细胞周期的精确调控涉及到多个关键控制点的大量基因的参与，这些关键基因的遗传变异可能导致正常的细胞周期调节失控，继而引起基因组不稳定和肺癌的发生。细胞周期相关基因同时也是目前肺癌药物治疗的主要靶点。本课题前期在5408例肺癌病例-对照人群中研究发现21个细胞周期关键基因的32个标签性SNPs位点与中国汉族人群发病有关，本项目拟在这一结果的基础上采用多中心、两阶段肺癌病例-对照研究（各2500对）和单纯肺癌患者预后研究，全面系统地探讨细胞周期关键基因的遗传变异单独作用、基因-基因、基因-环境交互作用与中国汉族人群肺癌发生风险和预后的关系；同时对发现的阳性位点，尤其对具有潜在调控功能的和具有基因-基因交互作用的遗传变异，进行生物学机制的深入探讨。本研究将进一步加深细胞周期调控关键基因与肺癌发生和预后关系的认识，研究发现的阳性遗传变异可为筛检我国肺癌发病的高危人群和监测肺癌患者的预后提供科学依据。

Precise regulation of cell cycle is a highly-ordered process, which involves a series of checkpoints and multiple key regulators. The genetic alterations of the key process genes may lead to disruption of the normal cell cycle progress, following by genome instability and lung cancer pathogenesis. Moreover, the major cell cycle regulators are also used as the main targets for therapeutic intervention of lung cancer patients.In the previous studies, we have analyzed 4621 single nucleotide polymorphisms (SNPs) of 161 key process genes of cell cycle in 2331 Chinese lung cancer patients and 3077 controls, and found that 32 tag SNPs in 21 genes were associated with lung cancer risk. As a result, in the present study, we aim to investigate the associations between these genetic variations and lung cancer susceptibility and prognosis in two additional 2500 pairs of lung cancer cases and control in Wuhan and Beijing cohorts, respectively. We will further evaluate the effects of the gene-gene, gene-environment interactions in this large-scale population. The biological mechanisms of the identified positive SNPs, especially SNPs locate in the gene regulation region and the missense SNPs, will be further assessed by the functional studies, including the reporter assay, electrophoretic mobility shift assay, co-immunoprecipitation, and western blotting in the normal and tumor lung tissues. This study will make a deep description about the biological effects of the major cell cycle regulators on the development of lung cancer. The identified functional SNPs will provide new insight into high-risk population screening and prognosis prediction of lung cancer patients.