基于全基因组外显子测序的哈萨克族食管癌发生与候选突变基因的关系研究

The 13 localized nationalities in xinjiang kazak people have the highest incidence of esophageal cancer 150.9/10 higher than the national average of 14.95/10.The causes and mechanisms of racial differences should to be elucidated. Oncogene activation and tumor suppressor gene inactivation caused by somatic mutations plays an important role in the development of cancer. Based on the pre-coding region of the whole genome sequencing experiments, we identified twelve tumor-specific mutated genes and initially identified two novel Kazakh esophageal cancer significant mutation genes THSD7A and RNF113A. The project select 12 kinds of high frequency of tumor-specific mutated genes, using quantitative RT-PCR and IHC methods intends to Screening differentially expressed genes in Kazakh esophageal cancer; to establish over expression or RNAi inhibition cell model of candidate gene, and to clarify the relationship of candidate gene with esophageal malignant phenotype. As well as elucidate regulatory networks, including signal transduction pathways and transcription factors for esophageal cancer cell differentiation, invasion and metastasis process regulatory mechanisms by animal model; To clarify treating sensitive screening intervention targets for molecular diagnostics individualized, targeted offers based therapy and prognosis.

新疆13个世居民族中哈萨克族人群食管癌的发病率最高，达150.9/10万，远远高于全国平均水平14.95/10万，其发病机制有待阐明。而体细胞基因突变造成的癌基因激活和抑癌基因失活在肿瘤发生发展过程中扮演重要作用。前期工作中，基于针对全基因组编码区进行测序的数据，发现12种肿瘤特异性高频突变基因，其中THSD7A基因是首次发现的食管癌突变基因。因此，本研究计划，选择12种肿瘤特异高频突变基因，采用分子生物学的方法，筛选与哈族食管癌差异表达基因；建立候选基因高表达或RNAi抑制细胞模型，探讨候选基因与食管癌发生、浸润和转移相关功能；基于移植瘤动物模型，探讨肿瘤增值、转移与候选基因表达水平的关系。从遗传和分子生物学角度挖掘哈族食管癌的发病机制，揭示食管癌关键基因遗传变异，寻找肿瘤基因突变相关的最佳药物靶点，从而改变相应分子调控网络和相关代谢途径，为个体化治疗奠定基础。

新疆13个世居民族中哈萨克族人群食管癌的发病率最高，达150.9/10万，远远高于全国平均水平14.95/10万，其发病机制有待阐明。而体细胞基因突变造成的癌基因激活和抑癌基因失活在肿瘤发生发展过程中扮演重要作用。前期工作中，基于针对全基因组编码区进行测序的数据，发现12种肿瘤特异性高频突变基因，其中THSD7A基因是首次发现的食管癌突变基因。因此，本研究计划，选择一些肿瘤特异高频突变基因，采用分子生物学的方法，筛选与哈族食管癌差异表达基因；建立候选基因高表达或RNAi抑制细胞模型，探讨候选基因与食管癌发生、浸润和转移相关功能；基于移植瘤动物模型，探讨肿瘤增值、转移与候选基因表达水平的关系。本研究项目完成了针对哈萨克族食管癌发生相关的高频突变基因NFE2L2，PARD3，FBXW7表达调控的关系研究，进一步明确哈萨克族食管癌发生与上述高频突变候选基因表达调控的关系研究；利用FBXW7候选基因高表达或RNAi抑制细胞模型，制作裸鼠移植瘤模型，研究肿瘤组织细胞形态学指标。