人類乳突病毒感染與女性肺癌及乳癌之分子流行病學研究

Abstract

肺癌及乳癌為台灣女性重要之癌症。從流行病學的研究中發現抽煙雖被廣泛認為是導致肺癌的主要原因，但台灣女性抽煙人口低於10%；已知與乳癌相關的危險因子如家族史、肥胖、荷爾蒙等，其可歸因百分比也僅佔20-40%，顯示仍有其他危險因子參與台灣女性肺癌及乳癌的發生。人類乳突病毒(human papillomavirus, HPV)感染不僅是子宮頸癌的必要因子，以往亦曾有病例系列及病例對照研究指出與肺癌與乳癌的相關性，但橫斷性研究無法提供明確的因果時序性，故本研究期望透過前瞻性長期追蹤之世代研究建立良好的時序性來探討人類乳突病毒感染與否對台灣婦女肺癌及乳癌發生之可能角色。 本研究係以1991年居住於台灣七個鄉鎮市接受子宮頸抹片檢查及子宮頸細胞檢體採集之10615名婦女(30-64歲)為研究對象，利用聚合酶素連鎖反應及HPV基因晶片檢測子宮頸細胞中HPV DNA並加以定型；新發之肺癌及乳癌個案則係與癌症登記檔、死亡檔及重大傷病檔連結獲得。統計分析採用Cox 比例危險模式(Cox proportional hazards model)計算相對危險性及95%信賴區間。 研究結果顯示在調整其他危險因子後，HPV11、74、CP8304、MM4、16、45、35、43、51及MM8等型別可能為致肺癌高危險型別，其罹患肺癌之危險性(RR)皆高於2倍，感染任一上述型別者發生肺癌之危險性為2.7倍(95%CI:1.5- 5.1)；另一方面，致乳癌之高危險型別則為HPV39、42、CP8304、51、CP8061、32、55及66等型(RR>=2.0)，感染其中任一型別亦有2.7倍(95%CI:1.5-4.7)的高風險。在排除子宮頸異常之可能干擾因素後，罹患肺癌及乳癌的危險性皆約為3倍。進一步針對女性肺腺癌之分析發現，感染HPV11、74、CP8304、MM4、45及35等之任何一型，其罹患肺腺癌之危險性高達5.4倍。 本研究發現許多不同人類乳突病毒型別的感染，可能與台灣女性乳癌及肺癌，特別是肺腺癌的發生有關。

Introduction: Cancers of lung and breast were major threats to women’ lives in Taiwan. Less than 50% of risk could be attributed to major risk factors, such as smoking to lung cancer as well as family history, obesity and female hormone to breast cancer. Since human papillomavirus (HPV) was ever proposed a positive association with lung/breast cancer by few cross-sectional case-series or case-control studies. For better temporality in causal inference, a long-term follow-up study using a community-based female cohort was subject of the role of HPV infection in cancer development of lung and breast. Method: A prospective cohort study of 10615 female participants (aged 30-64 years), who received examination of Pap smear and cervical cell collection at enrollment, recruited to a community-based cancer screening program in 1991-1992. HPV DNA and genotypes were performed by polymerase chain reactions and HPV Blot. Cox proportional hazards model was used to estimate HPV type-specific risk ratio (RR) and their confidence intervals (CIs) of lung/breast cancer with multiple adjustment. Result: HPV types of 11, 74, CP8304, MM4, 16, 45, 35, 43, 51 and MM8 were suggested as high-risk types (RR>=2) for lung cancer. The adjusted RR was 2.7 (95%CI:1.5-5.1) for women infected with any one of these types to develop lung cancer during follow-up. Considering high-risk types for breast cancer (HPV39, 42, CP8304, 51, CP8061, 55 and 66), its RR was 2.7(95%CI:1.5-4.7). Consistently, the RRs were about 3-fold for both sites of cancer while subjects with abnormal cervix further excluded. We also found that HPV 11, 74, CP8304, MM4, 45 and 35 were strongly associated with lung adenocarcinoma, and its RR (95% C.I.) was 5.4(2.1-13.6).