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研究生:姚昕妤
研究生(外文):Hsin Yu Yao
論文名稱:血液中HPV16/HPV58 DNA和hTERT mRNA為台灣肺癌之危險標記
論文名稱(外文):Detection of HPV16/58 DNA and hTERT mRNA in blood circulation act as risk markers of lung cancer in Taiwan
指導教授:李 輝鄭雅文鄭雅文引用關係
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:醫學分子毒理學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:97
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過去本研究室已發現HPV16/18感染與台灣肺癌形成有關,並發現偵測血液循環中之HPV16/18 DNA可做為肺癌之危險生物標記。最近族群研究台灣子宮頸癌和癌前患者之各種不同HPV型感染頻率,結果發現HPV58的感染率繼HPV16, 18之後排名第三位。因此擬了解台灣肺癌患者血液,是否如子宮頸癌患者一樣可偵測到HPV58之感染?本研究以168位肺癌及198位非癌症者之血液進行病例/對照組研究,結果發現肺癌患者HPV16和HPV58之感染率都顯著高於對照組 (38.7% vs. 3.5%,P < 0.0001 for HPV16 ; 15.5% vs. 3.5%, P < 0.0001 for HPV58)。同時發現HPV16之感染率在不抽菸、女性、晚期、腺癌之患者較抽菸、男性、早期和鱗狀細胞癌為高 (67.7% vs. 32.3% for smoking, P=0.038; 52.3% vs. 47.7%, P=0.036 for gender; 72.3% vs. 27.7%, P=0.02 for tumor stage; 70.8% vs. 29.2%, P=0.06 for tumor type)。而HPV58的感染率則以不抽菸和男性患者為高 (80.8% vs. 19.2% for smoke, P=0.01; 73.1% vs. 26.9%, P=0.085 for gender)。若肺癌患者分成男、女性不抽菸與男、女性抽菸患者四組,則發現不抽菸男性有最高之HPV58感染率 (46.7%, P < 0.0001)。以多變項邏輯式迴歸分析病毒感染情形與肺癌的危險性比較,即發現HPV16型感染者罹患肺癌的危險性為未感染者的38.21倍 (95% CI, 12.27−118.98, P < 0.0001),HPV58型感染者罹患肺癌的危險性是未感染者之5.82倍 (95% CI, 1.53−22.09, P=0.0097),若同時HPV16與58型之感染者罹患肺癌的危險性是未感染者之19.4倍 (95% CI, 4.93−76.33, P < 0.0001)。
過去有研究指出HPV感染會促進hTERT mRNA之表現。因而假設HPV感染之血液可能有較高hTERT mRNA之表現,或許可用來輔助檢測HPV DNA以及做為罹患肺癌之輔助性的生物指標。因此本研究以先前之病例組/非癌症對照組中,取得91名肺癌患者及81名對照組之血液檢體之cDNA,以定量PCR分析hTERT mRNA表現量,結果發現HPV16感染的血液之hTERT mRNA表現量顯著高於沒有感染者 (P=0.002) 。並發現血液中HPV16 DNA之複製數高者有較高之hTERT mRNA表現量 (P=0.013)。並發現血液中的 hTERT 表現量與HPV16 E6表現呈正相關性之趨勢 (P= 0.059)。以多變項邏輯式迴歸分析發現血液中hTERT mRNA的表現高者較表現低者有5.30倍罹患肺癌之風險。本研究結果顯示血液中hTERT mRNA表現量不僅可做為HPV16感染之生物指標,同時適合做為HPV感染之肺癌患者之輔助診斷標記。



