摘要:背景:胃癌目前仍是全球癌症死因前三名的癌症,全球每年約有 100 萬人死於胃癌。近年來的研究顯示 75%的胃癌與幽門桿菌有相關,對於此類胃癌的致病機轉及危險因子已有較清楚的瞭解。近年來的研究已證實早期根除幽門桿菌可以降低胃癌的發生率。然而有 25%的胃癌與幽門桿菌無關,對於此類胃癌的致病機轉及危險因子仍然不清楚,亟待進一步的研究來探索這個領域,以期能找到此類胃癌的預防方式。 研究目的:因此我們想探討⑴幽門桿菌陽性及幽門桿菌陰性的胃癌在臨床病理特徵、預後方面有無不同;⑵幽門桿菌陰性胃癌的危險因子-是否與 EB virus 感染有相關,是否與宿主基因因子有相關;⑶幽門桿菌陽性及陰性的胃癌在分子變異及致癌機轉上有無不同。 假設:我們的假設是幽門桿菌陰性的胃癌在臨床病理特徵、預後、危險因子、宿主易感受基因、分子變異及致癌機轉上與幽門桿菌陽性的胃癌是不同的。 研究方法:我們將利用 1998 Nov.- 2012 Dec.收集的 788名胃癌個案進行世代研究,並以 3000名健康族群以病例對照的方式進行病因分析 第一部分: 幽門桿菌陰性胃癌危險因子與預後因子的世代研究 我們預計將 790名胃癌個案依據幽門桿菌感染狀態區分幽門桿菌陰性胃癌與幽門桿菌相關胃癌以 Kaplan Meier method 進行存活分析並以 Cox proportional hazard model分析可能的預後相關因子。 第二部分:幽門桿菌陰性胃癌的病因分析研究(病例對照研究):分析幽門桿菌陰性胃癌與幽門桿菌相關胃癌(共 788名) 和 3000名健康族群在環境因子、EB virus、基因多形性之差異,以找出幽門桿菌陰性胃癌的危險因子。 第三部分: 幽門桿菌陰性胃癌的基因分子變化 (genetic and molecular alteration): 我們選取 40名幽門桿菌陰性胃癌與 160名幽門桿菌相關胃癌,以免疫組織染色法分析 p53、c-erbB2、E-cadherin、c-met的基因過度表現、PCR-LOH分析 APC、DCC的 loss of heterozygosity、Frameshift Mutation分析 TGF-βRII、IGFIIR、BAX的基因變異與 Microsatellite Analysis 分析 microsatellite instability。我們將進一步以次世代定序分析全基因的變異建構可能的發生機轉並以統計分析比較兩者在病理機轉的差異。 初步成果: 我們初步的研究結果顯示在台灣幽門桿菌陰性胃癌發病年齡較年輕、腫瘤位置多近端胃癌、多瀰漫性胃癌、臨床分期表現出較高的遠端轉移性但較低的腫瘤局部侵犯、血型表現以非 A血型為主。 預期成果: 我們的研究預期可以對幽門桿菌陰性胃癌從分子病理層次至流行病學的表現還有相關的危險因子或保護因子作全面且詳細的分析,預期對此疾病病因的了解、診斷及治療有所助益,也可以找到此類胃癌的預防方式。
Abstract: Background: Gastric cancer remains the top three causes of cancer related mortality worldwide. Recent studies have confirmed that 75% of gastric cancer is caused by Helicobacter pylori (H. pylori) infection. The pathogenesis and risk factors of H. pylori associated gastric cancer have been investigated extensively in the past two decades. However, about 25% of gastric cancer is not related to H. pylori infection. The risk factors, pathogenesis, and methods to prevent this type of gastric cancer remain poorly understood. More researches are warranted to investigate the causes of this subtype of gastric cancer to identify the optimal methods to prevent gastric cancer. Objectives: Therefore, we aimed to investigate (1) the clinicopathological features and prognosis of H. pylori-negative gastric cancer; (2) the risk factors-including environmental, pathogens, and host genetic factors, of H. pylori-negative gastric cancer; (3) the genetic and molecular alterations and carcinogenesis pathways of H. pylori-negative gastric cancer. Hypothesis: We hypothesized that H. pylori-negative gastric cancer is a distinct disease entity as compared to H. pylori-associated gastric cancer in terms of clinicopathological feature, prognosis, etiology, risk factors, molecular and genetic alterations and carcinogenesis pathways. Methods: Part 1: Clinicopathological features and prognosis of H. pylori-negative gastric cancer (cohort study): Cohort study in 788 patients with gastric cancer diagnosed between 1998 and 2012 will be conducted. Kaplan Meier method and Cox proportional hazard model will be used for survival analysis. Part 2: Risk factors of H.P negative gastric cancer (case control study): Another 3000 age sex matched healthy controls will be selected to identify the risk factors of H. pylori-negative gastric cancer. EB virus IgA antibody and immnunohistochemical staining of EBV will be done. Genetic polymorphisms will be analyzed by using the SEQUENOM MassARRAY® System in the National Genotyping Center (NGC). Part 3: Genetic and molecular alternations and carcinogenesis pathways of H.P negative gastric cancer (case control study): We will randomly select 40 H.P negative gastric cancer cases and 160 H.P associated gastric cancer cases. We schedule to perform 1.Polymerase Chain Reaction-LOH Analyses for APC, DCC, MCC 2. immunohistochemistry (IHC) staining for p53, c-erbB2, E-cadherin, c-met overexpression 3.Frameshift Mutation for TGF-βRII, IGFIIR, BAX 4. Microsatellite Analysis for microsatellite instability. Whole‐exome sequencing (WES) for gene alteration and gene polymorphisms will be completed by Next Generation Sequencing. Preliminary results: Our preliminary results showed that patients with H. pylori negative gastric cancer appeared to be younger, predominantly blood type A, with more proximal location, more advanced staging, and more distant metastasis, but less local invasion. Expected results: We expected that we can identify the risk factors and carcinogenesis pathways of H.P negative gastric cancer that might help us to find the best methods to prevent this subtype of gastric cancer.