Qidong hepatitis B virus infection cohort: a 25-year prospective study in high risk area of primary liver cancer

Abstract

Qidong hepatitis B virus (HBV) infection cohort (QBC) is a prospective community-based study designed to investigate causative factors of primary liver cancer (PLC) in Qidong, China, where both PLC and HBV infection are highly endemic. Residents aged 20-65 years, living in seven townships of Qidong, were surveyed using hepatitis B surface antigen (HBsAg) serum test and invited to participate in QBC from June 1991 to December 1991. A total of 852 and 786 participants were enrolled in HBsAg-positive and HBsAg-negative sub-cohorts in May 1992, respectively. All participants were actively followed up in person, received HBsAg, alanine aminotransferase, alpha-fetoprotein tests and upper abdominal ultrasonic examination, and donated blood and urine samples once or twice a year. The total response rate was 99.6%, and the number of incident PLC was 201 till the end of February 2017. The ratio of incidence rates was 12.32 [95% confidence interval (CI): 7.16-21.21, P < 0.0001] in HBsAg-positive arm compared with HBsAg-negative arm. The relative risk of PLC was 13.25 (95% CI: 6.67-26.33, P < 0.0001) and 28.05 (95% CI: 13.87-56.73, P < 0.0001) in the HBsAg⁺/HBeAg^- group and the HBsAg⁺/HBeAg⁺ group, respectively, as compared to the HBsAg^-/HBeAg^- group. A series of novel PLC-related mutations including A2159G, A2189C and G2203W at the C gene, A799G, A987G and T1055A at the P gene of HBV genome were identified by using samples from the cohort. The mutation in HBV basal core promoter region of HBV genome has an accumulative effect on the occurrence of PLC. In addition, the tripartite relationship of aflatoxin exposure, P53 mutation and PLC was also investigated. QBC will be used to develop dynamic prediction model for PLC risk by using its long-term follow-up information and serial blood samples. This model is expected to improve the efficiency of PLC screening in HBV infection individuals.

Keywords

Prospective cohort / hepatitis B virus / primary liver cancer

References

[1] Li JY,Li GY,Sun XI.Atlas of cancer mortality in the People's Republic of China. An aid for cancer control and research..Int J Epidemiol1981;10:127-33

[2] Chen JG,Parkin DM,Lu JH,Chen TY.Trends in the incidence of cancer in Qidong, China, 1978-2002..Int J Cancer2006;119:1447-54

[3] Lu JH,Jiang ZY,Huang F.Prospective survey on relationship between HBsAg carrier status and liver cancer..J Med Res1983;(5):13-4

[4] Wei YP,Huang QS,Zhang QN.Prospective study with 518 participants on relationship between HBsAg status and liver cancer incidence..J Clin Hepatol1992;8:77-8

[5] Wang YB,Ye BF,Li WG.Study on relationship between geographical distribution of liver cancer, climate and aflatoxin B1..Tumor1981;1:1-5

[6] Li WG,Yu SY,Gong XL.Relationship between geographic distribution of primary liver cancer and selenium level in Qidong county..Trace Elements1986;(3):58-61

[7] Liu PL,Yu SZ.HBV seroepidemiological study in population with different drinking water sources in Qidong county..Acta Acad Med Prim Shanghai1985;12:427-34

[8] Chen JG.Liver cancer endemic trend between 1972 and 1981 in Qidong county..J Med Res1983;(12):13-5

[9] Yang L,Whelan S,Chen Y,Li L.Statistics on cancer in China: cancer registration in 2002..Eur J Cancer Prev2005;14:329-35

[10] Sun GJ,Qian GS,Jin XP.Detecting urine aflatoxin metabolism by high performance liquid chromatography..J Health Toxicol2000;14:250-2

[11] Sun GJ,Qian GS,Jin XP.Detection of aflatoxin-ablumin adducts in human serum and its application..Wei Sheng Yan Jiu2001;30:185-7(in Chinese)

[12] Wu YQ,Lu PX,Kuang SY,Fang X,Zhang QN,Kensler T,Qian GS.Genotype of GSTT1 and GSTM1 among population in Qidong liver cancer high incidence field..Natl Med J China1999;79:517-8

[13] Wu YQ,Wang JS,Wan SG,Groopman JD.Correlation between the genetic polymorphism of EPHX and susceptibility to hepatocellular carcinoma..Tumor2003;23:287-9

[14] Xu L,Jin Y,Qian GS.A case-control study on polymorphism of DNA repair gene XPD and susceptibility to hepatocellular carcinoma..Tumor2004;24:526-9

[15] Qian GS,He X,Jackson PE.Sensitivity of electrospray ionization mass spectrometry detection of codon 249 mutations in the p53 gene compared with RFLP..Cancer Epidemiol Biomarkers Prev2002;11:1126-9

[16] Kuang SY,Wang JB,Mu-oz A,Kensler TW.Specific mutations of hepatitis B virus in plasma predict liver cancer development..Proc Natl Acad Sci U S A2004;101:3575-80 PMCID:PMC373504

[17] Guo X,Qian GS,Tu H.Full-genome sequence analysis of hepatitis B virus isolated from hepatocellular carcinoma in high incidence area Qidong..Tumor2007;27:429-32

[18] Bai X,Jin Y,Qian G,Zhang J,Groopman JD,Tu H.Temporal acquisition of sequential mutations in the enhancer II and basal core promoter of HBV in individuals at high risk for hepatocellular carcinoma..Carcinogenesis2011;32:63-8 PMCID:PMC3025712

