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標題: 探討雌性激素代謝及核酸修復之基因多型性與去鹼基核酸背景值及乳癌風險之相關性
Investigation of the Associations of Genetic Polymorphisms in Estrogen Metabolism and DNA Repair with the Background Levels of Abasic Sites and Risk of Developing Breast Cancer
作者: 陳政佑
Chen, Cheng-You
關鍵字: 乳癌
breast cancer
出版社: 環境工程學系所
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摘要: 本研究主要目的為探討台灣女性健康對照組與乳癌病人之風險因子比較,包括年齡、身體質量指標 (body mass index,BMI)、核酸修補 (DNA repair genes) 及雌性激素代謝基因 (estrogen bioactivation genes) 之基因多型性與去鹼基核酸 (abasic sites,AP sites) 背景值及乳癌風險之相關性。研究結果顯示,140位健康對照組AP sites背景值為 23.3± 13.5/106核苷酸 (平均 ± 標準偏差),相較本實驗室先前之148位乳癌病人 (50.3± 59.2/106核苷酸) ,發現AP sites背景值較健康對照組高約2.2倍 (p<0.001) 。由Putrescine-cleavage assay發現,健康對照組與乳癌病人之AP sites形成原因多為氧化壓力造成 (約60%) 。進一步研究發現,年齡<50之族群,乳癌病人之AP sites背景值較健康對照組高約2.7倍 (p<0.001)。相同的,BMI<27或APE1 Asp148Glu變異型族群中,乳癌病人之AP sites背景值皆較健康對照組高約2.4倍 (p<0.001) 。總結以上研究結果可知,年齡<50 years、BMI<27、與APE1 Asp148Glu變異型這三個條件,與乳癌病人AP sites遠高於健康對照組的趨勢有相關性。 單一核甘酸多型性實驗結果顯示,健康對照組與乳癌病人之核酸修補基因 (APE1 Asp148Glu) 之對偶基因變異頻率 (variant alleles frequency) 為46.2%、46.3% (p>0.05) ;而另一雌性激素代謝去活化基因 ( NQO1 C609T) 之對偶基因變異頻率於健康對照組與乳癌病人分別為45.5%、42.4% (p>0.05) ,由此可知此兩種基因多型性,對於台灣女性罹患乳癌之風險無顯著之相關)。但進一步研究發現健康對照組之APE1純合子變異型 (homozygous、Glu/Glu) 之AP sites背景值高於原生型 (wild type、Asp/Asp) 約1.3倍 (p<0.05) ,而乳癌病人則是雜合子 (heterozygous、Asp/Glu)之AP sites背景值高於原生型2.08倍 (p<0.05) (wild type、Asp/Asp) 。此一研究結果可推論,APE1 Asp148Glu變異,會造成APE1酵素活性下降,進而導致AP sites背景值上升。
The objectives of this research were to investigate the associations of the risk factors of breast cancer, including body mass index (BMI, Kg/m2) , age, and polymorphisms of genes involved in DNA repair and estrogen metabolism with the background levels of abasic sites (AP sites) in Taiwanese women with breast cancer and controls. Results indicated that the background levels of AP sites (mean � SD) in healthy controls (n=140) were estimated to be 23.3 � 13.5 per 106 nucleotides. There is a 2.2-fold increase in the background levels of AP sites when compared to our previous finding in breast cancer patients (50.3� 59.2 per 106 nucleotides) (p<0.001). The AP sites found in both controls and breast cancer patients were primarily derived from oxidative stress (~60%) as assayed by Putrescine-cleavage assay. Further investigation indicated that among subjects with age under 50, the number of AP sites detected in breast cancer patients was about 2.7-fold greater than that in controls. Similarly, levels of AP sites were about 2.4-fold greater in breast cancer patients than in controls among subjects with BMI<27 or with variant alleles of DNA repair genes APE1 Asp148Glu (p<0.001). This evidence suggests that circumstances associate with subjects status, including age under 50, BMI<27, and variant alleles of APE1 Asp148Glu, further enhance the levels of AP sites in breast cancer patients. Results from SNP analysis indicated that the frequencies of variant alleles of DNA repair genes APE1 Asp148Glu were estimated to be 46.2% and 46.3% (p>0.05) for controls and breast cancer patients, respectively, whereas bioactivation genes (NQO1 C609T) were estimated to be 45.5% and 42.4% (p>0.05) for controls and breast cancer patients, respectively. These findings strongly suggest that variant alleles of APE1 Asp148Glu and NQO1 C609T do not associate with the risk of developing breast cancer in Taiwanese women. However, we did observe the background levels of AP sites in controls with homozygous variant alleles (Glu/Glu) were about 1.3-fold greater than those with wild-type (Asp/Asp) whereas a 2.08-fold increase was found in breast cancer patients. This evidence infer that there is a significant decrease in repair efficiency of variant alleles of APE1 Asp148Glu, may further lead to the subsequent accumulation of AP sites in living cells.
其他識別: U0005-0508201314375500
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