Nucleotide Excision Repair Pathway Gene Polymorphism And Cancer Susceptibility

Part I:The Association Study between Single Nucleotide Polymorphisms in Human POLE1 and Susceptibility to Lung CancerLung cancer is one of the tumors with highest prevalence rate and fatal rate in the world, therefore it has became a global public health problem. The environment carcinogenic factors, such as tobacco smoke, are very important causes of the lung carcinogenesis. There are multiple varieties of components that might generate intensive carcinogen after the cell metabolism, such the PAHs. These chemicals can form DNA bulky adducts and cause mutations and accumulative DNA lesions, which may lead to the tumor genesis. In mammals, this kind of damage is repaired by the NER pathway, which could identify the lesion location and decerebrate the damage segment, and synthesis new DNA strand to fill the gap by using the other strand as the template. Half of the final synthesis and repair process is accomplished by DNA polymeraseε, which is encoded by POLE1 gene in human. In order to study the association between POLE1 and lung cancer risk, we selected 5 SNPs on this gene, and launched a case-control association study based on 462 lung cancer patients and 466 controls in Chinese Han population.Significant differences were observed in rs5744738 between cases and controls in recessive model. The lung cancer risk of A/A genotype carriers decreased to 0.47 times (95%CI:0.25-0.91),0.28 times in the age group of over 60 (95%CI:0.09-0.91), and 0.42 times in non-family cancer history group (95%CI:0.19-0.90)。The analysis of joint effect between accumulated smoking quantities and genotypes shows that G/G or G/A carriers have a significant raise in lung cancer risk with the increasing smoking quantity. The rs5744962 mutation allele significantly raises the lung cancer rise of non-smokers to 1.75 times (95%CI:1.02-3.00).For the conclusion, the 5 selected SNPs of human POLE1 gene show association with the lung cancer susceptibility in Chinese Han population. The population with homologous mutations of rs5744738, rs4883545 and rs5744873 shows significantly declined lung cancer risk, while the non-smoking carriers of rs5744962 and rs5745047 mutation allele have a increased lung cancer risk. Partâ…¡:ERCC4 R415Q Polymorphism and Cancer Susceptibility:A Meta-AnalysisThe ERCC4 gene is another key gene of NER pathway. Its expression product could form a 5' end endonuclease activated complex with ERCC1, which is an necessary process for the NER pathway. The human ERCC4 gene contains an important SNP site rs1800067 in its exon 8, the SNP belongs to the codon 415 of ERCC4, whose Gâ†'A polymorphism causes an missense mutation from Arg to Gln (Arg415Gln, R415Q). Recent published data have disputes on the relationship between this SNP and cancer susceptibility, so we conducted a meta-analysis based on the existed studies on this SNP.Our analysis covered 9491 cancer samples and 11586 controls. The overall analysis did not show any significant result. However, in the subgroup analysis, significant decrease of cancer risk for A allele and A/A genotype were observed in the Caucasian population (G vs A OR=0.87,95%CI(0.77,0.99) p=0.032; GG vs AA OR=0.32,95%CI(0.17,0.61), p=0.001; (GG+GA) vs AA OR=0.32,95%CI(0.17,0.61), p=0.001). The cancer type subgroup analysis didn't show any significant association with cancer risk both in breast cancer group and non-breast cancer ones.The results indicates that in Caucasian population, ERCC4 R415Q may play a protective role in the cancer development.