OGG1之基因多型性對口腔癌之基因易感性研究

抽菸、喝酒和嚼食檳榔都被認為是造成口腔病變的危險因子，而人暴露到這些因子後，在人體代謝過程中會產生一些活性氧類（reactive oxygen species；ROS），進一步造成 DNA 傷害，這些DNA傷害的衍生物又以 8-OH-dG 含量最多，OGG1 基因則是負責 8-OH-dG 的 DNA 傷害修復的主要基因之一。研究指出 OGG1 在 exon 7 的 Ser326Cys 基因多型性與癌症的形成有關，而 Cys326 相對於 Ser326 來說，Cys326 似乎有較低的 OGG1 活性。雖然已有許多癌症與 OGG1 基因多型性的相關性研究，但目前有關 OGG1 與口腔癌相關性的文獻仍然不多。因此，我們嘗試收集研究對象來瞭解 1) OGG1 的基因多型性在口腔癌前病變和口腔癌的頻率分佈是否不同，2) OGG1 的基因多型性是否扮演一個影響因子 (effect modification)，影響菸、酒、檳榔使用對口腔癌前病變轉變成口腔癌有不同的危險比，3）進一步調整相關的危險因子後，OGG1基因在 Ser326Cys 的基因多型性是否為口腔癌的危險因子。本研究收集完成來至高雄醫學大學口腔顎面外科口腔癌與口腔癌前病變患者共182個人，口腔癌前病變共63位，口腔癌共119位。經研究對象同意後，抽取週邊血液10 ml，並完成一份問卷，將 DNA 自血液萃取出後，以 PCR-RFLP 的方式獲得 OGG1 基因多型性的資料，發現口腔癌前病變患者基因型 Cys326Cys 得到口腔癌的機會是 Ser326 基因座 (allele) 的 2.05倍 (OR = 2.05, 95 % CI = 1.03-4.25)。利用單變項邏輯式回歸分析口腔癌危險因子，基因型 Cys326Cys 相對於 Ser326 基因座 (allele) 是癌症分期 Stage I/II 轉變成 Stage III/IV 的危險因子 (OR = 3.25,95% CI = 1.34-8.56)。在菸量 > 26 支/天的患者中，基因型 Cys326Cys 相對於 Ser326 基因座 (allele) 是口腔癌的危險因子 (OR = 10.35,95% CI = 1.80-196.61)。檳榔量 > 28 顆/天的患者中，基因型 Cys326Cys 相對於 Ser326 基因座 (allele) 是口腔癌的危險因子 (OR = 3.71,95 % CI = 1.04-15.66)。在調整菸、酒、檳榔和年齡後，基因型 Cys326Cys 相對於 Ser326 基因座 (allele) 是口腔癌的危險因子 (OR = 2.38,95 % CI = 1.17-5.10)；嚼食檳榔 (OR=3.14,95 %CI=1.17-8.85)亦是口腔癌前病變轉變成口腔癌的危險因子。根據我們的研究結果，OGG1 的基因型 Cys326Cys 在口腔癌的患者中出現的頻率較高；在調整相關因子後，嚼食檳榔及 OGG1 的基因型 Cys326Cys 是口腔癌的危險因子。因此我們建議 OGG1 基因在 Ser326Cys 的基因多型性在口腔癌前變病轉化成口腔癌的形成扮演了一個重要的角色。

關鍵字

基因修復；基因多型性；活性氧類；口腔癌；口腔癌前病變

並列摘要

Cigarette smoking , alcohol consumption, and betel quid chewing are important risk factors of oral cancer. Exposure to these carcinogens, some reactive oxygen species (ROS) were produced during the metabolisms of human cell. 8-Hydroxydeoxyguanine (8-OH-dG) is a major DNA lesion produced by ROS. Human 8-oxoguanine DNA glycosylase I (OGG1) gene is one of the genes that are responsible for repairing the DNA damage from 8-OH-dG. The OGG1 Ser326Cys polymorphisms at exon 7 are reported to be a risk factor for cancer. Comparing the Ser326 allele, the Cys326Cys seems to have lower activity of OGG1 gene. Although there are many studies indicate the association between the polymorphisms of OGG1 gene and cancers, the relationship between OGG1 genotypes and oral cancer are rare. In order to determine the oral cancer risks of OGG1 genotypes, we conduct a study to determine 1) the distributions of OGG1 polymorphisms between oral cancer and precancer patients. 2) the risks of gene-environment interaction between OGG1 polymorphisms, betel quid chewing , alcohol and cigarette smoking.3) the risks of OGG1 genotype, after adjusting for age, OGG1 genotypes, betel quid chewing, alcohol consumption, and cigarette smoking. In the present study, a total of 182 participants (63 oral precancer patients, 119 oral cancer patients) were recruited from the department of Oral and Maxillofacial Surgery of Chung-Ho Memorial Hospital, Kaohsiung Medical University. After getting the inform consent, 10ml peripheral blood were collected and questionnaires were interviewed . After extraction of DNA, we got the data of OGG1 polymorphisms by PCR-RFLP. Cys326Cys is a risk factor for oral cancer (OR = 2.05, 95 % CI = 1.03-4.25). Cys326Cys is a risk factor of low oral cancer stage (stage I and stage II) transforming to high oral cancer stage (stage III and stage IV)(OR = 3.25, 95 % CI = 1.34-8.56). Among the patients smoking >26 cigarette/per day, Cys326Cys comparative with Ser326 allele is the risk factor for oral cancer (OR = 10.35, 95 % CI = 1.80-196.61).Among the patients chewing betel quid > 28 grain/pre day, Cys326Cy comparative with Ser326 allele is the risks of oral cancer (OR = 3.71, 95 % CI = 1.04-15.66). After adjusting for cigarette smoking, alcohol consumption, betel quid chewing, age, the Cys326Cys is the risk factor for oral cancer (OR = 2.38, 95 % CI = 1.17-5.10). Betel quid chewing is also the risks of oral cancer (OR = 3.14, 95 % CI = 1.17-8.85). According to our studies, Cys326Cys has high frequency among oral cancer patients. After adjusting for risk factors, betel quid chewing and Cys326Cys are the risk factors for oral cancer. We suggest that OGG1 Ser326Cys polymorphisms play an important role in oral precancer transforming to oral cancer.