转移与复发是肺癌的主要恶性特征，也是导致肺癌死亡率一直居高不下的主要原因。当前，对肺癌转移和复发的机制研究大多集中在单个基因或信号通路，而从组学层面系统性揭示该疾病恶性病理进程的研究报道却十分匮乏。本项目基于我们前期积累的成规模临床样本多层次组学测序数据（包括外显子、甲基化、mRNA和miRNA），通过QTL遗传分析，识别控制肿瘤转移和复发临床表型和分子性状（包括甲基化状态、mRNA和miRNA表达水平）的遗传变异；计算推断影响临床表型的分子性状关联基因间的相互调控关系；最终整合数据库中分子间直接互作信息，构建具有机制性解释意义的肺癌转移和复发遗传调控网络。此外，实验验证遗传调控网络中致病遗传变异和关键调控基因对临床表型的生物学效应，并预测和验证新的肺癌分子标记物。本项目的实施将提供一个整合多层次生物信息揭示复杂疾病遗传机制的研究思路和技术路线，也将为肺癌的转移和复发积累新的科学知识。

Metastasis and recurrence are the main malignant characters of lung cancer, and are also the leading cause of lung cancer mortality. In the current researches, uncovering the mechanism of metastasis and recurrence of lung cancer mostly focused on single tumor-related gene (or signaling pathway), but it remains relatively rare to systematically reveal the malignant pathological progression of the disease at the omics level. Based on our obtained poly-omic sequencing data generated from large-scale clinical specimens of lung cancer, including exome-seq, methylation-seq, mRNA-seq and miRNA-seq, we will identify the genetic variants affecting clinical phenotypes of metastasis and relapse of lung cancer and the molecular traits, such as methylation level, mRNA and miRNA expression, through QTL mapping; statistically infer the mutual regulatory relationships among the methylated gene, mRNA and miRNA affecting the clinical phenotypes; and finally develop a genetic regulatory network which mechanistically elaborate the metastasis and relapse of lung cancer through integrating the molecular interacting information, such as protein interaction. Additionally，we will also experimentally testify the genetic effect of causal variants and key regulators in the genetic network on controlling the phenotypes of metastasis and recurrence, and predict and experimentally verify novel tumor biomarkers. The project will offer a new research idea and technical pipeline for revealing the underlying mechanism of complex disease by integrating multi-level bio-information, and will also accumulate new knowledge for the metastasis and recurrence of lung cancer.