Association Study Between Polymorphisms At6q25.1and Susceptibility And Prognosis Of Hepatocellular Carcinoma

Objective:The striking gender disparity was observed in the incidence of hepatocellular carcinoma. Estrogen and estrogen receptor (ESR) play an important role on the pathogenesis. But little is known about the mechanism by which estrogen signaling promotes or restrains hepatocellular carcinoma. Recently, some novel genetic susceptibility loci at chromosome6q25.1for breast cancer risk were identified through genome-wide association studies. These single nucleotide polymorphisms located in the upstream or intron of the ESR1gene which plays an important role in the carcinogenesis in hepatocellular carcinoma. However, the relationship between these polymorphisms at6q25.1and susceptibility and prognosis of hepatocellular carcinoma is not clear. Therefore, under this basis, we planned to determine whether these polymorphisms at6q25.1are associated with hepatocellular carcinoma risk and prognosis. Meanwhile, we analyzed different clinical characteristics and prognostic features on gender-specific patients with hepatocellular carcinoma.Methods:The association between the identified SNP and susceptibility to hepatocellular carcinoma were examined in a case-control set consisted of2568patients with hepatocellular carcinoma and2785controls derived from a Han Chinese population. The total DNA was isolated from lymphocyte of peripheral blood. We focused on rs9485372, rs9383951and rs2046210at chromosome6q25.1. Genotypes were determined by TaqMan platform. Logistic regression models were used to compute adjusted odds ratios and95%confidence interval. Cumulative survival rate was calculated by life table and compared by log rank test. Results:Case-control analysis showed that the rs9485372AG genotype was associated with significantly increased risk for hepatocellular carcinoma, with the OR being1.21(95%CI=1.06-1.39, P=0.0047), AA genotype was associated with significantly increased risk for hepatocellular carcinoma, with the OR being1.34(95%CI=1.13-1.59, P=0.0009), and AG+AA genotype was associated with significantly increased risk for hepatocellular carcinoma, with the OR being1.25(95%CI=1.10-1.42, P=0.0008), compared with the GG genotype. In women, this risk for hepatocellular carcinoma became more remarkable. AG genotype was associated with significantly increased risk for hepatocellular carcinoma, with the OR being1.45(95%CI=1.05-2.00, P=0.0217), AA genotype was associated with significantly increased risk for hepatocellular carcinoma, with the OR being2.21(95%CI=1.45-3.37, P=0.0002), and AG+AA genotype was associated with significantly increased risk for hepatocellular carcinoma, with the OR being1.62(95%CI=1.19-2.19, P=0.0020), compared with the GG genotype. The rs9383951CG genotype was associated with significantly increased risk for hepatocellular carcinoma, with the OR being1.23(95%CI=1.06-1.43, P=0.0065), CC genotype was associated with significantly increased risk for hepatocellular carcinoma, with the OR being1.82(95%CI=1.05-3.14, P=0.0318), and CG+CC genotype was associated with significantly increased risk for hepatocellular carcinoma, with the OR being1.26(95%CI=1.09-1.46, P=0.0020), compared with the GG genotype. No significant association was found between rs2046210and susceptibility of hepatocellular carcinoma (AG vs GG, P=0.8715; AA vs GG,.P=0.5345). There was no linkage disequilibrium between the two SNP. There was also no association between these gene polymorphisms and prognosis of hepatocellular carcinoma (log rank test, P>0.05). Female patients with hepatocellular carcinoma often had better liver function status than male in perioperative period (χ2test, P>0.05). The postoperative overall survival in female patients was longer than male (log rank test, P=0.04).Conclusion:We identified two independent genetic susceptibility locus at chromosome6q25.1for hepatocellular carcinoma by a case-control study derived from a Han Chinese population. The influence was more remarkable in female group. It is possible that the increasing risk of hepatocellular carcinoma may be mediated through regulating the ESR1gene. Besides, our survival analysis indicated the female patients with hepatocellular carcinoma often had better liver function status and might attain a better prognosis.