Elsevier

Journal of Hepatology

Volume 53, Issue 4, October 2010, Pages 671-676
Journal of Hepatology

Research Article
Genetic variations of hepatitis B virus and serum aflatoxin-lysine adduct on high risk of hepatocellular carcinoma in Southern Guangxi, China

https://doi.org/10.1016/j.jhep.2010.04.032Get rights and content

Background & Aims

Southern Guangxi area is one of the endemic areas for hepatocellular carcinoma (HCC) in China. This study evaluates the roles of genetic variations of hepatitis B virus (HBV) and aflatoxin B1 (AFB1) exposure in the formation of HCC in this high-risk area.

Methods

The study recruited 60 HCC patients and 120 age-, gender-, and residency-matched controls. HBV genotype and basic core promoter (BCP) mutations were determined by nested-PCR/direct sequencing. Serum AFB1-lysine adduct was measured by high performance liquid chromatography-fluorescence detection.

Results

HBV genotype C was predominant in 75.0% of cases and 84.2% of controls. The 1762T/1764A double mutations, 1753V mutations, and 1752V mutations were associated with HCC risk evidenced by the adjusted odds ratio (OR) [95% confidence interval (95% CI)] of 3.89 (1.40–10.77), 2.87 (1.49–5.49), and 5.96 (1.75–20.25), respectively. The adjusted OR (95% CI) was 6.94 (1.68–27.78) for subjects with 1762T/1764A double mutations and high AFB1-lysine adduct level; 2.01 (0.24–14.29), for those with only 1762T/1764A double mutations; and 4.26 (1.16–15.38) for those with only high AFB1-lysine adduct level, respectively. The adjusted OR was 5.13 (1.79–14.71) for subjects with 1753V mutations and high AFB1-lysine adduct level; 1.20 (0.47–3.08) for those with only 1753V mutations, and 2.28 (1.01–5.31) for those with high AFB1-lysine adduct level, respectively.

Conclusions

These data confirmed the association of BCP mutations with HCC risk and the additive effects of 1762T/1764A double mutations and 1753V mutations with dietary AFB1 exposure in this high-risk area for HCC.

Introduction

Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC) worldwide [1]. Although the mechanism is not well defined, variations in the viral genome, including specific genotypes and mutations, are thought to contribute to the formation of HCC [2], [3]. To date, eight HBV genotypes are classified (A–H) based on an inter-group divergence of equal or greater than 8% in the complete nucleotide sequence [4]. Infection with the genotype C was associated with greater severity of liver diseases compared to genotype B, although this is still controversial [2], [5]. The basic core promoter (BCP) resides in the overlapping HBV functional X gene domain and controls the transcription activity of procore RNA [6]. Mutations in this region were anticipated to influence HBV-induced chronic infection and hepatocarcinogenesis [7], [8]. The 1762T/1764A double mutations (1762A-to-T and 1764G-to-A) in BCP region were commonly found to be borne by HCC patients in some high-risk populations and were thus suggested as potential biomarkers for hepatocarcinogenesis [3], [9], [10], [11], [12], [13]. Also, the 1753V mutations (1753T-to-C/A/G) were associated with the progression of liver disease [14], [15]; nevertheless, their role in HCC development, especially in high-risk populations, remains controversial [9], [14], [16].

The Southern Guangxi area is one of the areas in China with endemic HCC, reporting an incidence and mortality rate of more than 50/100,000 people per year [17]. Chronic HBV infection and dietary aflatoxin (AF) exposure are the two major risk factors for HCC in this area [18], while hepatitis C virus (HCV) infection is extremely uncommon [19]. AFB1-lysine adduct in serum has been considered the most reliable biomarker in monitoring long-term human AFB1 exposure [20]. The association of this adduct with HCC has been well established in high-risk populations in China [21], while its application in assessing HCC risk in Southern Guangxi high-risk population has not yet been reported.

To this end, a case-control study was conducted to assess the role of HBV genetic variations, including HBV genotypes and BCP region mutations, dietary AFB1 exposure measured by serum AFB1-lysine adduct level, and their interactions in HCC risk in the Southern Guangxi population.

Section snippets

Study subjects, data collection, and sample collection

A total of 60 HCC patients were recruited at Guangxi Medical University Cancer Hospital from August 2004 to August 2005. The eligibility criteria for cases were: (1) permanent resident in Southern Guangxi area; (2) confirmed diagnosis of HCC as primary tumor by histological (surgical biopsy) or non-histological criteria (positive imaging test results, serum α-fetoprotein greater than 400 ng/ml, and clinical features); (3) no previous diagnosis of other cancers; (4) positive HBV surface antigen

Results

As shown in Table 1, the cases and controls, taking into account the frequency-matched age, gender, and residency, had similar demographic characteristics except for their first-degree familial history of cancer. Among 14 cases with first-degree family history of cancer, there were 12 liver cancers (85.7%), one esophageal cancer (7.1%), and one rectum cancer (7.1%). Among 13 controls with first-degree family history of cancer, there were 10 liver cancers (76.9%), one esophageal cancer (7.7%),

Discussion

Our study showed a significant association of increased HCC risk with HBV 1762T/1764A double mutations, 1753V mutations, and 1752V mutations in the Southern Guangxi area, a high-risk area for HCC in China. In addition, we found additive effects of HBV BCP mutations (1762T/1764A double mutations and 1753V mutations) and high serum AFB1-lysine adduct level on the risk of developing HCC. To our knowledge, there has been no previously published data exploring the interactions between HBV genomic

Funding

National Cancer Institute (RO1 90997) to J.-S W.

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding conflict of interest with respect to this manuscript.

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