血漿Epstein-Barr病毒DNA量與女性乳癌相關性之分子流行病學研究

Abstract

根據台灣地區2001年的癌症登記資料，在所有女性癌症中，乳癌是發生率排名第二的癌症，且發生率有持續成長的趨勢。先前研究已指出乳癌的危險因子包括賀爾蒙相關危險因子(hormone-related factors)、飲食、運動、體重或身體質量指數(body mass index, BMI)、遺傳易感受性等等。但這些傳統乳癌危險因子僅能解釋部分的乳癌發生率，其餘的乳癌是在沒有明顯的危險因子暴露下發生的。同時，考慮乳癌的病因具有高度的異質性，因此尋找未知的乳癌危險因子成為乳癌研究的一個重點，而Epstein-Barr virus (EBV)在近年被認為可能是乳癌的危險因子。 在1994到2005年間共有20個病例系列研究，利用各式檢驗方法檢測乳癌腫瘤檢體中的EBV盛行率，獲得盛行率的範圍由0%到66%，顯示EBV可能參與了乳癌發展過程。因此我們嘗試用病例對照研究設計，並在調整其他危險因子的干擾之後，計算乳癌與EBV病毒量的相對危險性，同時分析EBV病毒量與乳癌及其他危險因子之間的關係。 我們一共由國立台灣大學醫學院附設醫院收集了261名乳癌病例及222名對照。經由問卷收集了基本人口學變項及傳統危險因子的資料，並由病歷收集腫瘤臨床特徵及病例接受治療的資料，再利用定量聚合酶連鎖反應檢測血漿中EBV的病毒量。結果發現血漿EBV病毒量較高的女性中，乳癌危險對比值經多變項調整之後為2.55 (95% CI = 1.69-3.83)。將所有研究對象依照EBV病毒量之第一、二、三分位數分為四組之後，發現在Ct值最高與最低兩組之間，經多變項調整後的危險對比值為2.58 (95% CI = 1.5-4.44)。 在分層分析中發現，EBV病毒量不會與內生性或外生性荷爾蒙因子，包括初經年齡、初次生育年齡及是否曾使用口服避孕藥，對乳癌危險性產生交互作用。但EBV與家族中是否有人曾罹患乳癌此遺傳相關危險因子之間，是否有交互作用存在，則尚待後續研究之探討。以上結果顯示血漿EBV高病毒量為台灣地區女性乳癌的危險因子，且獨立於內生性及外生性荷爾蒙因子。但對於EBV在女性乳癌發生機轉中所扮演的角色，則還需要更深入的探討。

According to the statistics of Taiwan Cancer Registry, female breast cancer has become the second female malignancies in 2001, and its incidence is still rising. Previous studies showed that breast cancer has various risk factors, including hormone-related factors, dietary factors, physical activity, body weight or body mass index, and genetic susceptibility. These traditional risk factors can only be attributable to less than a half of the breast cancer risk in Taiwan. A large proportion of breast cancer risk remains to be elucidated. Therefore, searching for novel risk factors of breast cancer has long been an important issue. Epstein-Barr virus (EBV) has recently been considered as a possible risk factor of breast cancer. Among 1994 to 2005, there are 20 case series studies showed that the prevalence of EBV in breast tumor tissue ranged from 0 to 66%. These evidences indicated that EBV may play a role in the development of breast cancer. Following these studies, we conducted a cross-sectional case-control study to examine the correlation between plasma EBV DNA level and female breast cancer. A total of 261 cases and 222 controls were recruited from National Taiwan University Hospital. Exposures to conventional risk factors were obtained through standardized questionnaire interview. Medical charts were abstracted to obtain the clinical and pathological characteristics. Blood samples were collected and tested for EBV DNA level by quantitative polymerase chain reaction. Multiple regression analysis was used to derive odds ratios and their 95% confident intervals (CI) for various risk factors. We found that the female with higher EBV viral load (Ct value≦30.24) has an odds ratio of 2.55 (95% CI = 1.69-3.83), after multiple variable adjustment. By stratified analysis, we found that there was no interaction between EBV viral load and hormone-related risk factors, including early age of menarche, early age of first labor and history of using oral contraceptive. However, the possible synergistic interaction between EBV viral load and genetic susceptibility in breast cancer needs further investigation to confirm.