DEPDC5(Rsl012068) Genetic Polymorphism Is Not Associated With Susceptibility To Hepatocellular Carcinoma In Northern Chinese Patients With Chronic Hepatitis B

BACKGROUND AND OBJECTIVE:Hepatocellular carcinoma (HCC), as the sixth most common cancer and the third major contributor to cancer mortality, has been classically considered as a neoplasm with a dismal prognosis. The majority of HCC patients are diagnosed at the advantaged stages with a five-year survival rate of less than12%. Besides, it is estimated that more than700,000new cases of HCC are annually reported with an age-adjusted worldwide incidence of16cases per100,000residents, of which55%occur in China alone. In China, at least80%of HCC cases are related to HBV infection and nearly60-90%of these develop in patients with cirrhosis. However, only a fraction of patients with HBV infection eventually progress to HCC. Aetiologically, human hepatocarcinogenesis is a complicated, multistage and multifactor process with genetic-environment interaction. So the genetic polymorphism may play a role in the clinical progression after hepatitis virus exposure. DEPDC5, containing a DEP domain,as a functional subunit of GATOR1which has GTPase-activating protein activity, was negatively regulated by GATOR2to mediate the GATOR-Rag interaction with other two subunits of GATOR1and involved in autophagy regulation, as an indispensable component for mTORC1sensing amino acid. A recent genome-wide association study (GWAS) has identified that one intronic single nucleotide polymorphism (SNP) rs1012068in DEPDC5locus was significantly associated with progression to hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) by Daiki Miki et al. conducted in Japanese individuals. However, no comprehensive analysis has been implemented to explore the SNP effect on the development of HBV-related HCC. Therefore, we conducted a hospital-based case-control study to investigate whether the SNP rs1012068of DEPDC5gene increased the risk of HBV-related HCC in Northern Chinese individuals.METHODS:In this hospital-based case-control study,320chronic hepatitis B patients with and without HCC were separately recruited for cases and controls. Controls were selected to match cases in age and gender of the same period at same time considering cirrhosis status. Abundant information of the recruiters on HCC-related risk factors, such as age, gender, family history of HBV or liver cancer, smoking and drinking status, virus loads and platelet count, were fully and carefully collected. Clinical data such as categorical and continuous variables, appropriately, were evaluated by chi-squared test or Mann-Whitney U test separately for cases and controls. The Hardy-Weinberg equilibrium was assessed using Peason’s chi-squared test. The genetic effect of association between the SNP and the progression of HBV-related HCC was assessed using unconditional Logistic regression analysis, by the odds ratios (ORs) and95%confidence intervals (CIs), after adjusting for age, gender, drinking and smoking status and so on. For all tests, significance was considered when P<0.05. All data analysis was performed using SPSS v.17.0.RESULTS:1. Subject characteristicsBecause of exactly-matching, cases and controls had an extremely similar distribution of age and gender (P=0.993and P=1.000respectively). The mean age±standard error was54.63±9.144for cases and54.63±8.947for controls. HBV virus loads, HBeAg status, platelet counts were significantly different between cases and controls (all P<0.001).2. Allele and genotype distribution of rs1012068in cases and controlsTo explore the genetic effect of rs1012068on the susceptibility to HBV-related HCC, all subjects were genotyped. The genotype and allele distributions of SNP rs1012068conformed to Hardy-Weinberg equilibrium in the two groups. The frequencies of TT, TG and GG genotype were49.1%,41.9%and9.1%in cases and51.3%,41.6%and7.2%in controls, and no significant association was observed in the genotype frequencies between HCC cases and non-HCC controls (P=0.654). Also, no trend for association between the genotypes and HBV-related HCC susceptibility was obtained after adjusting for age, gender, family history of liver cancer, smoking and drinking status by logistic regression analysis.3. Stratification analysis for rs1012068different genotypes in all pooled subjectsThe association analyses between rs1012068genotypes and the demographic and clinic characteristics were shown that the age and gender distributions among TT, TG and GG genotype groups were comparable to each other (P=0.372and P=0.605respectively). Cirrhosis status after chronic hepatitis B infection was significantly associated with rs1012068TT, TG and GG genotypes (P=0.024).4. Association analysis of rs1012068effect on progression to cirrhosis after chronic hepatitis B infection in all pooled subjectsMoreover, the patients in cases and controls were pooled together and then divided into cirrhosis and non-cirrhosis groups. Because of prior case-control matching, the distributions of age and gender here should not be felt strange. Platelet count, HBVDNA load, HCC and HBeAg status were significantly associated with progression to cirrhosis (HBeAg:P=0.029, others:P<0.001). Multifactor logistic regression analysis that the association of rs1012068with progression to cirrhosis after chronic hepatitis B infection significantly increased after adjustment for age, gender, HCC, platelet count, HBVDNA loads, HBeAg and drinking status (TT genotype:P=0.001, OR=4.757,95%CI=1.955-11.578and TG genotype:P=0.009, OR=3.275,95%CI=1.342-7.993).CONCLUSION:Our study explored that the DEPDC5rs1012068polymorphism may not be associated with HBV-related HCC susceptibility but affect the pathological progression to cirrhosis after chronic hepatitis B infection.