| Objectives MSH2(Mut S homolog 2),as one of key proteins in the mismatch repair system,can recognize DNA mismatches and participate in the process of DNA repair.This study aims to explore the relationship between the genetic variation of MSH2 and cancer susceptibility,and association of genetic variants of in the promoter of MSH2 with the susceptibility and prognosis to lung cancer.Methods Chapter 1: We searched the literature about MSH2 gene single nucleotide polymorphism and tumor susceptibility through Pub Med,Embase,Web of Science and CNKI(China National Knowledge Infrastructure).Meta-analysis was performed using Meta package of R language.Chapter 2: Using database of The Human Protein Atlas to analyze protein of MSH2 in different tumor cells.Real-time fluorescence quantitative PCR(RT-q PCR)was used to detect MSH2 m RNA level of 20 pairs of lung cancer tissues and adjacent tissues.Difference analysis was performed using paired t test.In our case-control study,700 non-small cell lung cancer patients and 700 normal controls were involved.Polymerase chain reaction-restriction fragment length polymorphism(PCRRFLP)and Taqman probe method were used to genotype the rs6757310 and rs1863332 polymorphism,respectively.Chi-square test was used to compare the distribution of categorical variables.Unconditional logistic regression was used to analyze the relationship between MSH2 genetic variate and lung cancer susceptibility.Kaplan-Meier survival curve and Log-rank test were used to evaluate the influence of various genetic variations on the prognosis of lung cancer.Results Chapter 1: A meta-analysis was conducted to evaluate the association of MSH2 genetic variants(rs2303425,rs2303428)with multiple cancer risk.MSH2 rs2303425 study involved in 8 studies.In co-dominant model(CC versus TT)and recessive genetic model(CC versus CT + TT),we found that MSH2 rs2303425 CC genotype significantly increased cancer susceptibility with OR(95%CI)of 1.45(1.10 ~ 1.91)(P=0.01)and 1.44(1.10 ~ 1.89)(P=0.01).Chapter 2: According the data from The human protein atlas,the expression of MSH2 is depressed in lung cancer cells.RT-q PCR results showed that m RNA level of MSH2 in lung cancer tissues was significantly lower than that in adjacent tissues(P = 0.03).Our case-control study had shown that rs6757310 and rs1863332 polymorphism did not effect on the lung cancer susceptibility.Further stratified analysis showed that MSH2 rs6757310 CC genotype was associated with lung cancer susceptibility among smokers(OR = 3.30,95%CI = 1.10 ~ 9.88,P = 0.03)and even heavy smorkers(OR = 5.67,95%CI = 1.24 ~ 25.90,P = 0.03).When stratified by lung cancer type,we found an increased risk of squamous cell carcinoma(OR = 2.09,95%CI = 1.04 ~ 4.21,P = 0.04).For MSH2 rs1863332 polymorphism,GG genotype contributed to increase risk of lung cancer among the elderly(OR = 1.56,95%CI = 1.11 ~ 2.20,P = 0.01).Survival analysis showed that the median survival time(MST)of patients with MSH2 rs6757310 CC genotype was 31 months,which was lower than that of patients with CG genotype(61m)and GG genotype(45m)(P=0.02).Patients with MSH2 rs1863332 GG genotype had an MST of 19 months,which was lower than those with GT genotype(39m)and TT genotype(48m)(P = 0.02).Conclusions MSH2 rs2303425 variants increase tumor susceptibility.MSH2 rs6757310 and rs1863332 polymorphisms increase the development and the prognosis of lung cancer.Figure 17;Table 14;Reference 189... |
PDF Full Text Request