NER通路核心基因遗传变异与胃癌遗传易感性的相关性及机制研究

胃癌是世界范围内最常见的恶性肿瘤之一，其发病率及死亡率均名列前茅，早期诊断是患者获得及时治疗的关键。核苷酸切除修复（NER）通路在维持基因组DNA的稳定性和完整性中发挥着重要作用，该通路核心基因的异常表达与多种肿瘤的发生、发展及预后相关。我们前期研究发现ERCC1以及XPG基因多态性改变可显著增加胃癌的发病风险。为了进一步验证NER通路核心基因在胃癌发生发展中的作用，我们拟采用两阶段、大样本的病例-对照研究来探究其与华南地区胃癌遗传易感性的关系，并采用荧光素酶活性分析、EMSA、CHIP等方法系统探讨潜在功能性SNP位点影响基因转录调控的可能机制，从多个层面验证人群宏观研究结果；综合分析危险单倍型、基因-基因及基因-环境交互作用对胃癌发生发展的影响，寻找病因性变异及高危人群，从而为胃癌发病机制提供实验支撑及理论依据，为胃癌的风险评估、早期诊断及针对性的预防和个体化治疗提供理论依据。

Gastric cancer is one of the most frequently diagnosed cancers worldwide, with a much higher incidence and death rate than most type of cancers. Early diagnosis plays an important role in the management and prognosis of gastric cancer. Nucleotide excision repair (NER) pathway plays a crucial role in maintaining the stability and integrity of genomic DNA, gene expression abnormality of this pathway is associated with initiation, development and prognosis of different tumors. In our previous studies, we found that potential functional polymorphisms in the ERCC1 and XPG genes are associated with gastric cancer risk. In order to confirm the etiologic role of the genetic variations in the core genes of the NER pathway, we have planned to adopt a large two-stage case-control study to comprehensively investigate the associations of candidate SNPs in these genes and gastric cancer risk. SNPs associated with gastric cancer risk will undergo functional analysis. Real-time PCR, immunohistochemistry, Dual-Luciferase reporter assays, EMSA and CHIP will be utilized to examine effects of the SNPs in corresponding gene expression levels and protein products and underlying mechanisms. Furthermore, we will explore roles of the risk haplotype, gene-gene and gene-environment interactions in the development of gastric cancer and identify the etiological alterations and high risk populations. This study may provide valuable experimental evidence and clues to illustrate the pathogenesis of gastric cancer. Furthermore, causal variants revealed by the current study may be used as genetic markers for risk assessment, early diagnosis and screening of gastric cancer.