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Genetic Polymorphism of DNA Base-excision Repair Genes (APE1, OGG1 and XRCC1) and Their Correlation with Risk of Lung Cancer

Author: LiZuo
Tutor: WangDong
School: Third Military Medical University
Course: Oncology
Keywords: Lung cancer Base excision repair OGG1 XRCC1 APE1 Single nucleotide polymorphisms Genetic predisposition
CLC: R734.2
Type: Master's thesis
Year: 2011
Downloads: 129
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Lung cancer is one of the most common malignant tumors of the human, was among the first of the various types of cancer in the world overall morbidity and the total number of deaths, the 5-year survival rate is less than 15%, greatly to human health and life-threatening. Smoking is the most important environmental factors lead to lung cancer, 80 - 90% incidence of lung cancer and smoking important, but only 10-15% of smokers get lung cancer and some of the same non-smokers will get lung cancer deaths, prompted Lung cancer is a multifactorial disease, in which genetic and environmental factors in the incidence of lung cancer, play an important role in development. Gene polymorphism is to determine the individual susceptibility to disease phenotype and treatment differences in reactivity of the important factors, one of the most important and the most common is a single nucleotide polymorphism. The growing number of recent reports suggest significant correlation between individual genetic polymorphisms and susceptibility to lung cancer. The smoking generation of reactive oxygen species (ROS) and other carcinogens, can lead to a variety of DNA damage, wherein 8 - hydroxyguanine (8-oxo-G) is the most common oxidation base damage. Base excision repair (BER) is the the a repair pathways, and major repair of DNA base damage caused by oxidation reagents and alkylating agent, plays in the maintenance of DNA integrity can not be ignored major role in the DNA repair system. Molecular genetic basis of base excision repair gene polymorphisms as individual damage repair capacity differences may be important genetic predisposing factors for lung cancer. 8 - hydroxyguanine DNA glycosylase (OGG1), X-ray is interleaved repair genes (XRCC1) and apurinic / pyrimidine nucleic acid endonuclease 1 (APE1) genes in the base excision repair pathway play an important role, there are already single nucleotide polymorphisms combined effects of bladder cancer, breast cancer, esophageal cancer, cervical cancer susceptibility reported. On one or two single nucleotide polymorphisms and susceptibility to lung cancer reported, however, the combined effects of the three genes with susceptibility to lung cancer research has not been reported. Therefore, we predict that the base excision repair genes OGG1, XRCC1, of APE1 joint effects may be associated with lung cancer susceptibility. In order to reveal the Chinese population base excision repair gene polymorphism and the risk of lung cancer, looking for discovery the functional pathogenic potential sites, we use a case - control study method to select of OGG1, including XRCC1, of APE1 gene SNP loci , first in the Chinese Han population of 455 patients with lung cancer and 443 cases of age, gender, case group frequency matched normal control genotyping and association analysis. Research purpose of this study is to apply two pairs of primers - polymerase chain reaction (polymerase chain reaction withconfronting two-pair of primers, PCR-CTPP) to detect and analyze the China Chongqing Han population base excision repair gene OGG1 (326Ser/Cys) of XRCC1 (399Arg/Gln) of APE1 (148Asp/Glu, and-141T / G) single nucleotide polymorphisms and their joint role in lung cancer susceptibility and environmental exposure to risk factors interactions, to search for and susceptibility to lung cancer risk genotypes, and used as molecular markers to provide a theoretical basis for the high-risk groups for lung cancer screening and lung cancer in susceptible individuals, early diagnosis and prevention. Research content and methods of this study using a case - control study, including 455 cases of lung cancer patients, healthy controls randomly selected from the same period, 443 cases of healthy persons of the same community, frequency paired by age, gender and case group. Collected peripheral blood genomic DNA was extracted using two pairs of primers - polymerase chain reaction (PCR-CTPP) technology to detect and analyze the OGG1 (326Ser/Cys), XRCC1 (399Arg/Gln), APE1 (148Asp/Glu and-141T / G) four single nucleotide polymorphism; difference between the χ2 test was used to compare the case group and control group demographic variables, smoking, family history of cancer; multivariate logistic regression model analysis of base excision repair genes (of APE1, OGG1 XRCC1) single nucleotide polymorphisms and susceptibility to lung cancer relationship, as well as smoking, histological type in which the interaction; APE1 haploid reconstruction using PHASE software version 2.1, while analysis of its susceptibility to lung cancer relationship. All statistics are used SPSS16.0 software. Relationship with lung cancer susceptibility results. Single gene SNP logistic regression analysis showed that, after adjusting for age, gender, smoking status and family history of cancer, the carrying the the APE1-141G / G genotype individual risk of lung cancer than those with pure ). Stratified analysis of the lung cancer group, according to the type of pathological stratified analysis APE1 promoter region of adenocarcinoma -141 multi-locus genotypes distribution between the control group and the difference was statistically significant (P lt; 0.05) Stratified analysis according to the smoking status of the individual, the results show that the carrying the APE1-141G / G genotype risk of lung cancer than those with the homozygous wild genotype of APE1-141T / T individuals to reduce by 49% in the smoking group ( 3. APE1 haploid sick with lung cancer risk in order to further clarify APE1 gene polymorphisms and susceptibility to lung cancer, we use HaPloview software haplotype analysis showed this study APE1 two loci single nucleotide polymorphisms existence of linkage disequilibrium. Constructed four haploid two APE1 polymorphism loci according to the study. In these haploid, we found that, compared with normal APE1-141T/148Asp haploid, -141G/148Asp, and -141G/148Glu haploid can reduce the risk of lung cancer, but not statistically significant ( OR = 0.86 and OR = 0.86); and APE1-141T/148Glu haploids can significantly increase the risk of lung cancer (OR = 1.28,95% CI 1.01 ~~ 1.62, P = 0.04). Multilocus SNP combined effects of lung cancer susceptibility considerable number of individuals will have multiple gene single nucleotide polymorphisms change occurs, the specific combination of these special gene SNP may be related to disease susceptibility relationship important. Therefore, more homozygous individuals grouped together, to analyze the prevalence of lung cancer risk by calculating the value of these particular combinations adjusted OR. Reference population by individual homozygote. Locus analysis of OGG1 326Cys of XRCC1 399Gln of and APE1-141G three homozygote relative to the respective wild homozygote the OR value has reduced the prevalence of lung cancer have a protective effect. Therefore, we combined these polymorphic sites at the same time has the potential protective effect, further analysis of these combinations and the risk of lung cancer in relationship. After adjustment for age, sex, smoking status, and family history of cancer, we found to carry two or three of OGG1 326Cys of XRCC1 399Gln APE1-141G mutant homozygous individuals relative to the reference population, the risk of lung cancer was significantly lower (adjusted OR Conclusion APE1 gene promoter region-141T / G locus and susceptibility to lung cancer related-141GG genotype can significantly reduce the prevalence of lung cancer risk. APE1-141T/148Glu haploid may be an important genetic predisposing factors of lung cancer. Base excision repair gene three polymorphism sites the combination (OGG1 326Cys, and of XRCC1 399Gln and APE1-141G) significantly reduces the risk of lung cancer.

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