染色体3q13和5p13区域遗传变异与胃癌易感性的分子流行病学研究

Although H.pylori infection is one of the major risk factors for gastric cancer, only a small proportion of infected individuals develop gastric cancer, suggesting that both environmental and genetic factors play important roles in gastric cancer pathogenesis. Our latest gastric cancer GWAS study have identified two new susceptibility loci at 3q13 and 5p13 region, however, the exact genetic etiology and mechanisms of gastric cancer in these regions are unclear. On the basis of our previous GWAS study and combing with the databases of 1000 Genomes and Hapmap, this project is proposed to firstly resequence the GWAS-reported regions using Next-generation sequencing(NGS) technology, then perform fine-mapping study and related molecular biology assays by using a large-sample case-control design. Three aspects will be considered in the project: 1. Identify the genetic variations in 3q13 and 5p13 regions related to gastric cancer in Chinese population; 2. Detect gene-gene and gene-environmental interactions between genetic variants and related risk factors; 3. Reveal the regulatory mechanisms of the relevant genetic variations of susceptibility genes(such as PTGER4, PRKAA1 and ZBTB20). The results of this project could improve understanding of the etiology and mechanisms of gastric cancer development, which in turn is important for early detection, diagnosis and targeted treatment of gastric cancer.

幽门螺旋杆菌感染(H. pylori)是胃癌发生的主要危险因素之一，但仅小部分感染者最终罹患胃癌，提示胃癌的发生是环境和遗传因素共同作用的结果。本课题组最新全基因组关联研究发现，染色体3q13和5p13区域可能是胃癌的重要易感区域，但该区域遗传变异在胃癌发生中的具体遗传机制尚未阐明。本研究在前期工作的基础上，拟通过对上述两个区域进行重测序，结合千人基因组计划(1000 Genome)和人类单倍型计划(Hapmap)数据库，采用大样本精细作图研究以及分子生物学手段深入探讨：①染色体3q13和5p13区域的遗传变异在中国人群胃癌发生中的作用；②基因-基因、基因与环境暴露之间的交互作用；③相关遗传变异对候选易感基因(如PTGER4、PRKAA1和ZBTB20)的调控机制。研究结果将为胃癌发生机制的阐明提供理论基础，所发现的遗传标志物可为胃癌高危人群的筛查和早诊早治提供科学依据。

以课题组近年来在胃癌分子流行病学研究方面的成果为理论和技术基础，采用大样本的两阶段病例-对照研究设计，对染色体3q13 和5p13 区域遗传变异进行了精细作图研究，筛选并验证了这两个区域上多个功能性SNPs 和标签SNPs与胃癌遗传易感性的关系，以及相关的基因－基因和基因-环境在胃癌发生中的交互作用；验证各通路联合基因型与表型的相互关系及其在胃癌发病风险中的作用，并进行相关的生物学功能研究。研究结果将为胃癌发生机制的阐明提供理论基础，所发现的遗传标志物可为胃癌高危人群的筛查和早诊早治提供科学依据。