-S deletions, pre-S2 start codon mutations, and T53C mutation were significantly associated with HCC, showing adjusted odds ratios (ORs) from 1.914 to 3.199. HCC patients also had a lower frequency of T31C mutation in pre-S2 gene, compared with control subjects (0.524; 95% CI 0.280-0.982). HBV pre-S deletions were clustered mainly in the 5′ end of pre-S2 region. Multivariate analysis showed that pre-S deletions and pre-S2 start codon mutations were independent risk factors for HCC. The OR (95% CI) were 2.434 (1.063–5.573) and 3.065 (1.099–8.547), respectively. The longitudinal observation indicated that the pre-S deletion mutations were not acquired at the beginning of HBV infection, but that the mutations occurred during the long course of liver disease.ConclusionPre-S deletions and pre-S2 start codon mutations were independently associated with the development of HCC. The results also provided direct evidence that pre-S deletion mutations were not acquired from the beginning of infection but arose de novo during the progression of liver disease.

Potential Susceptibility Mutations in C Gene for Hepatitis B-Related Hepatocellular Carcinoma Identified by a Two-Stage Study in Qidong, China

“…During the course of chronic HBV infection, a wide variety of liver diseases are observed, ranging from an asymptomatic carrier state to liver cirrhosis and HCC [16]. In our previous studies conducted in Qidong, pre- S deletion and specific mutations in BCP were confirmed to be associated with a high risk of HCC occurrence [17,18]. However, the risk of mutations in other regions of the full HBV genome was seldom reported.…”

“…Meanwhile, the carcinogenic risk of pre- S deletion and pre- S 2 start codon mutation in pre- S gene, C1653T, and A1762T/G1764A mutations in X gene has been extensively investigated in this cohort [17,18]. Compared to those studies focusing on mutations in pre- S and X genes, only a few studies have investigated the effect of mutations in the C gene during natural HBV infection.…”

“…The recruitment of this cohort has been described elsewhere [17,18]. Briefly, a total of 2387 males living in 17 townships of Qidong who were seropositive for hepatitis B surface antigen (HBsAg) and free of HCC at recruitment were followed up from August 1996 to October 2006.…”

“…PCR was done under the same PCR condition described above, except the primers were used. Nested PCR for the amplification of pre- S , enhancer II, and basal core promoter regions was performed as previously described [17,18]. All necessary precautions to prevent cross-contamination were taken, and negative controls were included in each assay.…”

Variations and mutations in the hepatitis B virus genome and their associations with clinical characteristics

“…Clinical studies have revealed that pre-S deletions, pre-S2 start codon mutations, and the T53C mutation in the pre-S2 region are related to the development of HCC [60] .…”