基因修補酵素XRCC1與hOGG1與食道癌關係之研究(1/2)

Abstract

食道癌的發生與環境和遺傳因子有密切的關係。在我們過去的研究中發現， 吸煙、喝洒、嚼檳榔在台灣可增加食道癌的致癌危險性，這三種環境因子，彼此 間有明顯的加成作用。另一方面，個體在先天的遺傳變異，也可左右食道癌發生 的風險，各種解毒酵素，如GSTP1、P53 腫瘤抑制基因，基因修輔酵素如XRCC1、 hOGG1 等遺傳因子之基因多型式，亦可決定個體對食道癌的易感受性。由於各 種環境毒物，大部份都是透過對基因的損傷而促成癌化的作用，因此基因修補酵 素的正常功能可能在癌化的預防的過程中，扮演著重要的角色，因此本研究將進 一步探討XRCC1 與hOGG1 在食道癌癌化與腫瘤行為的角色。我們假設 XRCC1、hOGG1 的功能變異，包括遺傳子喪失、基因多型式、蛋白質表現可影 響食道組織基因修補能力，而導致食道癌癌化、機轉之啟動。 在去年當中，我們完成了hOGG1 基因多型性的基因檢定，我們發現hOGG1具有cys遺傳子者，分別在沒有嚼食檳榔、沒有飲酒及沒有抽煙習慣的個體中，可增加其 罹患食道癌的危險性。其OR（95﹪信賴區間）分別為：1.86（1.08-5.31）及 3.09（1.22-7.81）。我們也在病患腫瘤檢體中，測定了hOGG1 於Exon 7 及intron 4 等遺傳位置之遺傳子喪失的情形，我們發現食道癌在這些區域，有極高的比例 有遺傳子喪失的情形，其比例分別為55.66﹪（Exon 7）及62.22﹪（intron 4）。 在免疫螢光染色中，我們也發現了將近82﹪的腫瘤不表現hOGG1 腫瘤蛋白。我 們的研究顯示hOGG1 基因功能改變或是喪失在食道癌發展的過程中扮演著重要 角色。

The risk to develop esophageal cancer is associated with a variety of environmental and genetic factors. Previously, we have found that individual susceptibility to esophageal cancer in Taiwan was closely related to the consumption of tobacco, alcohol and areca. These factors exerted a synergistic effect on the risk for esophageal cancer. On the other hand, the genetic variation was also found important in determining the individual susceptibility to esophageal cancer. Genetic polymorphisms of the xenobiotic metabolizing enzymes, GSTP1, GSTT1, and CYP1A1, tumor suppressor gene, p53, or DNA repair enzymes, XRCC1 or hOGG1, can significantly influence the risk of esophageal cancer. Given that the DNA damage is the common form induced by the environmental carcinogens and the main contributor to esophageal carcinogenesis, the individual variation in the repairing capacity for damaged DNA would play a important role in determine the tendency for individual carcinogenesis of the esophagus. Therefore, the aim of this study was to investigate whether the genetic alteration of the DNA repair genes, hOGG1, and XRCC1 can modify the individual risk to esophageal cancer. Previously, we have developed the technique of laser capture microdissection (LCM) to obtain pure tumor DNA for analysis. Using this technique, we have alleotyping the hOGG1 on intron 4 and exon 7, where the genetic polymorphisms locates. We also genotyped the patients of esophageal cancer for the hOGG1 Ser 326 Cys genetic polymorphism on intron 7. The expression of the hOGG1 in tumor was also examined by immunohistochemical staining. Totally, we evaluated the status of LOH in tumor from 90 patients. Sixty-seven of them further received immunohistochemical staining for the hOGG1 expression. 204 patients and 266 normal control received genotyping for the hOGG1 polymorphisms. We found that, the risk for the esophageal cancer was enhanced by the presence of the hOGG1 326 Cys allele in the males who did not regularly consume tobacco, alcohol, or areca nut, with ORs(95% CI) being 3.09 (1.22-7.81) for the non-smokers, 2.40 (1.08-5.31) for the non-alcohol drinkers, and 1.86 (0.99-3.49) for the non-areca chewers. We also found the allelic loss in genetic locus of hOGG1 is a very common episode with 62.2% of cases on the intron 4 and 56.7% of cases on the exon 7. The expression of the hOGG1 in the tumor tissue were also reduced, with 82% of the patients having tumor without expressing or expressing only a very low level of hOGG1 (less than 10% of the tumor cells). This implies that repair of the oxidative damaged DNA, 8-oxoG, is an important mechanism for prevention of neoplasm in the esophagus. Through the genetic variation produced by the polymorphism, the function of the hOGG1 might have a further detriment once allele was lost under the continuous challenge of the DNA damage. Therefore hOGG1 is an important tumor suppressor gene for the esophageal carcinogenesis.