遗传与表观遗传变异在胃癌发生发展及预后中的作用及其分子机制研究

Gastric cancer is among the most common deadly cancer in China with a low 5-year survival rate. How to choose stable biomarkers for screening populations at high gastric cancer risk, prognosis, and accordingly applying for individualized prevention, intervention and treatment to improve the rates of early detection and treatment of gastric cancer, life quality of patients and survival time, is the current research focus. The prior studies of applicant suggest that genetic and epigenetic deregulation is involved in the process of pathogenesis and survival of gastric cancer, and its variation can be used as biomarkers for predicting gastric cancer development and prognosis. Based on precious findings, in the present study we will carry on screening genetic variation and epigenetic variation that is related to gastric cancer susceptibility and prognosis, elucidate its underlying molecular mechanism, and establish the causal relationship between the functional genetic and epigenetic variation and gastric cancer development and prognosis via a natural population cohort with large sample size and gastric cancer clinical cohort. Furthermore, we will comprehensively employ model recognition technology such as artificial neural network and support vector machine to predict the risk for gatric carcinogenesis and poor prognosis in different levels of combination of variation and environmental risk factors, and consequently provide theoretical basis and practical guidance for early detection and treatment of gastric cancer, individual therapy and prognostic judgement.

胃癌高居我国各种恶性肿瘤前列，死亡率高，5年生存率低。如何选择稳定的生物标志物以筛查胃癌易感/高危人群和预后判断是目前国内外研究的热点。申请者前期研究显示，遗传与表观遗传失调均参与胃癌发病和转归，其变异与胃癌发生发展和生存预后关联密切。本项目基于前期研究结果，采用高通量技术继续筛选并分析遗传、表遗传变异与胃癌易感及不良预后间的关联；采用报告基因转染、EMSA、集落形成、RIP、RNA pull-down、ChIP等方法深入探讨其分子机制；利用已建立的大样本健康人群和胃癌临床队列在人群中加以验证；运用人工神经网络和支持向量机等模型识别技术构建胃癌发生风险和不良预后预测模型。该研究较好地实现了标志物筛选、功能鉴定、队列验证三者有机结合，将为进一步揭示遗传与表遗传变异参与胃癌发生发展及预后的可能生物学机制提供重要理论依据，也为今后胃癌的个体化预防、干预、治疗以及药物研发、预后判断等提供重要参考。

胃癌发生发展及预后是多种遗传学和表观遗传学改变积累所致细胞调节和生长失控的多阶段复杂过程，是环境因素和遗传因素共同作用的结果。本项目基于既往研究成果提出科学假说：遗传变异（主要SNPs）、表观遗传变异（如DNA甲基化、miRNAs和lncRNAs等）以及二者共同作用，通过多种途径改变基因表达、通路活性以及细胞功能，影响中国人群胃癌发生发展及预后。因此，本研究采用候选基因、候选通路和区域，乃至全基因组等策略，系统分析并阐述遗传和表观遗传变异与胃癌发病风险及不良预后的关联性及分子机制。在遗传变异水平，本研究发现ERCC4 rs744154、ERCC2 rs13181、GBAP1 rs2990245、miR-196a2 rs11614913、miR-107 rs2296616、lncRNA HOTAIR rs4759314和GCLET rs3850997等十余个SNPs位点可作为胃癌易感和预后评估的遗传生物标志物，主要通过影响转录因子结合和启动子甲基化活性等，调控宿主基因或靶基因表达发挥生物学功能。在表观遗传水平，通过构建胃癌组织和血浆的miRNA、lncRNA以及DNA甲基化表达谱，联合生物信息学分析、多阶段人群样本验证，以及细胞分子生物学实验，发现miR-26a和miR-148a、lncRNA GC240、MT1JP和RP11-473O4.5，以及KCNMA1启动子区CpG位点cg24113782均表现抑制或促进肿瘤恶性表型，发挥表观遗传调控作用参与胃癌发生发展，且具有一定的胃癌诊断和预后判断的临床应用价值。另外，基于自然人群队列和胃癌临床随访队列，发现遗传变异位点和表观遗传分子能有效提升胃癌发病风险模型和不良预后模型的预测效能，为今后实施胃癌精准预防和治疗提供参考。本项目是遗传和表观遗传学相结合研究，为易感位点的遗传调控机制，以及表观遗传分子作为临床诊疗效果评价、病程跟踪和预后判断的潜在生物标志物提供重要思路和参考。