染色体2q33.1区域遗传变异调控CASP8基因表达影响肺癌易感性的分子流行病学研究

全基因组关联研究已鉴定出一系列肺癌的遗传易感变异，然而这些变异的生物学功能尚不明确。本项目前期的研究鉴定出六个新的肺癌易感区域，并基于功能基因组学数据对易感变异进行注释和功能评价，发现染色体2q33.1区域的CASP8基因受三个遗传变异（编码和非编码区）调控，然而这些变异调控CASP8表达的机制以及在肺癌发生中的功能都有待进一步探索。因此，本项目拟首先通过生物信息学分析和分子生物学实验明确2q33.1区域的致病变异，阐明其影响CASP8转录的机制；随后基于分子生物学实验探讨CASP8致病变异影响肺癌发生的生物学功能；最后基于巢式病例-对照研究，评估致病变异对血浆CASP8表达的影响以及CASP8与肺癌发生风险的关联。本项目的实施有助于阐明肺癌易感区域2q33.1的遗传易感机制，为揭示肺癌遗传病因提供新证据。此外，本研究发现的致病基因将有可能成为肺癌筛查的生物标志物，具有潜在公共卫生学意义。

Genome-wide association studies (GWAS) have implicated a large number of susceptibility variants for lung cancer; however, elucidating the underlying mechanisms of these variants during lung carcinogenesis remains challenging. Recently, we conducted a large-scale GWAS of lung cancer and identified six novel susceptibility loci. Then, we systematically evaluated the function of lung cancer susceptibility variants by integrating bioinformatics algorithms and functional genomics data. The preliminary result implicated that three functional variants at 2q33.1 could regulate the expression of CASP8 through affecting the protein coding function and the activity of promoter and enhancer elements. Nevertheless, the effects of these variants and CASP8 on the development of lung cancer remain to be explored. Thus, in this project, firstly, we intend to explore the biological mechanisms of genetic variants regulating expression of CASP8 underlying lung carcinogenesis by integrating bioinformatics analysis and functional experiment methods; secondly, we will explore the role of CASP8 in regulating ligand-induced apoptosis of tumor cells and the mechanism of CASP8 in the development of lung cancer at both the molecular and cellular levels; finally, we will evaluate the association between serum CASP8 and lung cancer risk based on a nested case-control study. In summary, the implementation of this project will help to unravel the effects of CASP8 and causal variants at 2q33.1 on the development of lung cancer. In addition, this project has important public health significance as it provides a new perspective for using susceptibility genes as biomarkers for risk stratification of lung cancer.