臺灣博碩士論文加值系統

乳癌是台灣女性最普遍癌症之一，在許多流行病學研究指出雌性激素劑量累積為乳癌風險之重要因素。實驗室先前研究證實雌性激素醌類代謝物會直接造成DNA (deoxyribonucleic acid) 氧化損害而形成去鹼基核酸 (AP sites)，此即為雌性激素致癌的重要起始化作用 (initiation)。本研究主要目的為探討台灣女性乳癌病患之乳癌風險因子，包括年齡、身體質量指數 (BMI) 及雌性激素代謝基因之基因多型性與去鹼基核酸背景值之相關性，此研究將以102位台灣女性乳癌病患之白血球進行分析。
研究結果顯示，乳癌病患AP sites背景值為 94.3 ± 107/106核苷酸 (平均 ± 標準偏差)。而乳癌病患之雌性激素代謝活化之對偶基因變異 (variant alleles) 頻率CYP1A1 T3801C與CYP1B1 Leu432Val分別為39.7%與7.35%。我們也發現在BMI < 27之乳癌病患其AP sites背景值較BMI ≧ 27病患為高，而此趨勢在年齡小於50歲研究族群更明顯。此外，乳癌病患CYP1A1 T3801C 不同基因型病患其AP sites背景值約略相當；但在年齡小於50歲的乳癌病患中，CYP1B1 Leu432Val Leu/Val+Val/Val基因型 (高活性) 之AP sites背景值較Leu/Leu基因型高約1.4倍。由AP site cleavage assay結果指出，乳癌病患之AP sites可能是由氧化作用引起。
綜合上述研究結果可發現，乳癌風險因子包括年齡及BMI與乳癌病患之AP sites背景值呈負相關；而CYP1B1 Leu432Val對偶基因之變異型與乳癌病患AP sites背景值呈正相關。

Breast cancer is one of the most prevalent cancer among women in Taiwan. Epidemiological studies suggest that cumulative estrogen dose is a key determinant of breast cancer risks. Laboratory research provides evidence that estrogen quinone-derived direct and oxidative DNA (deoxyribonucleic acid) damage and the subsequent formation of abasic sites (AP sites) play an important role in the initiation of estrogen carcinogenesis. The objective of this research was to investigate association of the risk factors of breast cancer, including age, body mass index (BMI), and polymorphism of genes responsible for estrogen disposition, with the background levels of AP sites in white blood cells derived from 102 female breast cancer patients in Taiwan.
Results indicated that the background levels of AP sites (mean ± SD) in breast cancer patients was 94.3 ± 107 per 106 nucleotides. The frequencies of variant alleles of CYP1A1 T3801C and CYP1B1 Leu432Val were estimated to be 39.7% and 7.35%, respectively. We noticed that the background levels of AP sites in breast cancer patients with BMI &lt; 27 were greater than those with BMI ≧ 27, and the tendency was more obvious in subjects under 50 years of age. Relatively similar levels of AP sites were detected in subjects with SNP of CYP1A1 T3801C T/T genotype when compared to those with T/C and C/C genotype. A 1.4-fold increase in the number of AP sites was detected in patients (age &lt; 50) with CYP1B1 Leu432Val Leu/Val+Val/Val genotype (high-activity) when compared to those with Leu/Leu genotype. Additionally, results from the AP site cleavage assay indicated that the AP sites detected in breast cancer patients were likely to derive from oxidative events. The background levels of AP sites had no significant difference distinguished by age or BMI in breast cancer patients who received chemotherapy.
In conclusions, the risk factors of developing breast cancer, including age, BMI, and variant allele of CYP1A1 T3801C, were negatively correlated with the background levels of AP sites whereas variant allele of CYP1B1 Leu432Val were positively correlated with the background levels of AP sites in breast cancer patients.

摘要 I
Abstract II
Abbreviations IV
目錄 VII
表目錄 XI
圖目錄 XII
第一章 前言 1
第二章 文獻回顧 2
2-1 乳癌 (Breast Cancer) 2
2-2 雌性激素 (Estrogen) 4
2-2-1 雌性激素代謝途徑 8
2-2-2 雌性激素與乳癌之相關性 10
2-3 核酸損害 (DNA Damage) 12
2-3-1 去鹼基核酸 (Apurinic/Apyrimidinic Sites, AP sites) 14
2-4 核酸修補 (DNA Repairs) 機制 17
2-5 基因突變 (Gene Mutation) 18
2-5-1 基因多型性 (Genetic Polymorphism) 21
2-6 乳癌風險因子 (Breast Cancer Risk Factors) 27
2-6-1 年齡 (Age) 27
2-6-2 身體質量指數 (Body Mass Index, BMI) 27
2-6-3 生殖 (Reproduction) 28
2-6-4 口服避孕藥 (Oral Contraceptive, OC) 28
2-6-5 荷爾蒙替代療法 (Hormone Replacement Therapy) 28
第三章 實驗架構與設計 30
3-1 實驗架構 30
3-2 實驗設計 32
第四章 實驗材料及方法 33
4-1 實驗材料 33
4-1-1 化學藥品及耗材 33
4-1-2 實驗設備 34
4-1-3 研究族群 35
4-2 實驗方法 36
4-2-1 全血血液分離 36
4-2-2 核酸萃取 (DNA Extraction) 37
4-2-3 核酸醛基損害分析方法 (Aldehyde Reactive Probe-Slot-Blot assay, ASB assay) 38
4-2-4 Putrescine-cleavage assay 39
4-2-5 單一核苷酸基因多型性 (Single Nucleotide Polymorphism, SNP) 40
4-2-5-1 CYP1A1 T3801C與CYP1B1 Leu432Val 40
4-2-6 聚合酵素鏈鎖反應 (Polymerase Chain Reaction, PCR) 產物 41
4-2-7 數據分析 45
第五章 實驗結果 46
5-1 方法偵測極限 (method detection limit, MDL) 與變異係數 (coefficient of variation, C.V.) 47
5-2 Real-Time PCR與DNA定序結果確認 47
5-3 分析乳癌病患AP sites背景值與雌性激素代謝活化基因之多型性 48
5-3-1 乳癌病患AP sites 背景值 48
5-3-2 乳癌病患雌性激素代謝基因SNP 48
5-4 未進行化療乳癌病患AP sites背景值與乳癌風險因子之相關性 49
5-4-1 未進行化療乳癌病患年齡對AP sites背景值之影響 49
5-4-2 未進行化療乳癌病患BMI對AP sites背景值之影響 49
5-4-3 未進行化療乳癌病患CYP1A1 T3801C對AP sites背景值之影響 50
5-4-4 未進行化療乳癌病患CYP1B1 Leu432Val對AP sites背景值之影響 50
5-4-5 未進行化療乳癌病患CYP1A1 T3801C及年齡對AP sites背景值之影響 50
5-4-6 未進行化療乳癌病患CYP1B1 Leu432Val及年齡對AP sites背景值之影響 51
5-5 進行化療乳癌病患對AP sites背景值之影響 51
5-6 未進行化療乳癌病患體內氧化壓力之AP sites背景值 52
第六章 討論 68
6-1 AP sites與乳癌風險因子 68
6-1-1 AP sites與年齡 68
6-1-2 AP sites與BMI 69
6-1-3 AP sites與基因多型性 (Polymorphisms) 69
6-2 AP sites、protein adducts與乳癌風險因子比較 74
6-4 總結 79
第七章 結論與建議 80
7-1 結論 80
7-2 未來研究方向與建議 81
參考文獻 82

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