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 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.
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 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. 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. The major etiological factors associated with development of HCC in these regions are infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) and lifetime exposure to high levels of aflatoxin B) in the diet (3, 4).
200,000 deaths annually in the People's Republic of China (P. Detailed knowledge of the etiology of HCC has spurred many mechanistic studies to understand the pathogenesis of this nearly always fatal disease, and this knowledge is beginning to be translated into preventive interventions in high-risk populations.
HBV is a significant risk factor for HCC in the developing world, where there are 400 million viral carriers (5, 6).The biology, mode of transmission, and epidemiology of this virus continue to be actively investigated and have been recently reviewed (5, 6).The contribution of HBV to the pathogenesis of liver cancer is multifactorial and is complicated by the identification of mutant variants in HBV that modulate the carcinogenesis process (7-9).The HBV genome encodes its essential genes with overlapping ORFs; 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 (1762), has been found in tumors (5, 10, 11).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 codons 130 and 131 of the HBV X gene reported in human HCC is identical to the 17 nucleotide changes (12, 13).