基于遗传易感位点的脑垂体瘤致病相关靶基因筛选和定位研究

Pituitary adenoma(PA), as the most common neuroendocrine neoplasm, presents severe clinical manifestations and leads to the difficulty in diagnosis and treatment. Recently, using genomic analysis to explore the pathogenesis mechanism of PA is one of the hotspots in neuroendocrinal area. The results of our preliminary genome-wide association study identified three genetic susceptibility loci (10p12.31, 10q21.1 and 13q12.13), closely related with the pathogenesis of PA in the Chinese population, for the first time in the world. The work was publish in the journal Nature Genetics. To further clarify the mechanism of these susceptibility loci in the pathogenetic process of PA, we plan to explore the candidate target genes of these loci by using circular chromosome conformation capture (4C) technology, and then to screen the objective target genes which could be regulated by susceptibility loci through first-stage functional verification, and finally to precisely localize the target genes related to the pathogenesis of PA through second-stage functional verification. This study provide the theoretical basis for developing new target for prophylaxis and treatment of PA.

脑垂体瘤是最常见的神经内分泌肿瘤，临床危害严重，诊疗仍存在困难。从基因组学的角度探索垂体瘤的发病机制是当前神经内分泌领域的研究热点之一。申请者所在团队在前期研究中，通过大样本全基因组关联分析，在国际上首次发现了三个与中国人垂体瘤发病密切相关的基因易感位点（10p12.31，10q21.1和13q12.13），相关论文发表于国际顶级学术期刊Nature Genetics。为进一步明确这三个易感位点在垂体瘤发病过程中的具体作用机制，本研究拟首先通过环状染色质构象捕获（4C）技术获取与上述易感位点相关联的候选靶基因；进而通过第一重功能验证，筛选出可被上述易感位点调控的目标靶基因；通过第二重功能验证，最终精确定位出垂体瘤致病相关靶基因。以期为研发垂体瘤新的防治方法提供理论依据。

脑垂体瘤是最常见的神经内分泌肿瘤，临床危害严重，诊疗仍存在困难。从基因组学的角度探索垂体瘤的发病机制是当前神经内分泌领域的研究热点之一。申请者所在团队在前期研究中，通过大样本全基因组关联分析，在国际上首次发现了三个与中国人垂体瘤发病密切相关的基因易感位点（10p12.31，10q21.1和13q12.13）。本项目①采用环状染色质构象捕获（4C）技术获取上述遗传易感位点的互作基因，然后通过功能验证，证实了10p12.31遗传易感位点通过染色质空间结构改变，作为增强子参与了PLXDC2基因的垂体瘤致病过程。②利用家族性垂体瘤，筛选并验证了CDH23基因是其遗传致病基因，同时也是散发性垂体瘤的易感基因。该成果对深入开展垂体瘤的精准医学研究具有重要的指导意义，并有助于开发垂体瘤早期筛查的新标志物。