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Association between the Variations of hOGG1Gene and the Gynecologic Oncology Risk, and the Mechanism of These Variations Effect on the Gene Function

Author: ChenXiaoXiang
Tutor: WangYaPing
School: Nanjing University
Course: Internal Medicine
Keywords: Base excision repair hODGG1gene 5’-UTR age-related diseases 8-OHdG promoter breast cancer triple negative breast cancer epithelial ovariancancer type Ⅱ EOC SNP qRT-PCR tissue microarray
CLC: R737.9
Type: PhD thesis
Year: 2011
Downloads: 10
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Abstract


Part One:Two Functional Variations in5’-UTR of hOGGl Gene are Associated with the Risk of Breast Cancer in ChinesePurpose8-hydroxy-2’-deoxyguanine (8-OHdG) is an oxidative stress induced damage in DNA, which could pair with adenine (A) during DNA replication, leading to G-T transversion mutations. Glycosylase hOGG1can recognize and excise oxidized guanines from duplex DNA. This work aims to investigate the relationship between the functional variations in5-untranslated region (5’-UTR) of hOGG1gene and the risk of breast cancer.Materials and Methods Genotypes were analyzed in518sporadic breast cancer patients and777health controls. Odds ratios (ORs) and95%confidence intervals (CIs) were estimated by logistic regression. Risk-stratified subgroup analysis was performed to reveal the associations between the detected variations and the risk of characteristic breast cancer. In addition, immunohistochemistry was carried out to assess the functional effect of these variations on hOGG1gene expression.Results There were five variations in5’-UTR of hOGG1gene in this study. Three of them, c.-18G>T, c.-23A>G, and c.-53G>C, were known single nucleotide polymorphisms, the other two, c.-45G>A and c.-63G>C, were rare variations. The frequencies of genotypes C.-18G/T and C.-53G/C were significantly higher in breast cancer patients than those in health controls (p=0.03, OR=2.01,95%CI=1.04-3.90; and p=0.01, OR=2.43,95%CI=1.17-5.04respectively). c.-18G>T and c.-53G>C were prevalent in premenopausal and the triple negative breast cancer cases (p<0.05), c.-18G>T was more common in comparatively younger (<55yrs) and p53positive subgroups (p=0.03, p=0.04). Compared with wild genotype C.-18G/G, hOGG1expression is decreased in tumor-adjacent normal tissue carried C.-18G/T (p=0.01).Conclusions Both variations of c.-18G>T and c.-53G>C can increase breast cancer risk and are especially prevalent in premenopausal status and TNBC subgroups. Moreover, c.-18G>T variation could cause a reduced expression of hOGG1gene.Part Two:Functional polymorphisms of the hOGG1gene confer risk to type II epithelial ovarian cancer in ChinesePurpose8-Hydroxydeoxyguanosine (8-OHdG) is an oxidized nucleoside that could lead to misincorporation of bases. Human8-oxoguanine DNA glycosylase (hOGG1) is the key defense enzyme against mutation by cellular8-OHdG in duplex DNA. The aim is to explore whether variations of the hOGG1gene were associated with epithelial ovarian cancer (EOC) or not.Materials and Methods Germline variations in5’-UTR (c.-18G>T, c.-23A>G, c.-45G>A, and c.-53G>C) and c.977C>G (Ser326Cys) polymorphism in Exon7of the hOGG1gene in420sporadic EOCs and840controls were detected. Immunohistochemical, immunoblot and promoter Luciferase activity assays were used to explore the effect of c.-18G>T functional variation on hOGG1expression.Results Different with type Ⅰ, type Ⅱ EOCs were usually older, in the advanced stage, and common with p53over-expression. The frequencies of genotype C.-18G/T and C.977G/G in hOGG1were significantly higher in type II EOC cases (OR=2.83,95%CI=1.45-5.52; OR=1.66,95%CI=1.26-2.17), but not in type I ones. The average level of hOGG1in normal tissues adjacent to type II EOC carried C.-18G/T was lower than those with C.-18G/G (p=0.01), and the promoter activity in the C.-18T allele was lower than that in the c.-18G allele (p=0.001).Conclusions The genotypes of c.-18G/T and c.9c77G/G of the hOGG1gene confer risk to the type Ⅱ EOC. The variation of c.-18G>T could reduce transcriptional activity of hOGG1gene and thus a decrease in hOGG1protein expression.Part Three:Expression of hOGG1gene in typing of epithelial ovarian cancerPurpose To explore the relationship between the mRNA and protein expression level of hOGG1gene and the typing of epithelial ovarian cancerMaterials and Methods qRT-PCR was used to assay the mRNA expression level of hOGG1in tumor and tumor-adjacent normal tissues from32HG-SPCs and10LG-SPCs; Tissue microarray was used to assay hOGG1protein expression of120HG-SPCs and35LG-SPCs.Results There was no difference of hOGG1gene mRNA expression level between tumor and adjacent normal tissue from ovarian serous cancer (p=0.95). Also there is no difference of hOGG1gene mRNA level in tumor or adjacent normal tissue between two types of ovarian serous cancer (p=0.69; p=0.92). Tumor tissue expressed less hOGG1mRNA than the corresponding adjacent normal tissue is62.5%in HG-SPC, while40.0%in LG-SPC, while without significance (p=0.21). There was no difference of protein expression level of hOGG1gene between two types ovarian serous cancer (p=0.19).Conclusions There is no difference of hOGG1gene expression between two types of ovarian serous cancer, but it’s more common in HG-SPC with decreased expression of hOGG1mRNA in tumor tissue comparing with adjacent normal tissue.

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