Specific mutations of hepatitis B virus in plasma predict liver cancer development.
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.
Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Shuang-Yuan
SY
Kuang
Peta E
PE
Jackson
Jin-Bing
JB
Wang
Pei-Xing
PX
Lu
Alvaro
A
Muñoz
Geng-Sun
GS
Qian
Thomas W
TW
Kensler
John D
JD
Groopman
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000821:virology*; D002681:China; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000097:blood / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006509:Hepatitis B / Q000150:complications* / Q000821:virology*; D006515:Hepatitis B virus / Q000235:genetics* / Q000472:pathogenicity*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D014774:Virulence / Q000235:genetics
D004279:DNA, Viral