2.15.7.8.3 HBV infection biomarkers in liver cancer
HBV is a significant risk factor for HCC in the developing world where there are over 400 million viral carriers (Lee 1997). The biology, mode of transmission, and epidemiology of this virus continues to be actively investigated and has been well reviewed (Lee 1997). The HBV genome encodes its essential genes with overlapping open-reading frames; therefore, a mutation in the HBV genome can alter the expression of multiple proteins. In many cases of HCC in China and Africa a double mutation in the HBV genome, an adenine to thymine transversion at nucleotide 1762 and a guanine to adenine transition at nucleotide 1764 (1762T/1764A), has been found in tumors (Arbuthnot and Kew 2001; Hou et al. 1999). This segment of the HBV genome contains an overlapping sequence for the base core promoter and the HBV X gene; therefore, the double mutation in codon 130 and 131 of the HBV X gene reported in human HCC is identical to the 1762 and 1764 nucleotide changes (Lee 1997).
Kuang et al. (2004) examined, with mass spectrometry (MS), the temporality of an HBV 1762T/1764A double mutation in plasma and tumors. Initial studies found 52 of 70 (74.3%) tumors from Qidong, PRC, contained this HBV mutation. Paired plasma samples were available for six of the tumor specimens; four tumors had the HBV 1762T/1764A mutation while three of the paired plasma samples were also positive. The potential predictive value of this biomarker was explored 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 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 1762T/1764A mutation up to 8 years prior to diagnosis. Finally, 15 liver cancers were selected from a prospective cohort of 1638 high-risk individuals in Qidong on the basis of available plasma samples spanning the years before and after diagnosis. The HBV 1762T/1764A mutation was detected in 8 of the 15 cases (53.3%) prior to cancer. The persistence of detection of this mutation was statistically significant (p = 0.022, two tailed). It was therefore found that a prediagnosis biomarker of specific HBV mutations can be measured in plasma and this marker is suggested for use as an intermediate endpoint in prevention and intervention trials.
The work described above for the HBV mutations has been extended a male cohort of 5581 HBsAg carriers in Qidong, PRC, who were recruited starting in 1989. By December 2003, 667 liver cancer cases were diagnosed in this group and plasma samples collected at the initial screening at enrollment were available in 515 cases who had succumbed to liver cancer. HBV DNA could be isolated in 355 (69%) of these samples. In 14, 15, 19, 31, and 22%, screening took place at < or = 1.5, 1.51 to 3, 3.01 to 5, 5.01 to 9, and >9 years before death, respectively; and 39% died at age below 45 years. The relation between mutations in HBV and time to death were determined by logistic regression for the odds of mutation and by survival analyses methods with age as the time scale. In 279 (79%) of these individuals, the samples contained a two-nucleotide 1762T/1764A HBV mutation. Sixteen samples lacking the 1762T/1764A mutation had novel mutations elsewhere in the 1761–1767 region of the HBV genome. There was a statistically significant difference (p = 0.012) for the high prevalence of the HBV mutations in the men who died from HCC under the age of 45 years relative to those who died after 55 years of age and HBV mutations accelerated death (relative hazard, 1.40; 95% CI = 1.06–1.85) and that the effect was attenuated by age from 2.04 for age 35 years to 1.0 for age 65 years with the 90% confidence band being above 1 for ages <50 years. These findings provide a conceptual framework to explain the acceleration of mortality in individuals infected with HBV (Chen et al. 2007).
To explore the association of HBV genotypes and 1762T/1764A double mutations with HCC in Guangxi, PRC, a case–control study including 46 HBsAg-positive HCC cases and 92 gender-, age-, and residential-matched asymptomatic HBV carriers was conducted (Xu et al. 2007). All the HCC cases were hospital diagnosed and histopathologically verified. Among the 46 cases, 34 (73.91%) were C genotype, 9 (19.56%) were B genotype, and the remaining 3 (6.52%) were BC-mixed genotype. In 92 matched controls, 80 (86.86%) were C genotype, 10 (10.87%) were B genotype, and 2 (2.17%) were BC-mixed genotype. No significant difference was found in the genotype distribution between cases and controls. However, a significant association was found on 1762T/1764A double mutations and risk of HCC, as demonstrated by detectable 1762T/1764A double mutations in 42 (91.30%) of cases and 70 (76.09%) of controls, respectively. The odds ratio is 3.30 with 95% CI between 1.064 and 10.236 (p = 0.037 6). Data from this study demonstrated that HBV X-gene 1762T/1764A double mutations, as a promising biomarker for HCC study, may contribute to the process of hepatocarcinogenesis in this high-risk area.
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