Specific mutations of hepatitis B virus in plasma predict liver cancer development

Abstract

A major risk factor for hepatocellular carcinoma (HCC) is hepatitis B virus (HBV), whose pathogenesis is exacerbated by the acquisition of mutations that accelerate carcinogenesis. We examined, with mass spectrometry, the temporality of an HBV 1762 T ͞1764 A double mutation in plasma and tumors. Initial studies found that 52 of 70 (74.3%) tumors from patients residing in Qidong, People's Republic of China, contained this HBV mutation. Paired plasma samples were available for six of the tumor specimens; four tumors had the HBV 1762 T ͞1764 A mutation, whereas three of the paired plasma samples were also positive. The potential predictive value of this biomarker was explored by using stored plasma samples from a study of 120 residents of Qidong who had been monitored for aflatoxin exposure and HBV infection. After 10 years of passive follow-up, there were six cases of major liver disease including HCC (four cases), hepatitis (one case), and cirrhosis (one case). All six cases had detectable levels of the HBV 1762 T ͞1764 A mutation up to 8 years before diagnosis. Finally, 15 liver cancers were selected from a prospective cohort of 1,638 high-risk individuals in Qidong on the basis of available plasma samples spanning the years before and after diagnosis. The HBV 1762 T ͞1764 A mutation was detected in 8 of the 15 cases (53.3%) before cancer. The persistence of detection of this mutation was statistically significant (P ‫؍‬ 0.022, two-tailed). We therefore found that a prediagnosis biomarker of specific HBV mutations can be measured in plasma and suggest this marker for use as an intermediate endpoint in prevention and intervention trials.

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

“…Only a few studies have addressed the questions of the rate of HBV mutations in tumor tissues (Pontisso et al, 1984;Raimondo et al, 1988;Clementi et al, 1993). However, our group and others have shown that mutations in basal core promoter, PreC/C, envelope and X sequences can be identified in HCC tissues (Minami et al, 1996;Fan et al, 2000Fan et al, , 2001Tu et al, 2001;Oon et al, 2002;Iavarone et al, 2003;Kao et al, 2003;Kuang et al, 2004). We have observed that in the Core gene, most of the non-synonymous mutations (i.e.…”

“…HBx with mutations in amino acids 130 and 131 have been frequently reported and may be associated with the severity of chronic hepatitis; these mutations have also been detected in HCC (Yotsuyanagi et al, 2002;Iavarone et al, 2003;Leon et al, 2005), and a recent study of serum samples indicated that these mutations arise before the development of HCC (Kuang et al, 2004). However, the functional consequences of these mutated HBx proteins are still unclear.…”

A case–control study on sequence variations in the enhancer II/core promoter/precore and X genes of hepatitis B virus in patients with hepatocellular carcinoma

“…Also, the magnitude of the OR of HCC associated with the presence of the BCP double mutants in this study was approximately 3 to 4-fold, which was similar with reports of other studies. In fact, a prospective cohort of approximately 1,600 high-risk individuals in Qidong, China, showed that A1762T/G1764A mutations were detected in approximately 50% of HCC cases before cancer development, suggesting that these variants would indicate a high potential risk for hepatocarcinogenesis [22]. It has been reported that the development of A1762T/G1764A mutations is associated with HBV genotype and their prevalence is higher in genotype C than genotype B [8].…”

TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer

“…Molecular epidemiological studies also support the hypothesis that mutant HBx integrated in HCC is positively associated with TP53 249 ser mutations. In both China and Thailand, analysis of plasma DNA revealed a frequent concordance between HBV 1762 T /1764 A and TP53 249 ser DNA in plasma at the time of HCC diagnosis (Kuang et al, 2004(Kuang et al, , 2005. The double mutant resides in the HBx open reading frame within HBV, and results in lysine to methionine and valine to isoleucine at HBx codons 130 and 131, respectively.…”