DAXX/ATRX缺失及端粒替代性延伸在胰腺神经内分泌瘤中作用的研究进展  

Research progress on the role of DAXX/ATRX deficiency and alternative lengthening of telomeres in pancreatic neuroendocrine tumors

作　　者：杜信纬 李刚[1] 卢军 李炳琦 任思谦 原春辉[1] Du Xinwei;Li Gang;Lu Jun;Li Bingqi;Ren Siqian;Yuan Chunhui(Department of General Surgery,Peking University Third Hospital,Beijing 100191,China)

机构地区：[1]北京大学第三医院普通外科,北京100191

出　　处：《中华实验外科杂志》2024年第10期2403-2409,共7页Chinese Journal of Experimental Surgery

基　　金：北京市希思科临床肿瘤学研究基金(Y-Young2021-0116);北京大学第三医院人才孵育基金(BYSYFY2021047);北京大学第三医院临床重点项目(BYSYZD2021017)。

摘　　要：胰腺神经内分泌瘤(PNETs)起病隐匿,呈高度异质性,虽然部分PNETs呈惰性生长,但仍有大量PNETs容易出现转移且预后较差,因此寻找能够准确反映PNETs恶性潜能的生物标志物,一直是该疾病研究的重点之一。继死亡结构域相关蛋白基因(DAXX)和α-地中海贫血伴智力低下综合征基因(ATRX)突变在PNETs中首次被发现后,研究者们又发现在PNETs中端粒替代性延伸机制(ALT)与DAXX/ATRX缺失高度关联,并初步揭示了ALT激活的具体过程以及DAXX/ATRX对于ALT的调控作用。此外,还有大量研究结果显示DAXX/ATRX缺失及ALT激活与PNETs患者的肿瘤远处转移和预后相关,这些相关性也存在于惰性较强的小体积非功能性胰腺神经内分泌瘤及胰岛素瘤中,以上发现对PNETs侵袭性的预测具有重要意义。有研究证实,术前内镜穿刺检测DAXX/ATRX免疫组织化学和ALT的结果可信度高,揭示出这两项生物标志物在临床应用的光明前景。故本文将综述ALT激活机制以及DAXX/ATRX缺失对于ALT的调控作用,整合两者在PNETs预后和远处转移方面的研究进展和在临床实践中的应用价值,总结现有研究的不足并提出展望。Pancreatic neuroendocrine tumors(PNETs)are a highly heterogeneous type of neuroendocrine tumors with subtle early symptoms.While some PNETs are indolent,a subset may widely metastasize,resulting in a relatively poor prognosis.Hence,identifying biomarkers that accurately reflect the malignancy of PNETs has consistently been a key research focus.Since the initial identification of alterations in the death-domain-associated protein gene(DAXX)and the alpha-thalassemia/mental retardation syndrome X-linked gene(ATRX)in PNETs,researchers have observed a strong correlation between these alterations and the alternative lengthening of telomeres(ALT)mechanism.Studies have also provided preliminary insights into both the activation process of ALT and the regulatory influence of DAXX/ATRX on it.At the same time,numerous studies have identified that DAXX/ATRX deficiency and ALT activation were correlated with the prognosis and distant metastases of PNETs,including small non-functional PNETs and insulinomas,which were considered to be relatively indolent.These findings are thought to be important for predicting the aggressiveness of PNETs.In terms of DAXX/ATRX immunohistochemistry and ALT status,less invasive preoperative detection methods such as Endoscopic Ultrasound Guided Fine-Needle Aspiration(EUS-FNA)exhibited highly consistent results with postoperative biopsy which are commonly used in clinical research,revealing a bright future of these two biomarkers in clinical practice.In this article,we provide a brief overview of the ALT activation mechanism and the regulatory influence of DAXX/ATRX on it,review research progress on the role of DAXX/ATRX deficiency and ALT in PNETs,and specifically summarize the shortcomings and prospects in this field.

关 键 词：胰腺神经内分泌瘤 死亡结构域相关蛋白/α-地中海贫血伴智力低下综合征蛋白 端粒替代性延伸 预后 远处转移 

分 类 号：R735.9[医药卫生—肿瘤]