| As one of the most common cancers, primary hepatocellular carcinoma(PHC) is the second leading cause of cancer-related death in China, with higher degree of malignancy and poor prognosis, and severely threatens the public health. The data from epidemiological investigations and animal studies indicate that hepatocellular carcinoma is a complex and multi-stage process that requires interaction among virus, environment and hereditary factors. Up to now, the evidenced virus and environmental factors include hepatitis B virus, hepatitis C virus, intake of aflatoxin or polluted water, alcoholism and long term smoking. However, only small part of these exposed to the risk factors mentioned above developed hepatocellular carcinoma, which may be due to the difference of the individual susceptibility to cancer.Hereditary factors play critical roles in the pathogenesis of PHC. As the third generation molecular maker, Single-nucleotide polymorphism(SNP) is the most common form of human genetic variation, with notable individual differences. It has been reported that SNP can not only predict the risk of disease development based on the significant relationship with cancer susceptibility, but also be a marker indicating the progression and prognosis of the disease.The main function of DNA mismatch repair is to keep the hereditary information in intact and stable manner and avoid of genetic mutation through repairing the mis-incorporation of bases. The ability of DNA MMR is based on the SNP of the MMR gene, which may influence the individual cancer susceptibility and prognosis. It has been documented that DNA MMR gene is associated with Colon cancer, gastric cancer, lung cancer, while up to now, there is no data about the relationship between the SNP of DNA MMR gene and hepatocellular carcinoma has been reported.The present study aimed to investigate the relationship between the selected 15 cancer related polymorphisms of DNA MMR genes with the risk and prognosis of PHC in han nationality from north China, as well as the effects of different factors on the life quality of PHC patients by application of EORTC QLQ-C30 scale, and finally clarify the role of the SNP of DNA MMR gene in the pathogenesis of PHC and decrease the incidence of PHC, improve the life quality of PHC patients through protective measures.Part 1 The relationship between SNP of DNA MMR Gene and Susceptibility to Primary Hepatocellular CarcinomaObjective: To investigate the relationship between the risk of PHC and 15 polymorphisms in 9 genes, including MSH5(rs1150793, rs2075789, rs3117582 and rs3131379), MSH3(rs26279 and rs184967), MSH4(rs5745549 and rs5745325), MSH2(rs1800152 and rs1802577), MLH1rs1799977, MLH3rs175080, MSH6rs1042821, PMS1rs5742933 and PMS2rs1059060.Methods: A case-control study was conducted based on the data from 508 cases, which were divided into case group and control group.The general data and clinical information were collected by questionnaire survey, sample from tumor tissue was harvested and stored at-80℃.DNA was extracted from the sample by Qiagen DNA Mini Kit(Hilden, Qiagen, Germany), Sna Pshot platform was used for SNP genotyping.An unconditional logistic regression was performed after a single factor analysis to identify the association between SNP genotypes and susceptibility to PHC, analysis were carried out using SPSS 16.0 statistical analysis software.Results:1 The Relationship between MLH3 polymorphic site rs175080 and the susceptibility to PHCMLH3 polymorphic site rs175080 is associated with the susceptibility to PHC. After adjustments for age and gender, these carry AA genotype had significantly higher risk of PHC(OR=3.424, 95% CI=1.097-10.689)(P=0.034), so were in the hidden gene model, the subjects carrying AA genotype had 3.380 times(1.090, 10.481) higher risk of PHC than those carrying GG or AG genotype.