胰腺神经内分泌瘤基因组学和表观遗传学的研究进展

Updates on the research of genetics and epigenetics of pancreatic neuroendocrine tumors

目前大量研究发现对染色质结构起调控作用的ATRX-DAXX和多发性内分泌肿瘤1型（MEN-1）基因,哺乳动物雷帕霉素靶蛋白（mTOR）信号通路相关基因的突变共同参与了胰腺神经内分泌肿瘤（pNETs）的发生和发展.这些突变基因主要通过DNA甲基化、组蛋白修饰、染色体重塑和替代性端粒延长机制激活等表观遗传学的异常改变使染色质变异以及pNETs相关信号通路的异常激活协同引起pNETs肿瘤形成和侵袭.这些证据表明基因组学和表观遗传学的异常改变共同激活了pNETs的肿瘤生物学行为.这些发现对胰腺神经内分泌肿瘤的临床诊治及预后判断有重要的现实意义,并可据此研究出特异性靶向治疗的新策略.分子靶向药物与根治性手术治疗联合应用将是未来针对pNETs主要的治疗手段.

Mounting evidences suggest that the ATRX （α-thalassaemia/mental retardation syndrome X-linked） and DAXX （death-domain associated protein） which encode 2 subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres,and multiple endocrine neoplasia type 1 （MEN-1） genes are significantly mutated in most patients with pancreatic neuroendocrine tumors （pNETs）,as are genes encoding key molecules of the mammalian target of rapamycin （mTOR） signaling pathway.These mutated genes promote deregulation of epigenetic processes such as chromatin remodeling,histone modification and activation of alternative lengthening of telomeres,and thus combined alteration of these genes may contribute to drive tumorigenesis and metastasis of pNETs which are characterized by complex patterns of phenotypes.These findings may have great significance in the diagnosis and treatment of pNETs and predicting the prognosis,as well as providing clinical implications for targeted cancer therapy.