Association Between Single Nucleotide Polymorphisms And Radiation-induced Adverse Effects On Normal Tissue:Systematic Review With Meta-analysis

Background: The heterogeneity of radio-sensitivity exists between the patients who received radiotherapy. Single nucleotide polymorphism(SNP) was suspected to be one of the most important sources of this heterogeneity. DNA is widely considered the main target of radiotherapy. SNPs in genes involved in DNA repair may interfere with an individual’s DNA repair capacity and thus further influence the occurrence of radiation-induced adverse effects. Basing on this hypothesis, several trials have been conducted. However, inconsistent results were reported. Our study focused on three genes: XRCC1, XRCC3 and ERCC2, which are involved in the repair of single-strand breaks(SSBs) and double-strand breaks(DSBs). The aim of our study is to comprehensively collect the relevant evidence and to systematically evaluate the association between the SNPs in these three genes and the risk of radiotoxicity.Methods: Publications were identified through a comprehensive search of the Pub Med and Web of Science databases up to August 1, 2015. The pooled odds ratios(ORs) with corresponding 95% confidence intervals(CIs) were calculated to evaluate the association between polymorphisms and radiotoxicity. Trial sequential analysis(TSA) and power calculation were performed to evaluate and control the potential type 1 and type 2 errors.Results: For XRCC1 Arg399Gln(rs25487) polymorphism, 29 studies involving 4865 patients were ultimately included in this meta-analysis. Conventional meta-analysis identified a significant association with the risk of early adverse effect(OR=1.29, 95%CI: 1.02-1.63, P=0.04), while the association with late adverse effect was not significant(OR=1.03, 95%CI: 0.86-1.25, P=0.73). TSA ruled out any clinical relevance with late adverse effect. For early adverse effect, TSA also suggested that additional studies with about 1700 patients were need to draw any definite conclusion. Three SNPs of XRCC3 were included in our meta-analysis: rs861539, rs1799794 and rs1799796. Basing on 2849 patients of 17 studies, our study suggested that rs861539 significantly correlated with the risk of early adverse effect following radiotherapy(OR=1.99, 95%CI: 1.31-3.01, P=0.001), and the association with late adverse effect was not significant(OR=1.28, 95%CI: 0.97-1.68, P=0.08). Rs1799794 may correlate with late adverse effect(OR=0.47, 95%CI: 0.26-0.86, P=0.01). The number of included studies for rs1799796 was too small, and a meta-analysis was not performed. Three SNPs of ERCC2 were include in our meta-analysis: rs13181, rs1799793 and rs1052555. Eleven studies involving 2584 patients were included. Conventional meta-analysis identified a significant association between rs13181 and the risk of radiotherapy-induced adverse effect(OR=0.71, 95%CI: 0.55-0.93, P=0.01). TSA suggested that additional 1700 patients were need to reach a definite conclusion at the level of OR=0.71. for rs1799793 and rs1052555, no significant association was found.Conclusions: XRCC1 rs25487, XRCC3 rs861539 and ERCC2 rs13181 polymorphisms may affect the risk of radiation-induced adverse effect. It is rational to expect these polymorphisms to be components of a risk prediction model of radiotoxicity.