Precore mutation of hepatitis B virus may contribute to hepatocellular carcinoma risk: evidence from an updated meta-analysis

Abstract

Background: Studies focused on the correlation of mutations in the genome of Hepatitis B Virus (HBV) like Pre-S mutation, Basal Core promoter (BCP), Enhancer II (EnhII), especially Precore mutation, with the risk of hepatocellular carcinoma (HCC) have triggered stiff controversies. With an increasing number of studies in this field recently, we conducted this meta-analysis to appraise the correlations.

Methods: We searched the commonly used databases both in English and Chinese till February 1(st), 2012. Meta-analysis was performed in fixed/random-effects models using STATA 10.0. Publication bias was examined through Egger's test and Begg's funnel plot.

Results: In total, 85 case-control studies were included involving 16745 HBV-infected patients, of whom 5781 had HCC. Statistically significant correlations were observed in Precore mutation G1896A (OR = 1.46, 95% confidence interval [CI] = 1.15-1.85, P(OR) = 0.002), G1899A (OR = 3.13, 95%CI = 2.38-4.13, P(OR)<0.001) and Pre-S mutation especially Pre-S1 deletion (OR = 2.94, 95%CI = 2.22 to 3.89) and Pre-S2 deletion (OR = 3.02, 95%CI = 2.03 to 4.50). Similar correlation existed between BCP double mutation A1762T/G1764A, T1753V, C1653T and HCC. In subgroup analysis, the Asians, genotype C or HBeAg positive patients with certain above mutations may be more susceptible to HCC. Besides, the mutations like G1896A and BCP double mutation may be associated with the progression of the liver diseases.

Conclusions: Precore mutation G1896A, G1899A, deletions in Pre-S region as well as the other commonly seen mutations correlated with the increased risk of HCC, especially in Asians and may predict the progression of the liver disease.

Figure 1. Flow chart for article screening in the meta-analysis.

After a comprehensive screening, a total of 85 case-control studies were identified.

Figure 2. Forest plot for the correlation between Precore mutation G1896A and HCC risk.

(A) Pooled odds ratio for correlation of Precore G1896A with HCC (before adjustment for heterogeneity). (B) Pooled odds ratio for association between G1896A and HCC risk after adjustment for heterogeneity. (For the forest plot, the black diamond represented the OR estimate for each study and the size of the grey area reflected the weight in the pooled analysis; the horizontal line indicates the 95% confidence interval (CI); the white diamond represented the pooled odds ratio).

Figure 3. Galbraith plots for heterogeneity test of G1896A and Pre-S2 deletion.

(A) Galbraith plot of the association between precore G1896A and HCC risk (The studies outside the range between −2 and 2 were seen as the outliers and the major source of heterogeneity); (B) Galbraith plot of the correlation between Pre-S2 deletion and HCC risk.

Figure 4. Forest plot for the correlation between Precore mutation G1899A and HCC risk.

Figure 5. Forest plot for the correlation between Pre-S deletions and HCC risk.

(A) Pooled odds ratio for correlation of Pre-S1 deletion and HCC risk using fixed-effects model; (B) Pooled odds ratio for association of Pre-S2 deletion and HCC risk using random-effects model.

Figure 6. Funnel plot of association between Pre-S2 deletion and HCC risk (After adjustment for heterogeneity).