臺灣博碩士論文加值系統

外生性環境的暴露（例如離子輻射）或內生性細胞的代謝（例如女性賀爾蒙的代謝）產生的自由基會攻擊DNA，產生thymine glycol、8-hydroxyguanine等常見的DNA氧化性傷害，進而與癌症的生成有關。在生物體內，主要是透過鹼基切除修復機制（base excision repair, 簡稱BER）來對抗這些DNA氧化性傷害，以維持基因體的穩定。而除了BER之外，最近幾年對於cockayne syndrome（一個導因神經系統氧化性傷害的遺傳性神經退化疾病）的分子機轉研究發現，轉錄同步修復機制（transcription-coupled repair, 簡稱TCR），亦參與DNA氧化性傷害的修復。因此，我們假設在女性賀爾蒙代謝過程中產生的DNA氧化性傷害，若無法有效的進行修復，可能與女性乳癌的發生有關。
為了檢定這個假說，我們自台大醫院選取138位確診為原發性乳癌的病例與244位健康的對照進行病例對照研究，以探討DNA易感受基因（基因多形性）與乳癌的相關，這些易感受基因包括參與BER的hOGG1（Ser326Cys）、APE （Asp148Glu）、XRCC1（Arg399Gln），及TCR的XPD（Lys751Gln）、BRCA1 （Ser1613Gly）。我們以聚合酵素連鎖反應（polymerase chain reaction）配合的限制酵素片段長度多形性（restriction fragment length polymorphism）進行基因型的鑑定，以非條件式對數複迴歸（unconditional logistic regression）模式進行單變項及多變項分析，以瞭解DNA修復基因的獨立作用，及與環境或易感受基因間的交互作用。
研究結果顯示，各個DNA修復基因多形性的獨立作用並沒有顯著增加乳癌的危險性，然而，我們進一步發現，除了APE（Asp148Glu）及BRCA1 （Ser1613Gly）之外，其它的DNA修復基因為假想危險性基因型與第一次活產懷孕前女性賀爾暴露大於10年的交互作用會增加發生乳癌危險性的傾向，支持了女性賀爾蒙可以透過DNA氧化性傷害的方式啟始乳癌發生的假設。此外，異常BER與TCR有增加發生乳癌危險性的趨勢，這項發現支持整個修復系統對乳癌的重要性。最後，就修復乳房組織中的DNA氧化性傷害而言，BER似乎比TCR重要，然而，這只是我們初步的探討，在未來仍需要有更大的樣本數以探討BER與TCR路徑內多基因間的交互作用，進一步釐清其相對重要性。

Both exposure to environmental agents such as ionizing radiation, and endogenous cellular metabolic processes result in the formation of reactive oxygen species or hydroxyl radicals, that can cause oxidative damage to DNA. The common oxidative DNA lesions include thymine glycol and 8-hydroxyguanine. In all organisms, base excision repair (BER) pathway is the major mechanism that removes oxidatively damaged bases from DNA to maintain the integrity of genomic DNA. Furthermore, recently, alternative repair system i.e. transcription-coupled repair (TCR) pathway defect of which is responsible for the development of the neuro-degenerative disease Cockayne syndrome, has been found to play an important role in repairing oxidative DNA damage. Given oxidative damages have been suggested to be related to estrogen metabolites, and have been considered important for triggering tumor formation, defects in the two repair pathways may be associated with breast cancer development.
We conducted a case-control study of 138 primary breast cancer patients and 244 healthy controls to explore the association between genotypic polymorphisms and breast cancer incidence. The genes assayed were BER genes, hOGG1 (Ser326Cys), APE (Asp148Glu), and XRCC1 (Arg399Gln), and TCR genes, XPD (Lys751Gln) and BRCA1 (Ser1613Gly) with breast cancer incidence. PCR-based RFLP assays were used to determine the genotypes, which are suggested to be linked with aberrant activity. Unconditional logistic regression models were used to assess the independent and interactive effects of gene-hormone and individual genes.
The associations were not statistically significant between individual genes and breast cancer risk. However, the effects of repair genes become obvious reflected by a higher risk of breast cancer associated with longer estrogen exposure before full-term pregnancy, if a women harboring putative low-activity genotypes of these genes. Furthermore, a trend of increasing risk for developing breast cancer was found in women defect in both BER and TCR pathway. Accordingly our results suggest that DNA repair genes may be associated with the risk of developing breast cancer via the interaction of gene and estrogen exposure. In addition, our results show that BER is more important than TCR for developing breast cancer, because a relatively higher risk for breast cancer was observed in women harboring defective BER genes than those harboring defective TCR genes. To further explore this issue, a study based on larger sample size is essential to determine which pathway is the major one to repair oxidative DNA damage.

目 錄
頁碼
中文摘要 -----------------------------------------------------I
英文摘要 -----------------------------------------------------II
目錄 --------------------------------------------------------III
表次 ----------------------------------------------------------V
圖次 ---------------------------------------------------------VI
第一章 前言 ------------------------------------------------1
第二章 文獻探討 --------------------------------------------3
第一節 女性賀爾蒙與乳癌之相關研究 ----------------------3
第二節 DNA的氧化性傷害 ---------------------------------5
第三節 鹼基切除修復機制 --------------------------------8
第四節 轉錄同步修復機制 -------------------------------14
第五節 鹼基切除與轉錄同步修復基因之簡介 ---------------15
第三章 材料與方法 -----------------------------------------24
第一節 研究個案與檢體的選取 ---------------------------24
第二節 問卷設計與收集 ---------------------------------24
第三節 DNA的備製 --------------------------------------25
第四節 聚合酵素連鎖反應（PCR）-------------------------27
第五節 限制片段長度多形性（RFLP）----------------------32
第六節 資料處理及統計分析 -----------------------------32
第四章 結果 ----------------------------------------------35
第一節 基本人口學特徵 ---------------------------------35
第二節 危險因子與女性乳癌的相關 -----------------------35
第三節 DNA修復基因多形性與女性乳癌的易感受性 ----------39
第四節 DNA修復基因多形性與女性賀爾蒙對女性乳癌的交互用 46
第五節 DNA修復基因多形性間對女性乳癌的交互作用 --------49
第五章 討論 -----------------------------------------------57
第六章 總結與未來展望 -------------------------------------67
參考資料 -----------------------------------------------------68

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