Association Study Between Nucleotide Excision And Repair Gene Polymorphisms And Environmental Factors In Human Pancreaticcancer

Background and Objective Pancreatic cancer is one of the most malignant tumors.At present,there is no definite conclusion about the etiology of pancreatic cancer,but it is generally believed that it is mainly related to environment and heredity.The main purpose of this study is to investigate the single nucleotide polymorphisms of the major genes in DNA repair pathway by nucleotide excision,and to analyze the major environmental impact factors.We selected 36 loci of eight genes,ERCC1,ERCC2,ERCC3,ERCC4,ERCC5 DDB2,XPA and XPC,to explore the effects of environment,heredity and their interaction and the impact of adenocarcinoma susceptibilityon pancreas through case-control study.Methods 1)Through case-control study,254 patients with pancreatic cancer diagnosed in Affiliated Hospital of Inner Mongolia Medical University from January 2013 to March 2015 were selected as case group,and 277 people who received health examination in our hospital at the same time were selected as control group.The questionnaire was used to conduct face-to-face survey on the subjects.The survey included basic information,dietary habits,living habits,mental status,disease history and family history.Statistical description was used for quantitative variables.T test was used for quantitative variables and chi-square test was used for classification data.The differences between groups were compared.Through univariate and multivariate unconditional logistic regression,the environmental factors of pancreatic cancer were analyzed.2)Matrix-assisted laser desorption ionization time-of-flight mass spectrometry(MALDI-TOF-MS)was used to detect eight genes in the nucleotide excision repair(NER)pathway:ERCC1,ERCC2,ERCC3,ERCC4,ERCC5,DDB2,XPA and XPC genotypes and alleles in Inner Mongolian population.The distribution characteristics of these genes were analyzed by single-factor,multi-factor unconditional logistic regression.To analyze the relationship between polymorphism of these loci and susceptibility to pancreatic cancer.SHEsis system was used to understand the linkage imbalance of these gene loci,to construct haplotypes,and to analyze the association between haplotypes and susceptibility to pancreatic cancer.3)Based on the study of environmental risk factors and gene polymorphism,the interaction between genes and environment was further discussed,and the influence of interaction on susceptibility of pancreatic cancer was analyzed.Results The first part Multivariate unconditional logistic regression analysis showed that heavy smoking(OR = 2.249,95%Cl = 1.085-4.660),excessive drinking(OR = 2.030,95%CI = 1.013-4.488),and a history of type 2 diabetes(OR = 21.073,95%CI= 2.436-182.323)were risk factors for pancreatic cancer.The second part 1)ERCC1 rs3212986?rs3212930?rs3212951,ERCC2 rs13181.?rs1618536.?rsl799786,ERCC3rs4150416.?rs4150441,ERCC5rs3759500,XPC rs2607775,DDB2 rs3781620,those allele frequencies of 11 loci were different between the case group and the control group.(p<0.05).2)ERCC1 rs3212986?rs3212930.?rs1007616?rs2298881?rs3212951,ERCC2 rs238406?rs1618536?rs1799786,ERCC3 rs4150416?rs4150441,ERCC4 rs3136099,ERCC5 rs3759500?rs4150306?rs2296147?rs873601,XPC rs3729587?rs2607775?rs2228001?rs3731055?rs1126547,DDB2rs3781620,those genotype frequencies of 21 loci were different between the case group and the control group(p<0.05).3)The rs3212986 CA+AA genotype,rs2298881 CA+AA genotype,rs3136099 TC+CC genotype,ERCC5 rs873601 AG+GG genotype,XPC rs3729587 CG+GG genotype,rs2228001 GT+TT genotype,rs3731055 CT+TT,DDB2 rs37810 CG+GG genotype can increase the risk of pancreatic cancer compared with the reference genotype.The rs3212930 AG+GG genotype,rs3212951 GA+AA genotype,ERCC2 rs13181 GT+TT genotype,ERCC3 rs4150441 TC+CC genotype and XPC rs2607775 CG+GG genotype can reduce the risk of pancreatic cancer compared with the reference genotype.4)ERCC1 gene rs11615,rs3212986,rs2298881,rs3212955 four loci,ERCC2 gene rs238406 one locus,ERCC3 gene included three loci,ERCC5 gene rs3759500,rs751402,rs2296147,rs873601 four loci,XPA gene rs1962592,XPC gene rs2228000,rs2607775,rs2228001,rs3731055 four loci,DDB2 gene did not find linkage disequilibrium(D'value<0.5,R2<0.8).The third part 1)ERCC1 rs3212930 AA genotype had negative interaction with ERCC3 rs4150441 TT genotype,ERCC1 rs3212930 AG+ GG genotype and ERCC3 rs4150441 TC + CC genotype,which could reduce the risk of pancreatic cancer.ERCC3 rs4150441 TT genotype had positive interaction with XPC rs3729587 CC genotype,XPC rs2607775 CC genotype and DDB2 rs3781620 GG genotype,which could increase the risk of pancreatic cancer.2)There is a positive interaction between ERCC1 rs3212986 CA+AA genotype,ERCC1 rs2298881 CA+AA genotype,XPC rs3729587 CG+GG genotype and the history of type 2 diabetes mellitus,which can increase the risk of pancreatic cancer.Conclusions Massive smoking,excessive drinking and type 2 diabetes history are the environmental risk factors of pancreatic cancer.For people with type 2 diabetes mellitus,the prevention and intervention of pancreatic cancer should focus on carrying ERCC1 rs3212986 CA + AA genotype,ERCC1 rs2298881 CA + AA genotype and XPC rs3729587 CG + GG genotype.