Association Between Nucleotide Excision Repair Genes Polymorphism And Colorectal Cancer Risk

Background:Colorectal cancer is the third most common cancer and the fourth leading cause of cancer-related mortality,it is a disease involving environmental factors,diet,smoking,and drinking.In addition,more and more studies have shown that single nucleotide polymorphisms of genes may lead to changes in the susceptibility of individuals to colorectal cancer.Nucleotide excision repair genes play a crucial role in maintaining genomic stability.Nucleotide excision repair genes polymorphisms may affect DNA repair ability and thus affect individual susceptibility to colorectal cancer.This study investigated the association between three single nucleotide polymorphisms(rs3212986,rs6498486,rs17655)in three nucleotide excision repair genes(ERCC1,ERCC4,ERCC5)and the risk of colorectal cancer.And further studied its potential molecular mechanism.Methods:In our study,we screened 3 NER-related SNPs,according to the minimum allele frequency>0.05,and the genotype distribution was consistent with the Hardy-Weinberg equilibrium(HWE)requirement.We used Taqman genotyping technology to perform genotyping analysis of 1101 colorectal cancer patients and 1175 normal controls in Jiangsu,China.The genotyping results were analyzed using SAS,with a P value of less than 0.05 being statistically significant.We performed a biological prediction(AliBaba2.1)on the selected statistically significant SNPs,predicting that rs6498486 A>C polymorphism alter the binding of transcription factors(NF-kB)to promoter regions,and verified them by functional experiments such as dual luciferase reporter gene assay,EMSA and immunohistochemistry,and further explored the potential functional mechanisms of SNPs.Results:A total of three NER pathway-related SNPs were included in our study:ERCC1 rs3212986,ERCC4 rs6498486,and ERCC5 rsl7655.Genotyping results showed that the ERCC4 gene rs6498486 A>C mutation was associated with the risk of colorectal cancer.Individuals carrying the rs6498486AC/CC genotype had a significantly lower risk of developing colorectal cancer than individuals carrying the AA genotype(P=0.043,adjusted OR=0.82,95%CI=0.69-0.97).The results of the dual luciferase reporter gene assay showed that the ERCC4 transcriptional activity of the rs6498486 C allele was significantly reduced.Immunohistochemistry and qRT-PCR results showed that the rs6498486A>C mutation reduced the mRNA level of ERCC4 and the protein level of ERCC4.Conclusion:ERCC4 rs6498486 is closely related to the risk of colorectal cancer,which may affect the expression of ERCC4 by affecting the binding of ERCC4 by affecting the binding affinity of NF-kappaB,and then participate in the development of colorectal cancer.