| Abstract: | 二十年來惡性腫瘤一直是台灣民眾的首要死因，而其中肺癌又是女性癌症的第一大死因。但男性則位居第二。最近二十年來抽菸量有漸漸減少之趨勢，但是肺癌之死亡率卻不減反增，尤其是與抽菸較沒有相關之肺腺癌的增加趨勢最為顯著。雖然肺腺癌之形成之病理機轉至今未明，但是大多數之研究認為，肺腺癌之形成與慢性發炎有關，發炎路徑大多經由體內產生之 reactive oxygen species (ROS) 之活化，因此本研究擬探討香菸或其他來源之污染物之暴露，而在體內代謝活化產生之 ROS，以及直接經由發炎反應產生之 ROS，都可能直接攻擊 DNA，而形成 8-OHdG DNA 鍵結物。這種氧化性之 DNA 鍵結物，大多經由 base excise repair (BER) 路徑之 hOGG1 和 APE1 兩種主要酵素移除。為了了解氧化性 DNA 傷害在肺癌形成之貢獻，本研究選取 205 位肺癌患者和年齡、性別、抽菸與否頻率配對之 206 位非癌症對照組之血液或腫瘤週邊之正常肺組織 DNA，分別利用 PCR-RFLP 和 PCR-CTPP 分析 APE1 Asp148Glu 和hOGG1 Ser326Cys 之基因多形性與台灣肺癌發生是否有關？結果發現 hOGG1 Ser/Cys + Cys/Cys 罹患肺癌的危險是 Ser/Ser 的 2.01 倍。若將肺癌研究的對象進行抽菸與否分層分析，結果發現抽菸男性以及非抽菸之女性 hOGG1 Ser/Cys + Cys/Cys 基因型者罹患肺癌的危險分別是 Ser/Ser 基因型之 2.61 與 2.72 倍，都達到統計顯著意義。但非抽菸男性則沒有相關。在 APE1 基因多形性之研究發現，具有 Asp/Gln + Gln/Gln 變異基因型者罹患肺癌的危險是 Asp/Asp 基因型者的 0.53 倍；而在非抽菸男性、抽菸男性以及非抽菸之女性三組中，僅抽菸男性具有 Asp/Glu + Glu/Glu 變異基因型者罹患肺癌的風險是 Asp/Asp 的 0.49 倍。將 Asp/Glu + Glu/Glu 和 Ser/Ser 合併為參考組，則同時具有 APE1 Asp/Glu + Glu/Glu 和 hOGG1 Ser/Cys + Cys/Cys 基因型者罹患肺癌的危險增至 2.80 倍，同時具有 APE1 Asp/Asp 和hOGG1 Ser/Ser 基因型者為 3.20 倍，而同時具有APE1 Asp/Asp 和 hOGG1 Ser/Cys + Cys/Cys 基因型者為 4.15 倍。因此 APE1 與 hOGG1 多形性之基因-基因交互作用，可能會增加罹患肺癌之危險。本研究進一步分析這 APE1 與 hOGG1 之多形性，與肺癌患者發生 p53 和 EGFR 基因突變之相關性，結果發現 APE1 Asp/Asp 基因型者發生 p53 基因突變之危險是 APE1 Asp/Glu 與 Glu/Glu 基因型的 1.77 倍，但是 p53 突變與 hOGG1 Ser326Cys 基因型則無相關。若考慮 APE1 與 hOGG1 基因型之交互作用，則同時具有 APE1 Asp/Asp 與 hOGG1 Ser/Ser 者發生 p53 突變之危險會增至 2.84 倍，但無統計上顯著差異。更有趣的是，hOGG1 變異基因型與 p53 以及 EGFR exon 19 之缺失突變發生具有顯著相關。因此，APE1 和 hOGG1 兩種參與氧化性 DNA 傷害之修補酵素的基因多形性可能與台灣肺癌之發生有關。尤其可能會參與在 p53 和EGFR 基因缺失突變的發生。因此推測氧化壓力引起之 DNA 傷害在台灣肺癌之形成中扮演重要的角色。
Neoplasm is the leading cause of death in Taiwanese people since 1982. Among the cancers, lung cancer is the leading cause of cancer death in women and the second cause of cancer death in men. Cigarette smoking is the major cause of lung cancer, however, the cigarette consumption is gradually decreased, the lung cancer motarity rate is remarkablly increased, espcially in lung adenocarcinomas. The pathogenesis of lung adenocarcinoma is unclear, but chronic inflammation is considered to associate with developing lung adenocarcinoma. Reactive oxgen species (ROS) is linked with chronic inflammation and cancer development. Therefore, the association between genetic polymorphisms of base excision repair genes and human cancers have been extensively investigated including lung cancer, especially in hOGG1 ser326Cys and APE1 Asp148Glu. However, the conflicting results were reported in several studies. The genetic polymorphisms of both genes were not studied in Taiwanese population, except the study on the assocation between hOGG1 and NPC. Thus, In this study, 205 lung cancer cases and 206 mached non-cancer hospital controls were enrolled to verify the association between both genetic polymorphisms and lung cancer risk. The genetic polymorphisms were determined by PCR-RFLP and PCR-CTPP, respectively. Our data indicated that subject with hOGG1 Ser/Cys, Cys/Cys variants had 2.01 fold of lung cancer risk as compared with that of Ser/Ser genotype. Being stratified three categories by gender and cigarette smoking, the the lung cancer risk of variant genotypes was increased to 2.61- and 2.72-fold in smoking male and nonsmoking female subjects, respectively, but not observed in nonsmoking male subjects. Interestingly, the lung cancer risk of subject with APE1 Asp/Glu + Glu/Glu variants was 0.53-fold of that of Asp/Asp genotype. Among these categories, only smoking male subject with APE1 variants had about one-half of lung cancer risk (OR = 0.49). When combined the genotypes of both genes, the lung cancer risk was increased in subject with variants of hOGG1 and APE1 (OR = 2.80), Asp/Asp and Ser/Ser (OR = 3.20), and Asp/Asp and Ser/Cys + Cys/Cys (OR = 4.15) as compared with subject with the combination of APE1 variants and hOGG1 Ser/Ser genotype (OR = 1). These results suggest that gene-gene interaction of hOGG1 and APE1 may increase the lung cancer risk in Taiwanese population. On the other hands, we futher understand the correlation between both genetic polymorphisms and p53 and EGFR mutations in lung cancer patients. Our data indicated that patients with APE1 Asp/Asp genotype had 1.77-fold risk of p53 mutation occurrence as compared with those of variants, moreover, the risk of p53 mutation was increased to 2.84-fold in patients with the combined genotypes of Asp/Asp and Ser/Ser. More interestingly, the deletion mutation of p53 and EGFR was frequently occurred in patients with hOGG1 variant genotypes. These results suggest that hOGG1 and APE1 involved in the removal oxidative DNA damage plays an important role in lung carcinogenesis, at least in Taiwanese population. |
