Association Of CSB Genetic Variants With The Susceptibility To Certain Cancers And The Prognosis Of Lung Cancer

Objective CSB(Cockayne syndrome type B) plays an essential role in the process of nucleotide excision repair(NER) and further contribute to development of cancer. The aims of this study is to demonstrate the association of CSB single nucleotide polymorphisms(SNPs)with the risk of cancer and to investigate evaluate the effect of CSB tag SNPs on the prognosis of non-small cell lung cancer(NSCLC) patients after treated with platinum-based chemotherapy.Methods Part I: We used Pub Med, Embase and Chinese National Knowledge Infrastructure databases to identify the related publications for this meta-analysis. The pooled odds ratio(OR) and 95% confidence interval(CI) were calculated using random effect model to evaluate the association of CSB genetic variants with cancer susceptibility. Q-test was used to examine the heterogeneity assumption and the funnel plot and Egger's test were used to examine the potential publication bias. Part II: This prognosis analysis included in 238 NSCLC patients after treated by platinum-based chemotherapy. All participants were recruited at North China University of Science and Technology Affiliated Tangshan Gongren hospital(Tangshan,China) between March 2008 and December 2012. Base on the Chinese population data from Hap Map database, we used Haploview 4.2 software to select candidate tag SNPs of CSB.Genotyping of CSB polymorphisms were conducted using i Plex Gold Genotyping Assay and Sequenom Mass Array. Kaplan-Meier survival curves and log-rank test were used to assess the effect of CSB tag SNPs on the survival time of NSCLC patients. Multivariate Cox Regression analysis was performed to determine the independent prognosis factors of NSCLC.Result Part I: After screening and selecting, there were 26 publications fitting our purpose.This meta-analysis involved in four CSB genetic variants. They were CSB rs2228526(3206cases/3694 controls), rs2228527(4634 cases/6063 controls), rs2228529(2467 cases/32634controls) and rs4253211(4870 cases/6561 controls) polymorphisms. Our data didn't show any association of these CSB variants with the risk of cancer. Part II: Using Haploview software, nine tag SNPs(rs2228526, rs2228528, rs2281793, rs3750751, rs4253101, rs2274097,rs2377902, rs4240506, rs4253212) of CSB were selected for further study. Then, we investigated whether there was significant different in median survival time among patients carrying different CSB genotype after treated with platinum-based chemotherapy. Survival analysis showed that males has shorter median survival time(MST) than females(24m versus32m; Log-rank P=0.012). Patients carrying rs2228526 AA genotype had significantly longer median survival time than patients carrying rs2228526 AG genotype(29m versus 21m; Log- rank P = 0.002). Compared with the rs2281793 CC genotype, the patients carrying TT genotype had a longer MST(25m versus 55 m, Log-rank P=0.004). Compared with rs4253101 AA genotype(MST=21 months), the patients carrying AC genotype had a poorr MST(29months)(Log-rank P=0.002). Compared with rs4240506 AA genotype, the patients carrying at least one G allele had a shorter MST(Log-rank P=0.026, 0.042). Cox's multivariate analysis demonstrated that a poor prognosis of NSCLC was observed to associate with CSB rs2228526 AG and rs4253101 AC allele both with HR(95%CI) of 1.86(1.16-2.99)(P=0.011).Conclusion We identified CSB SNPs(rs2228526 and rs4253101) which were associated with the efficacy of platinum-based anticancer treatment. If confirmed in further perspective studies, the CSB SNPs might serve as simple biomarkers for personalized chemotherapy of platinum-based chemotherapy.