(P=0.035). Rs175080 A is a risk factor of susceptibility to PHC.2 The relationship between MLH3 Polymorphic Site Rs26279 And The Susceptibility to PHCMLH3 polymorphic site rs26279 is associated with the susceptibility to PHC. MSH3rs26279 AG and GG genotypes increased the risk of PHC, with ORs(95% CI) of 1.644(1.112-2.428) and 3.300(1.765-6.168), respectively. After adjustments for age and gender, the subjects carrying AG genotype had significantly higher risk of PHC(OR=1.644, 95% CI=1.112-2.428)(P=0.013) than the subjects carrying AA genotype, cases carrying GG genotype had significantly higher risk of PHC(OR=3.300, 95% CI=1.765-6.618)(P<0.001) than the subjects carrying AA genotype, so were in both the dominant and hidden gene model, the subjects carrying GG or AG genotype had 1.913 times(1.328, 2.756) higher risk of PHC than those carrying AA genotype.(P<0.001) Rs175080 A is a risk factor of susceptibility to PHC. the subjects carrying GG genotype had 2.666 times(1.463, 4.858) higher risk of PHC than those carrying AA and AG genotype(P<0.001). Rs26279 G is a risk factor of susceptibility to PHC.3 The Relationship between MSH5 polymorphic site rs2075789 and the susceptibility to PHCMSH5 polymorphic site rs2075789 is associated with the susceptibility to PHC. MSH5rs2075789 AA increased the risk of PHC(OR=9.229, 95% CI= 1.174-72.535). MSH6(rs1042821)CT genotype decreased the risk of PHC(OR=0.629,95%CI=0.428-0.924).After adjustments for age and gender, the cases carrying AA genotype had significantly higher risk of PHC(OR=9.229, 95% CI=1.174-72.535)(P=0.035) than those carrying GG genetpye, so were in the hidden gene model, the subjects carrying AA genotype had 8.829 times(1.126, 69.214) higher risk of PHC than those carrying GG or AG genotype.(P=0.038). Rs2075789 A is a risk factor of susceptibility to PHC.4 The relationship between MSH6 polymorphic site rs1042821 and the susceptibility to PHCMSH6 polymorphic site rs1042821 is associated with the susceptibility to PHC. After adjustments for age and gender, the cases carrying CT genotype had significantly lower risk of PHC than those carrying CC and TT genotype(OR=0.629, 95% CI=0.428-0.924)(P=0.018), so were in the dominant gene model, the subjects carrying CT and TT genotype had 0.677 times(0.470, 0.974) lower risk of PHC than those carrying CC genotype. rs1042821 T is a protective factor of susceptibility to PHC.Conclusions:1 The polymorphic sites of rs175080 in MLH3, rs26279 in MSH3, rs2075789 in MSH5, and rs1042821 in MSH6 are associated with the susceptibility to PHC in han nationality from north China.2 The polymorphic sites of rs175080 in MLH3, rs26279 in MSH3, rs2075789 in MSH5, and rs1042821 in MSH6 are risk factors of PHC, those carrying rs175080 A, rs26279 G and rs2075789 A genotype are susceptible to PHC.3 MSH6 polymorphic site rs1042821 is a protective factor for PHC, those carrying rs1042821 T genotype are unsusceptible to PHC.4 No significant association was found between the susceptibility to PHC and polymorphic sites of rs1150793 in MSH5, rs5742933 in PMS1 and rs1059060 in PMS2.Part 2 The relationship between the SNP of DNA MMR and the prognosis of primary hepatocellular carcinomaObjective: To investigate the relationship between the prognosis after primary hepatocellular carcinoma radical resection and 15 polymorphisms in 9 genes, including MSH5(rs1150793, rs2075789, rs3117582 and rs3131379), MSH3(rs26279 and rs184967), MSH4(rs5745549 and rs5745325), MSH2(rs1800152 and rs1802577), MLH1rs1799977, MLH3rs175080, MSH6rs1042821, PMS1rs5742933 and PMS2rs1059060.Methods: The general data and clinical information were collected by questionnaire survey from 250 cases, sample from tumor tissue was harvested and stored at-80℃. DNA was extracted from the sample by Qiagen DNA Mini Kit(Hilden, Qiagen, Germany), Snapshot platform was used for SNP genotyping. The relationship between polymorphic sites and PHC patient survival period was analyzed by using one-way ANOVA and multivariate Cox regression analysis, and the risk ratio(Hazard ritiao, HR) and 95% confidence intervals(95% confidence intervals, 95% CI) were calculated, A two-sided p <0.05 was considered to be statistically significant., statistical analysis were carried out using SPSS 16.0 statistical analysis software.Results:1 The relationship between MSH3 gene polymorphic site rs26279 and prognosis of PHC after radical resection.By univariate analysis, the risk of death in the cases carrying AG genotype is 1.507(1.101,2.062) times higher than the AA genotype(P = 0.010) in the co-dominant model; the risk of death in the