吸烟可能增加结直肠癌（Colorectal cancer, CRC)发病的风险，但二者的因果联系并未确立。因此戒烟在预防CRC中的重要性不能突出，从而有可能阻碍了CRC这一第二肿瘤杀手的一级预防。然而，以观察性流行病学方法证实因果联系一直是个难题，申请人为此设计了一种孟德尔随机分析及基因-环境交互作用的新方法，并以之阐明了吸烟在CRC的癌前病变-结直肠息肉发病中的因果联系。但是直接探讨吸烟与CRC的的因果联系的研究尚未展开。因此，课题组拟在申请人前期系列癌前病变研究的基础上，进一步发展孟德尔随机分析方法，以之揭示吸烟与CRC发病的直接因果联系。同时拟在本项目中深入研究吸烟及其烟雾致癌物与相关代谢酶基因的交互作用在CRC发病中的机制。并在此基础上，首次在各分子亚型CRC中检查该交互作用的异质性，用以探索不同分子亚型的CRC的成癌机制及阐明病因的异质性，为个体化控制CRC的发病提供坚实的科学依

The causal role of cigarette smoking in the risk of colorectal neoplasm has been suggested but not established. The causation has not been proven so that the importance of smoking cessation cannot be highlighted thus potentially defer the primary prevention of colorectal cancer (CRC). We plan to use a novel Mendelian randomization analysis (MRA), which was designed by the applicants through using gene-environment interaction (GXE) and pathway analysis, to clarify the causal role of cigarette smoking in CRC carcinogenesis. We plan to further develop these methods and examine our findings stratified by different CRC molecular subtypes. The study aims to understand the heterogeneous nature and mechanisms of CRC progression, and to provide evidences for implementing smoking cessation to prevent CRC, the second cancer killer.