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.
Kuang
Shuang-Yuan
SY
Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Jackson
Peta E
PE
Wang
Jin-Bing
JB
Lu
Pei-Xing
PX
Muñoz
Alvaro
A
Qian
Geng-Sun
GS
Kensler
Thomas W
TW
Groopman
John D
JD
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