| [Objective] To investigate the epidemiological features and trends of hepatocellular carcinoma(HCC) in Xiamen and to study the association between the HBV genotype distribution and the risk of HCC among general population. To demonstrate the association of HBV infection, environmental factors and the risk of HCC and to further explore the relationship between polymorphisms in oncogenes and tumor suppressor genes and the susceptibility of HCC.[Methods] 1. Descriptive study was employed to collect and analyze the mortality data of HCC between 2002 to 2013 and the incidence between 2009 to 2013 in Xiamen. Inorder to describe the epidemiological feature and the trend, the three W distribution was obtained and predicted by using cumulative generating algorithm with a GM(1,1) model with SPSS software version 9.0. 2. The genotyping assay of HBV was performed in the HBV DNA positive samples from sampling survey in Xiamen city, and chi-square test was applied to compare the difference on the risk factors between the carriers of HBV genotype B and C. 3. Cohort study with 8 years of follow up was employed to investigate the differences on the incidence of HCC among population with different HBV genotypes. In total, 2,544 study participants aged from 15 to 59 years old from 36 residents were included in the cohort by stratified random sampling and all 6 districts of Xiamen city have been covered. 4. Case-control study was conducted among 314 HCC cases and 346 controls. The information on environmental exposures was collected by identical questionnaire. Eachparticipants provided blood sample to test the HBV serum markers. Various statistical methods were performed to analyze the association between HBV infection, environmental factors and the risk of HCC by using SPSS software version 19.0, including Mantel-Haenszle, Breslow-Day and Delta. In addition, we further explored the confounding and interactions between factors. 5. Genomic DNA was extracted from blood sample collected from cases and controls. The polymorphisms in tumor suppressor genes including TP53, KIF1 B and RECK and the oncogene MDM2 were genotyped by using MALDI-TOF. Stratified analysis by HBV infection was conducted and the HCC risk of all polymorphisms included in our study calculated by using SPSS software version 19.0, and also the interaction between HBV infection and polymorphisms was demonstrated. 6. We performed a Meta-analysis to further clarify the relationship between polymorphisms in TP53, MDM2 and KIF1 B and the HCC risk. Newcastle-Ottawa Scale(NOS) was employed to evaluate the quality of studies included and heterogeneity analysis, publish bias and subgroup analysis were conducted by using Revman software version 5.0 developed by Cochrane Collaboration. The pooled ORs were calculated and illustrated by using forest plot.[Results] 1. During 2009 to 2013, the average standardized incidence of HCC was 50.97/100,000. Comparing with the national level in corresponding period, the incidence was 3.74-fold higher. The data also demonstrated that male maintained approximately 4-fold incidence when comparing to the counterpart, and the incidence reached peak in the population aged over 75. In total, the potential years of life lost due to HCC during 2002 to 2013 reached 109920 person-year(PY), and the APYLL in rural area was 19.33 years, and the PYLLR was 7.96‰. All above-mentioned indicators were significantly higher in rural area when comparing with the urban. The prediction indicated that the incidence of HCC in Xiamen next 5 years would be 41.77/100,000, 39.57/100,000, 37.49/100,000, 35.52/100,000 and 33.66/100,000, respectively. 2. 228 subjects with chronic HBV infection were genotyped, among them, 78.07% of them was genotype B and 21.49% was genotype C. The age and history of blood transfusion were significantly different between subjects with genotype B and C. Thegenotype distribution was similar among subjects with occult infection when comparing with HBs Ag positive subjects. 3. The total person-year of observation for 8 years of follow-up reached 17299.20 and the incidence density(ID) of HCC was 80.93/100,000 person-year(PY). The ID in population with HBs Ag positive was 8.78-fold higher when comparing with negative population(95%CI: 3.26-29.13) and the attributable risk percent was 88.60%. The PY of observation among population with genotype B and C infection was 1339.60 and the ID of HCC in population with genotype B infection was 572.96/100,000 PY and 1025.99/100,000 PY for genotype C, however, no significant difference was observed. 4. The risk factors of HCC among Xiamen population were identified after the control of confounding caused by HBs Ag as follows: exposure to pesticide, indoor decoration, consumption of smoked food, moldy food, environmental tobacco smoking in home and working place, drinking alcohol, and liver disease history. The tea consumption, high intake of fruit and vegetables and the installation of refrigerator were identified as protective factors. Additive interaction was found between drinking alcohol and HBs Ag positive, and multiplicative interaction was detected between liver disease history and HBs Ag positive. 5. We managed to minimize the confounding caused by HBs Ag and the odd ratio of polymorphisms was calculated as follows: the carrier of genotype GG of rs1042522 in TP53 possess 3.67-fold risk(95%CI:2.10-6.43)of HCC when comparing with the carrier of genotype CC; The OR for genotype CC of rs10814325 in RECK was 5.35(95%CI:2.86-10.01)when comparing with genotype TT. As for the rs2279744 in MDM2, the HCC risk for genotype GG was 2.65-fold(95%CI:1.54-4.55)higher when comparing with genotype TT. We found no significance in the statistical analysis of rs17401966 in KIF1 B. 6. The results indicated that both mutant allele of rs1042522 in TP53 and GG genotype of rs2279744 in MDM2 are capable of elevating HCC risk significantly.[Conclusion] 1. The analysis indicated that Xiamen can be qualified as HCC epidemic area innational wide range, and HCC has placed heavy burden on both public health system and patients’ family. 2. Genotype B of HBV was predominant among general population in Xiamen. 3. The major risk factor of HCC in Xiamen was chronic HBV infection, and the association between polymorphisms and HCC risk requires further observation. 4. Other than HBV infection, we identified the risk factors of HCC in Xiamen as follows, liver disease history, drinking alcohol, pesticide exposure, indoor decoration, and environmental tobacco smoking. 5. The polymorphisms rs1042522 in TP53, rs10814325 in RECK and rs2279744 in MDM2 were associated with the susceptibility among population in Xiamen. In addition, the analysis also demonstrated that polymorphism rs10814325 in RECK has associated with HCC and further investigation is required. |
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