介白質素-18其基因多型性與口腔癌的相關性探討

口腔癌(oral cancer)是發生在口腔的惡性腫瘤之總稱，可出現在口腔的任何部位，大多數是由黏膜上的鱗狀細胞惡化而成，在台灣地區以舌癌與頰黏膜癌佔大多數。口腔鱗狀細胞癌的特性具有高度侵襲性並且容易轉移到淋巴結，罹患後患者的預後差、存活率低，因此我們需要更清楚了解口腔癌造成高度侵襲的機制，才能進行有效的預防及治療。介白素-18 (interleukin-18, IL-18)也稱γ型干擾素誘導因子(interferon-gamma inducing factor, IGIF) 是一種具多效性的發炎細胞激素，可由各種不同的細胞分泌而產生，主要由活化的巨噬細胞(macrophage)分泌；IL-18除了可以調控先天性及後天免疫反應，在發炎反應也扮演重要的角色，且已經被證明具有促進及抑制腫瘤生成的作用。過去研究中也發現在多種癌症患者的血清中均有高濃度的IL-18的表現，並且是癌細胞發展相關的重要指標。因此本研究的目的在於探討IL-18之基因多型性是否與口腔癌的罹患易感性有關，及其與口腔癌患者的疾病嚴重程度是否有相關性。我們收集了559位健康成人對照組與567位罹患口腔癌的患者，利用Real-Time PCR方法分別進行IL-18 -137 G/C (rs187238)及-607 A/C (rs1946518)的單核苷基因多型性分析，同時也分析IL-18之單核苷基因多型性與口腔癌相關臨床參數，包括臨床分期、腫瘤大小、淋巴結轉移、遠端轉移、細胞分化狀態等的相關性。統計分析結果發現，IL-18基因 -137位置上的變異在口腔癌病例與對照組之間基因頻率的分佈具有顯著差異，基因型GC者罹患口腔癌的比例與基因型為GG有顯著差異(OR= 1.704, p=0.001)；基因型為GC+CC，罹患口腔癌的比例也有顯著差異(OR= 1.706, p=0.001)，且腫瘤分期容易在第Ⅰ/Ⅱ期，且腫瘤的大小較不易大於T2期，淋巴結也較不易有轉移的情形；而IL-18 -607的單核苷酸多型性則與罹患口腔癌沒有直接的關係。因此我們認為，IL-18 -137的單核苷酸多型性與中台灣族群罹患口腔癌的易感性有關，可被視為口腔癌發生的相關因子。

All malignant tumors occurred in the oral cavity are generally called as oral cancers which can be found in any parts of oral cavity, and most of them are developed from the squamous cells of mucous membrane. A great majority of oral cancers in Taiwan are tongue cancers and buccal mucosa cancer. The squamous cell carcinoma in the oral cavity is highly invasive and easily metastatic to lymph nodes, and patients usually have poor prognosis and lower survival rates. Therefore, we need to understand more about the mechanism of how oral cancers become highly invasive in order to prevent and cure them more effectively. Interleukin-18 (IL-18), also known as interferon-gamma inducing factor, is a multi-functional inflammatory cytokine which can be secreted by various cells, and among them mainly are macrophages. Besides regulating both congenital and acquired immunity, IL-18 also play an important role in controlling inflammatory reactions while it has been proved that it has effects of promoting and inhibiting tumor growth. Other studies also found that IL-18 was highly expressed in the serum of patients suffering from various kinds of cancers and was recognized as an important index of tumor growth. Therefore, the purpose of this study was to access the correlations between IL-18 polymorphism and the susceptibility and the severity of oral cancers. We collected 559 healthy adults as control group and 567 patients with oral cancers using Real-Time PCR to analyze the single nucleotide polymorphisms of IL-18 -137 G/C (rs187238) and -607 A/C (rs1946518) and to access the correlations between IL-18 SNP and clinical parameters including tumor stage, tumor size, lymphatic metastasis, distant metastasis and cell differentiation. Our statistical results showed that there was a significant difference between the frequency distribution of genetic variants in loci -137 of IL-18 in oral cancers and control groups. That is, there was a significant difference of susceptibility between patients with a GC genotype and a GG genotype (OR= 1.704, p=0.001) and between patients with GC+CC geneotype (OR= 1.706, p=0.001), We also found that the tumor staging was most likely in I/II, the tumor sizing was most likely less than T2, and the lymph node was most likely not to metastasis while IL-18 -607 SNP showed less correction with oral cancer. In sum, we believed that IL-18 -137 SNP is related to the susceptibility of patients with oral cancers in the central Taiwan and it could be considered as a correlation factor of the development of oral cancers.