cases carrying GG genotype is 0.544(0.330,0.898) times lower than the AA + AG genotype(P = 0.017) in the hidden gene model; the same results were observed in the survival time that calculated using Cox regression analysis adjusted for gender, age, tumor size, tumor type, Child-Pugh classification, portal tumor thrombus, TNM.2 The relationship between MSH6 gene polymorphic site rs1042821 and prognosis of PHC after radical resection.By univariate analysis, the risk of death in the cases carrying CT genotype is 1.518(1.097,2.101) times higher than the CC genotype(P = 0.012) and the risk of death in the cases carrying TT genotype is 3.067(1.888,4.985) times higher than the CC genotype(P<0.001) in the co-dominant model; the risk of death in the cases carrying CT+TT genotype is 1.738(1.289,2.344) times higher than the CC genotype(P<0.001) in the dominant model; the risk of death in the cases carrying TT genotype is 2.661(1.665,4.254) times higher than than the CC+CT genotype(P<0.001) in the hidden model; the same results were observed in the survival time that calculated using Cox regression analysis adjusted for gender, age, tumor size, tumor type, Child-Pugh classification, portal tumor thrombus, TNM.3 The relationship between PMS1 gene polymorphic site rs5742933 and prognosis of PHC after radical resection.By univariate analysis, the risk of death in the cases carrying CG genotype is 1.494(1.088, 2.051) times higher than the GG genotype(P =0.013) in the co-dominant model; the risk of death in the cases carrying CG+CC genotype is 1.499(1.114, 2.017) times higher than the GC genotype(P=0.008) in the dominant model; no association was found between Rs5742933 and the survival of PHC patients in the hidden model. The survival time was calculated using Cox regression analysis adjusted for gender, age, tumor size, tumor type, Child-Pugh classification, portal tumor thrombus, TNM, the risk of death in the cases carrying CC genotype is 1.941(1.135,3.319) times higher than the GG genotype(P=0.013) in the co-dominant model; no association was found between Rs5742933 and the survival of PHC patients in the dominant model; the risk of death in the cases CC genotype is 1.823(1.096,3.033) times higher than the GG+CG genotype(P=0.021) in the hidden model.4 The relationship between PMS2 gene polymorphic site rs1059060 and prognosis of PHC after radical resection.By univariate analysis, the risk of death in the cases carrying AG genotype is 2.176(1.598,2.964) times higher than the AA genotype(P<0.001) in the co-dominant model; the risk of death in the cases carrying AG+GG genotype is 1.698(1.260,2.289) times higher than the AA genotype(P=0.001) in the dominant model; the risk of death in the cases carrying AA+AG genotype is 0.445(0.235,0.843) times lower than the AA+AG genotype(P=0.013) in the hidden model; The survival time was calculated using Cox regression analysis adjusted for gender, age, tumor size, tumor type, Child-Pugh classification, portal tumor thrombus, TNM, the risk of individual death carry on AG genotype is 2.123(1.476,3.053) times than the AA genotype(P<0.001) in the co-dominant model; The risk of death in the cases carrying AG+GG genotype is 1.563(1.122, 2.179) times higher than the AA genotype(P=0.008) in the dominant model; no association was found between the rs1059060 and survival of PHC patients in the hidden model.5 The relationship between MLH3 gene polymorphic site rs1059060, MSH5 gene polymorphic site rs1150793、rs2075789 and prognosis of PHC after radical resection.No association was found between rs175080, rs1150793, rs2075789 and the prognosis of PHC patients by the univariate and multivariate analysis.6 The combined effect of each polymorphic site on prognosis of PHC after radical resection.The survival time was calculated by multivariate Cox regression analysis adjusted for gender, age, tumor size, tumor type, Child-Pugh classification, portal tumor thrombus, TNM and genotyping. The results showed that the risk of death in the cases carrying three risk genotype simultaneously is 4.114(2.210,7.659) times higher than these carrying no risk genotype(P<0.001), the risk of death in the cases carrying four risk genotype simultaneously is 10.066(2.927,34.618) times