转录因子PDX1靶基因结合区遗传变异与胰腺癌易感性及机制研究

胰腺癌是一种预后极差的消化系统恶性肿瘤，积极探索与胰腺癌易感相关的功能性遗传变异对于理解病因，促进个体化预防具有重要意义。胰腺十二指肠同源框蛋白PDX1是一种在胰腺中高表达并与胰腺癌发生发展相关的重要转录因子。PDX1靶基因结合区遗传变异很可能通过介导转录因子对下游基因的表达调控从而影响个体对胰腺癌的易感性。本项目首先利用ChIP-seq和生物信息学手段，在全基因组范围内系统挖掘出所有位于PDX1结合区的遗传变异。然后拟通过两阶段独立样本的人群关联研究，从中鉴定出胰腺癌的易感位点。最后将在分子、细胞和动物层面进一步开展实验，深入解读易感相关遗传变异的生物学功能。本研究不仅将深化对于PDX1下游转录调控机制在胰腺癌易感性中作用的认识，也为在后全基因组关联研究时代，识别影响胰腺癌易感性的功能性遗传变异提供了思路。所识别的遗传变异可能为胰腺癌高危人群筛查和精准防治提供理论依据。

Pancreatic cancer is a digestive malignancy with a very poor prognosis. Exploration of functional genetic variations associated with pancreatic cancer susceptibility is of great significance to understanding the etiology and promoting individualized prevention. PDX1 is an important transcription factor highly expressed in the pancreas and associated with the development of pancreatic cancer. The genetic variations in the PDX1 binding sites may influence the binding process of the transcription factor and the expression of target genes, which may affect the susceptibility to pancreatic cancer ultimately. In this project, ChIP-seq and bioinformatics methods were firstly used to systematically mine all genetic variants located in the PDX1 binding sites throughout the whole genome. Then we intend to identify the variants associated with pancreatic cancer susceptibility through a two-stage case-control study in Chinese populations. Finally, further experiments will be carried out at the molecular, cellular and animal levels to further investigate the biological function of the variants. This study will not only deepen our understanding of the important PDX1 pathway in pancreatic cancer susceptibility, but also provide ideas for identifying functional genetic variations in the post-GWAS era. The identified genetic variants may be helpful in screen and precision medicine in the future.