Our previous report indicated that HPV16/18 infection was associated with developing nonsmoking female lung cancer in Taiwan. We further found that the presence of HPV16/18 DNA in the blood circulation may serve as risk biomarker of lung cancer. A recent population study showed that the most prevalent of HPV subtype in Taiwanese cervical cancer and cervical intraepithelial lesion (CIN) was HPV16 subtype followed by HPV18 and HPV58 subtypes. In this study, we questioned whether HPV58 was infected in the blood circulation of lung cancer patients to be further acting as a risk biomarker of lung cancer as similar as HPV16. Thus, a case-control study was conducted enrolling 168 lung cancer patients and 198 non-cancer control subjects and the blood samples were collected for the detection of HPV16 or 58 DNA by nested PCR. Our data showed that the infection rate of HPV16 or HPV58 in patients’ blood was significantly higher than that of non-cancer controls (38.7% vs. 3.5%,P < 0.0001 for HPV16 ; 15.5% vs. 3.5%,P < 0.0001 for HPV58). Among the clinical paramethers, HPV16 infection was more common in nonsmokers, female, tumors with late-stage and adenocarcinomas compared with their counterparts (67.7% vs. 32.3% for smoking status, P=0.038; 47.7% vs. 52.3%, P=0.036 for genders; 72.3% vs. 27.7%, P=0.02 for tumor stage; 70.8% vs. 29.2% P=0.06 for tumor type). More interesting, HPV58 infection was more prevalent in male and nonsmokers than in female and smokers, respectively (73.1% vs. 26.9%, P=0.085 for genders; 80.8% vs. 19.2% for smoking status, P=0.01). Multivariate logistic regression analysis showed that subjects with HPV16 or HPV58 infection had 38.21 or 5.82-fold of lung cancer risk than those without HPV16 or HPV58 infection in blood circulation, and then both HPV16 and HPV58 infection had 19.4-fold of lung cancer risk. These results clearly indicated that the presence of HPV58 in the blood circulation may serve as a risk marker of lung cancer. Our present result from HPV16 infection was consistent with our previous report showing that HPV16 may be a risk marker of lung cancer.
hTERT transcription has been shown to be upregulated by HPV16 E6 in keratinocytes and lung cancer cells. In this study, blood cDNA of 91 lung cancer case and 81 non-cancer controls was collected to evaluate hTERT mRNA expression level by real-time RT-PCR. Our results showed that a significant higher hTERT mRNA expression level was observed in HPV16-infected lung cancer patients compared with that of HPV non-infection (P=0.002). Additionally, hTERT mRNA expression level was positively correlated with HPV16 viral load (P= 0.013). Moreover, a marginal significant correlation was observed between HPV16 E6 and quantitative hTERT mRNA expression level (P=0.059). After adjusting the effects of age, gender, smoking status, subjects with higher hTERT mRNA level had 5.30-fold of lung cancer risk than those with lower hTERT mRNA level (P < 0.0001). In summary, HPV58 DNA detected in blood circulation was similar as HPV16 DNA may act as a potential risk marker of lung cancer. Additionally, evaluating hTERT mRNA expression may be more feasible to serve as an adjuvant diagnostic marker of lung cancer, specially for HPV-associated lung cancer.




壹、中文摘要 1
貳、英文摘要 3
參、文獻綜論 5
一、肺癌之流行病學 5
二、肺癌的相關危險因子 5
2.1環境暴露與肺癌 5
2.2微生物感染與肺癌 8
三、人類乳突瘤病毒 (Human papillomavirus; HPV) 感染
與癌症的相關性 9
3.1 HPV感染之盛行率 9
3.2 HPV結構 11
3.2.1早期基因 (early gene) 12
3.2.2 晚期基因 (late gene) 15
3.2.3 Long control region (LCR) 15
3.3 HPV的致病機轉 15
3.4 HPV感染與癌症的相關性 17
3.5 HPV與肺癌之相關性 18
3.6人類乳突瘤病毒感染途徑 19
四、人類端粒酶反轉錄酶 ( Human telomerase reverse
transcriptase; hTERT ) 20
4.1 hTERT簡介的構造與功能 20
4.2 hTERT和癌症的相關性 21
4.3 hTERT與HPV感染之相關性 23
肆、研究動機 25
伍、材料與方法 27
一、材料與藥品 27
二、檢體收集 29
三、實驗方法 30
3.1 血液之DNA萃取 30
3.2 血液HPV DNA測定 31
3.3 HPV58載體建構 33
3.4 質體DNA萃取 34
3.5 PCR產物純化與基因定序分析 35
3.6 血液樣本中HPV16複製數 (copy number ) 分析 36
3.7 肺癌患者血液之RNA萃取 38
3.8 RNA純化 39
3.9 反轉錄聚合酶連鎖反應 (RT-PCR) 40
3.10 血液中hTERT與HPV16 E6表現定量分析 40
3.11 統計分析 43

陸、結果 44
一、肺癌患者與非癌症對照組之血液中HPV16/58感染率
44
二、血液中HPV感染與肺癌和非癌症患者之臨床因子
的相關 44
三、血液中HPV16或58感染為罹患肺癌的危險指標 45
四、評估血液HPV16與58之感染是否更適合
做為不抽菸男性和女性罹患肺癌之危險因子 46
五、肺癌患者之與非癌症對照組之血液hTERT mRNA
表現之比較 47
六、肺癌患者血液中之hTERT mRNA表現與臨床因子
之相關性 47
七、hTERT mRNA表現與HPV16 copy number和HPV16
E6之相關性 47
八、血液hTERT mRNA表現可做為肺癌的危險指標 49


柒、討論 50
一、周邊血液HPV16和HPV58 DNA做為台灣肺癌
患者之危險指標 50
二、hTERT與HPV感染與罹患肺癌之相關 53

捌、參考文獻 57
玖、表與圖 72
拾、附錄 89



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