Association And Functional Study Between-1310C>G Polymorphism In The Promoter Region Of Ku70and Renal Cell Carcinoma Risk And Prognosis

Renal cell carcinoma (RCC) is the third leading cause of death among patientswith urological tumors, accounting for about2%~3%of adult malignancies, nearly100,000patients die from RCC each year. It is estimated that approximately8.4menand5.1women per100,000Chinese individuals are diagnosed with RCC every year.In the same environmental exposures, different individuals have different risk ofkidney cancer incidence and different survival time after suffering from RCC, agrowing number of studies have shown that individual differences, including geneticsusceptibility in critical genes, may have an important role in RCC carcinogenesis.The DNA repair gene Ku70plays a key role in the DNA double strand break (DSB)repair system. Defects in DSB repair capacity can lead to genomic instability, besidesthat Ku70can also independently involved in the regulation of tumor cells apoptosisand the sensitivity of radiotherapy and chemotherapy, which might be related to thedevelopment and survival of tumor. We hypothesized that the Ku70-1310C>Gpolymorphism (rs2267437) was associated with susceptibility and survival of renalcell carcinoma (RCC).We genotyped the Ku70-1310C>G polymorphism in a case-control study of620patients and623controls in a Chinese population by the method of PCR-RFLP andassessed the effects of-1310C>G polymorphism on RCC susceptibility bymultivariate unconditional logistic regression. The controls had no biology associatedwith cases. The cases and controls were frequency matched in age and sex. We then used luciferase assay in vitro and RT-PCR in vivo to examine the functionality of thispolymorphism. To investigate the association between the-1310C>G polymorphismand survival of RCC, we chose311patients with renal cell carcinoma who had beenrecruited from May2004to October2010for an ongoing study, patients follow-upwas performed by telephone every six months. The single factor analysis of eachrelevant factor by Log-rank test, Survival curve is drawn by the Kaplan-Meiermethod. The different of survival time is tested by the Log-rank test. Multivariate Coxregression model to calculate hazard ratios (hazard ratios, HRs) and95%confidenceinterval (confidence intervals, CIs).Compared with the Ku70-1310CC genotype, we found the CG and CG/GGgenotypes had a significantly increased risk of RCC [adjusted odds ratio (OR)=1.47,95%confidence interval (CI)=1.16–1.87for CG and OR=1.47,95%CI=1.16–1.86for CG/GG]. In vitro luciferase assays in various cell lines showed lowerluciferase activity for the-1310G allele than for the-1310C allele. The in vivoRT-PCR experiments with38normal renal tissues revealed statistically significantlylower Ku70mRNA expression in samples with CG/GG genotypes relative to thosewith the CC genotype (P <0.05). Survival analysis showed that the survival time ofthe elderly and hypertensive patients significantly reduced. However, the-1310C>Gpolymorphism did not influence the survival of RCC.These results suggested that the Ku70-1310C>G polymorphism is involved inthe etiology of RCC and thus may be a marker for genetic susceptibility to RCC inChinese populations.