阐述肺癌的遗传机制具有重要的理论和临床意义。我们前期实验和临床研究发现，13q12.12肺癌风险染色质区的13q-Enh2增强子在支气管上皮细胞中的活性显著升高；增强子中3个与肺癌Tag-SNP rs753955高度连锁的SNPs与肺癌组织中TNFRSF19基因表达下调紧密关联，且TNFRSF19表达水平与肺癌TNM分期显著负相关；这3个SNPs均位于增强子p53结合位点的侧翼序列中。本项目将系统运用细胞分子基因编辑和染色质分析等技术，验证我们的研究假设：13q-Enh2增强子对靶基因的调控活性，生物学功能及其对p53蛋白的反应性构成一个紧密联系的功能体系，在保护支气管上皮细胞正常表型中发挥重要生物学功能。增强子元件内的肺癌风险SNPs能够干扰增强子对p53的正常反应，抑制其对TNFRSF19基因的调控活性，促进肺癌发生与发展。该研究将为阐述肺癌的遗传机制提供富有启发性的新线索新思路。

Understanding lung cancer genetic mechanisms is critical for the disease diagnosis and individualized treatment, while elucidating biological consequences of risk SNPs is an attractive and challenging way to reveal cancer genetic mechanisms. SNP rs753955 within non-coding region of the 13q12.12 risk locus is highly associated with lung cancer risk of Chinese population. In our previous work we identified a new enhancer named 13q-Enh2 harboring three common genetic variations in high LD with the risk SNP rs753955. These three linked risk SNPs distributed within the flanking sequences of p53 binding sites. eQTL analysis in 117 Chinese NSCLC samples and GTEx data suggested suppressive effects of mutant enhancer alleles on the TNFRSF19 expression that was closely related to high tumor staging and short survival time. We hypothesize that the regulatory activity on target gene, biological functions and reactivity to p53 protein of the 13q-Enh2 enhancer form a functional system to help maintain normal phenotype of bronchial epithelia cells. The risk SNPs within the enhancer can interfere with the normal response of the enhancer to p53, inhibit its regulatory activity on TNFRSF19 gene, and thus impact on lung carcinogenesis. The aim of this project is to test our hypothesis by integrating cellular and molecular biological methods, gene editing and chromatin function analysis techniques and mouse model with xenograft tumors. The study will provide an illuminating new clue to the genetic mechanism of lung cancer.