higher than these carrying no risk genotype(P<0.001), the risk of death in the cases carrying one and two risk genotypes were not found to be associated with the prognosis of PHC patients.7 Based on the results of the combined effects of each polymorphic site on prognosis of PHC, all cases were divided into two groups according to the amount of carrying risk genotype: no more than 2 risk genotypes or more than 2 risk genotypes. The survival time was calculated by multivariate Cox regression analysis adjusted for gender, age, tumor size, tumor type, Child-Pugh classification, portal tumor thrombus, TNM and genotyping. The results showed that the risk of death in the cases carrying f more than three risk genotypes simultaneously is 2.010(1.471,2.747) times higher than these carrying no more than two risk genotypes(P<0.001).Conclusions:1 MSH3 gene polymorphic site rs26279 is associated with prognosis survival after PHC radical resection.2 MSH6 gene polymorphic site rs1042821 is associated with survival of PHC patient. rs1042821 T is a risk genotype of the survival of PHC patients.3 PMS1 gene polymorphic site rs5742933 is associated with survival of PHC patient. rs5742933 C is a risk genotype of the survival of PHC patients.4 MSH3 gene polymorphic site rs1059060 is associated with prognosis survival after PHC radical resection. rs1059060 T is a risk genotype of the survival of PHC patients.5 There was no association was found between rs175080, rs1150793 and rs2075789 and PHC patient survival.6 Tumor size, portal vein tumor thrombus, TNM are independent factor affecting survival. There are positive correlations between the risk of death and tumor size, portal vein tumor thrombus, TNM staging, respectively.Part Ⅲ The study of the factors influence PHC for the Han population in northern ChinaObjective: To investigate the effect of risk factors about PHC and factors influence the quality of patients for the Han population in northern China by epidemiological survey and the application of EORTC QLQ-C30 scale, and finally to decrease the incidence and improve the life quality of PHC patients through protective measures.Methods: data of the eligible subjects were collected by questionnaire survey and scale. In this case-control study, a non-conditional logistic regression analysis was performed to assess the predisposing factors of PHC for the Han population in northern China; Multiple linear regression analysis was used to study the influence of different factors on the quality of life of PHC patients; the difference of scores of life quality was analyzed by t test and variance analysis.Results:1 The risk factors of PHC included increased BMI, male, smoking, drinking, eating moldy food, leftovers or pickled food, family history of hepatitis B or liver cancer, history of diabetes, HBV and HCV infection(P<0.05). Higher vegetable and fruit intake were protective factors of PHC(P<0.05).2 Age, family monthly income, marital status, hepatitis, nutritional status of PHC patients are closely related with their quality of life(P<0.05), whereas gender, culture degree, mode of payment and place of residence of PHC patients was not statistically associated with the quality of life.3 Cronbach’s coefficient values of EORTC QLQ-C30 scale were more than 0.710, the correlation coefficient of two measurements were more than 0.690. The extracted common factors and the distribution of the maximum load value on each issue are consistent with structure of the questionnaire survey; the effects of gender, age and marital status on the quality of PHC patients were statistically significant(P<0.05).Conclusions:1 Change in smoking, drinking and other unhealthy lifestyle, improve eating habits, treatment of diabetes, HBV and HCV infection and other disease play key role in preventing the PHC for the Han population in northern China.2 More attention should be paid to the influence of different factors on quality of life in PHC patients and therefore accordingly taking preventive measures.3 Evaluation quality of life in patients with PHC by the EORTC QLQ-C30 scale is helpful to guide clinical treatment and improve the quality of patients’ life. |
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