鼻咽癌與FAS、FASL、NF-κB 和 TRAF3基因多形性之流行病學研究

Abstract

背景介紹:鼻咽癌 (nasopharyngeal carcinoma, NPC) 是一種在其他族群非常罕見，但卻是中國南方和東南亞常見的癌症。過去文獻指出遺傳因子和環境因子共同在鼻咽癌的發展過程中扮演重要角色，包括Epstein-Barr virus (EBV) 感染、飲食因子例如中國鹹魚、職業上的暴露、家族性聚集傾向，宿主易感受性遺傳因子都被證實和鼻咽癌的危險性有關。EB病毒在體內的持續性感染被視為鼻咽癌致病機轉的重要因素之ㄧ，EB病毒會引起B細胞的不朽化。腫瘤壞死因子受體相關因子3 (tumor necrosis factor receptor-associated factor3, TRAF3) 為細胞內辨識EB病毒進而引起第一型干擾素的重要因子，同時也會和EB病毒轉譯的潛伏膜蛋白1 (latent membrane protein 1, LMP1) 結合而引起B淋巴細胞的轉形。FAS (CD95, APO-1)、FAS配體 (FASL) 和 核因子-κB (nuclear factor-kappa B, NF-κB) 在細胞凋亡的訊息傳遞路徑扮演重要的角色。本研究欲探討細胞凋亡相關基因多形性與鼻咽癌發生的相關性。 研究方法:總共有317名經由組織病理學確認的鼻咽癌病患與268名符合條件的健康對照納入本研究。從台北市兩大醫院中選取確診為鼻咽癌的個案為病例組，依病例的性別、年齡(每五歲一組，在相同年齡組別中)、居住地作1:1個別配對，從戶籍資料系統中選取符合條件的為對照組。訪員對納入收案對象以結構式問卷進行標準化訪視，取得個案的社會人口學及暴露鼻咽癌相關危險因子的資料，抽取個案周邊血，血清進行EB病毒抗體標誌的檢測；白血球的DNA進行細胞凋亡相關基因的單一核苷酸多形性分析。結果以卡方檢定和費雪精確檢定分析病例組與對照組的基本人口學變項、危險因子狀態及基因頻率分布，以適合度檢定對照組的基因頻率是否符合哈溫平衡，利用非條件式羅吉斯迴歸方式評估單一核苷酸多形性(single nucleotide polymorphism, SNP) 標記對鼻咽癌的危險性。所有的危險性估計值都有調整年齡、性別、教育程度和種族。 結果: FAS (-1377)、FAS (-670)、FASL (-844) 和NF-kB(-94)之基因型與鼻咽癌發生的危險性沒有統計顯著相關，FAS (-1377) 和 FAS (-670) 所建構的haplotype和鼻咽癌的發生也沒有統計顯著相關，而在TRAF3基因上，若600的位置為AA或AG基因型有較高的鼻咽癌發生風險(ORadj, 1.85; 95% CI, 1.12-3.04)。將病例組以鼻咽癌家族病史進行分層分析，發現TRAF3基因型和鼻咽癌家族病史沒有統計顯著相關，。在對照組與病例組，EB病毒的抗體陽性狀態與TRAF3基因型也無統計顯著相關。在感染EB病毒之溶解期相關蛋白的抗體標誌陽性狀況下，TRAF3基因型與鼻咽癌發生有統計顯著相關。 結論: TRAF3 (codon 600) 的基因多形性與鼻咽癌的發生有密切相關；而FAS、FASL 和NF-kB的基因多形性，則與鼻咽癌無統計顯著相關。

Background: Epstein-Barr virus (EBV) infection is an important risk factor for nasopharyngeal carcinoma (NPC). EBV causes the immortalization and transformation of infected cells. Tumor necrosis factor receptor-associated factor 3 (TRAF3) is required for EBV recognition and initiation of type I interferon production. It is also required for activation of B lymphocytes by EBV latent membrane protein 1 (LMP1). FAS (CD95, APO-1), FAS ligand (FASL) and nuclear factor-kappa B (NF-κB) also play important roles in the apoptosis. This case-control study aimed to examine the associations between NPC and polymorphisms of these genes. Methods: A total of 317 cases affected with histologically confirmed NPC and 268 healthy community controls matched with cases on gender, age and residence were enrolled. Blood samples were collected for the examination of IgA antibodies against EBV-specific viral capsid antigen (anti-EBV VCA IgA) and Epstein-Barr nuclear antigen 1 (anti-EBNA 1 IgA) and IgG antibodies against DNA binding protein (anti-EBV DBP IgG) and DNase (anti-EBV DNase IgG). The real-time PCR assay was used for genotyping of TRAF3 (codon 600), FAS (-1377 and –670), FASL (-844) and NF-κB (-94). Logistic regression analysis was used to estimate multivariate-adjusted odds ratio (ORadj) with its 95% confidence interval (CI) for each genotype after adjustment for age, gender, educational level, and ethnicity. Results: Genetic polymorphisms of FAS (-1377), FAS (-670), FASL (-844) and NF-kB (-94) were not significantly associated with the risk of NPC. The haplotype of FAS (-1377 and -670) was not significantly associated with NPC risk either. Individuals with the TRAF3 (codon 600) AA or AG genotype had an increased NPC risk compared with GG genotype as the referent group (ORadj, 1.85; 95% CI, 1.12-3.04). In NPC cases, family NPC history was not associated with TRAF3 (codon 600) genotype. The seropositivity of various antibodies against EBV was not significantly associated with TRAF3 (codon 600) genotype in either NPC cases or controls. TRAF3 (codon 600) genotype was associated with an increased risk of NPC in those who were seropositive on anti-EBV VCA IgA, anti-EBV DBP IgG, and anti-EBV DNase IgG. Highest NPC risk was observed for those who were anti-EBV-seropositive with AA/AG genotype of TRAF3 (codon 600). Conclusions: There is a significant association with NPC for TRAF3 genotype, but not for FAS, FASL and NF-κB genotypes. TRAF3 (codon 600) AA/AG genotype was associated with an increased risk of NPC compared with GG genotype, especially in those who were seropositive on antibodies against EBV proteins expressed in lytic infection.