摘要:背景:胃癌為異質性疾病推測其致病原因來自於先天基因缺陷與後天環境因素的共同影響與相互作用,。隨著分子生物技術的進步,近年來Landscape study 對於胃癌發生的起始基因變異(drive gene alteration)或是表徵基因變異(epigenetic change)已有完整的了解,研究發現胃癌依照分子病理差異可區分為(1)微衛星不穩定型(microsatellite instability)、(2) EB 病毒相關、(3)染色體不穩定型(chromosomal instability)與(4)基因體穩定型(genomical stability)的胃癌,然而各些不同亞型胃癌患者在存活有無不同仍無定論。更重要的是這些不同分類的胃癌其危險因子與致病原因是否有所不同仍未被探討過。研究目的探討不同分子病理分類的胃癌其危險因子與致病原因是否有所不同。此外,也將探討這些不同分子病理分類的胃癌之進展、轉移與預後有所不同。我們將進行病理分子檢測,將台大的胃癌世代的分子病理的變化區分為四組,將所得資料包括流行病學資料、存活時間、環境因子與各組特異的分子病理變異關聯性進行分析,以探討不同分子病理分類之胃癌致病因子以及對於預後的影響。方法: 本研究共分成三個部分第一部分:hospital based cohort 的分析 :1. 以先前的研究為基礎,應用分子生物技術(IHC staining、qPCR的方式)將所得胃癌的cohort進行病理分子的分組包括: microsatellite instability group、EBV related gastric cancer group 、genomically stable group、chromosomal instability group,將所得分組進行存活分析與流行病學分析以統計分析方式確認各分析結果之顯著性第二部分:EBV related gastric cancer 其疾病特色之分析以病理上特殊的表現的lymphoepithelioma-like carcinoma 以診斷EBV related gastriccancer,選取EBV related GC group 並與其他組別進行存活分析與流行病學分析,以統計分析方式確認各分析結果之顯著性第三部分:進行hospital based cohort 與致病因子的case-control study選取先前文獻胃癌相關的致病因子,以健康人族群為對照組在胃癌次族群中進行分析,找出每個次族群的致病因子並以多變數分析方式針對胃癌族群的致病因子與保護因子進行分析預期成果: 我們研究深入完整的分子病理分析確立胃癌的分子病理特性的不同表現,結果預期在各組預後的差異可能影響未來術後化學治療或追蹤策略的擬定,而分析各組致病因子與環境因子之不同表現,將有助於胃癌預防醫學的發展,同時我們預期由所得的,可找到關鍵的biomarker 以有效診斷區分胃癌的分子病理差異,針對不同屬性的胃癌其基因表現與變異進一步研究,預期對日後的分子標靶治療藥物的設計研發與胃癌的治療將有所助益。
Abstract: Gastric cancer (GC) is globally the fifth most common cancer and the third leading cause ofcancer death. Gastric cancer is heterogeneous diseases which arise from the interaction ofenvironmental and host genetic factors. Environmental factors including H. pylori infection, dietand smoking all play critical roles in GC develop. Recent studies have demonstrated that the nearlycomprehensive “driver“ genetic alteration and epigenetic change in GC. Previous landscape studydivided GC into microsatellite instability (MSI), EBV-positive GCs, genomic stable(GS) andchromosomal instability(CIN) according to the specific driver genetic alterations. The impact ofdifferent molecular subgroups of gastric cancer on the metastasis, progression and prognosis ofthese patients remains uncertain.We hypothesized that the biologic effect, the etiology and the pathogenesis between thesubgroups of gastric cancer are different and remain to be further investigated. The aim of ourstudy is to investigate the distinct molecular alteration between the subgroups of the gastriccancer and correlate to demographic data, survival analysis and environmental factors. Based onour finding, we can find the unique clinical feature, the etiology and the specific molecular changein the subgroups. Further, we plan to perform a validation cohort for clinical application.We select gastric cancer patients with AJCC 7th stage II or III who receive surgical resection fromour cohort and further perform immunochemistry staining in the selected cases. We divide theselected cases into four subgroup according to the previous landscape study. The IHC for lossexpression of MLH1 is defined as the MSI group. The specific pathologic report oflymphoepithelioma-like carcinoma is considered as EBV-positive GC. In the GS group, theproportion of diffuse histology type is more than 70 %. Therefore, we define the GS group as theRhoA, ARHGAP26 or CDH1 mutation expression in IHC staining which also present diffuse histologytype in H & E staining. The CIN group show higher heterogeneous molecular signal expression inRTK/RAS pathway, Wnt pathway, and p53 related pathway. Herein, we perform IHC staining ofTP53, APC, Kras, MET, MUC6, ERBB2 and also perform molecular assay in each group for analysis.We compare the survival, demographic manifestation and environmental factor between the foursubgroups.We expect the analyzed result will show difference between the subgroups in survival whichmight influence the future management strategy. The expected result will correlate to theenvironmental factor and etiology analysis which can help us to develop preventive medicinestrategy. We also expect to find reliable serologic biomarker or key IHC staining of the subgroupswhich can link to the prognosis and the choice of the molecular target therapy.