[19] Guo X,Qian G.Sequential accumulation of the mutations in core promoter of hepatitis B virus is associated with the development of hepatocellular carcinoma in Qidong, China..J Hepatol2008;49:718-25

[20] Bai X,Jin Y,Guo X,Chen T,Wang J.Correlation of the mutations in N terminal of hepatitis B virus X protein with tumorigenesis of hepatocellular carcinoma..Tumor2010;30:433-7

[21] Cao Z,Guo X,Qian G.High prevalence of hepatitis B virus pre-S mutation and its association with hepatocellular carcinoma in Qidong, China..Arch Virol2008;153:1807-12

[22] Zhu Y,Cai X,Chen M,Wang J,Gu J,Tu H.Hepatitis B virus core protein variations differ in tumor and adjacent nontumor tissues from patients with hepatocellular carcinoma..Intervirology2012;55:29-35

[23] Zhu Y,Guo X,Chen T,Qian G,Gu J,Tu H.Comparison study on the complete sequence of hepatitis B virus identifies new mutations in core gene associated with hepatocellular carcinoma..Cancer Epidemiol Biomarkers Prev2010;19:2623-30

[24] Wu Y,Gao F,Jin Y,Sun Z,Chen T,Sun Y,Xiang Y,Groopman JD,Tu H.Novel natural mutations in the Hepatitis B Virus reverse transcriptase domain associated with hepatocellular carcinoma..PLoS One2014;9:1-10

[25] Gao FM,Zhao ZM,Qian GS,Zhang YW,Gan Y,Tu H.The association between mutations in the reverse transcriptase domain of hepatitis B virus polymerase gene with tumorigenesis of hepatocellular carcinoma..Tumor2014;34:141-6

[26] Zhao ZM,Wu Y,Chen TY,Tu H.Development and application of a reverse hybridization method for detection of hepatitis B virus precore mutation associated with hepatocellular carcinoma..China Oncol2014;24:266-72

[27] Zhao ZM,Gan Y,Chen TY,Sun Y,Qian GS.Novel approach to identifying the hepatitis B virus pre-S deletions associated with hepatocellular carcinoma..World J Gastroenterol2014;20:13573-81 PMCID:PMC4188909

[28] Lu P,Wang J,Zhang Q,Lu Z.Hepatitis B virus infection and aflatoxin exposure in the development of primary liver cancer..Natl Med J China1998;78:340-2

[29] Lu P,Huang Q.The HBV and HCV infection rates among various populations in high incidence area of hepatocellular carcinoma (HCC) and their relationship with HCC..Tianjin Med J1999;27:6-7

[30] Lu P,Wu Y,Wu Y,Kuang S,Qian G.Significance of prospective follow-up cohort study in diagnosis and treatment of primary hepatic cancer among HBsAg carriers..Natl Med J China2001;81:856-9

[31] Sun Y,Wang J,Zhang Q.A prospective study of the relationship between hepatitis B virus markers and primary liver cancer..Tianjin Med J2010;38:81-3

[32] Sun Y,Lu P,Wu Y,Jin Y,Tu H.A seventeen-year prospective cohort study on association of hepatitis B virus e antigen with the risk of hepatocellular carcinoma..Tumor2011;31:841-5

[33] Sun Y,Lu P,Wu Y,Qian G.Relationship between serum hepatitis B virus DNA load and hepatocellular carcinoma in Qidong, China: a cohort follow-up study of 14 years..Natl Med J China2012;92:1874-7

[34] Iloeje UH,Chen CJ.Natural history of chronic hepatitis B: what exactly has REVEAL revealed?.Liver Int2012;32:1333-41

[35] Liu TT,Xiong H,Ni ZP,Zhao NQ.A case-control study of the relationship between hepatitis B virus DNA level and risk of hepatocellular carcinoma in Qidong, China..World J Gastroenterol2008;14:3059-63 PMCID:PMC2712175

[36] Liu S,Gu C,He Y,Cao G.Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis..J Natl Cancer Inst2009;101:1066-82 PMCID:PMC2720989

[37] Qian GS,Yu MC,Gao YT,Woqan GN.A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People's Republic of China..Cancer Epidemiol Biomarkers Prev1994;3:3-10

[38] Lu P,Zhang Q,Sun Y.Longitudinal study of aflatoxin exposure in the development of primary liver cancer in patients with chronic hepatitis..Natl Med J China2010;90:1665-9

[39] Jackson PE,Friesen MD,Lu P,Wu Y,Vogelstein B.Specific p53 mutations detected in plasma and tumors of hepatocellular carcinoma patients by electrospray ionization mass spectrometry..Cancer Res2001;61:33-5

[40] Luo H,Lu P,Wang J,Wu Y.The p53 overexpression in Qidong liver cancer tissues analysed immunohistochemically..Tumor2002;22:101-3

[41] Rashid A,Qian GS,Hamilton SR.Genetic alterations in hepatocellular carcinomas: association between loss of chromosome 4q and p53 gene mutations..Br J Cancer1999;80:59-66 PMCID:PMC2362990

[42] Jackson PE,Wang JB,Mu-oz A,Qian GS.Prospective detection of codon 249 mutations in plasma of hepatocellular carcinoma patients..Carcinogenesis2003;24:1657-63

[43] Chen JG,Ng D,Muñoz A,Qian GS,Yuan JM,Kensler TW.Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China..Cancer Prev Res (Phila).2013;6:1038-45 PMCID:PMC3800239