胰腺神经内分泌肿瘤病因学及基因分型  

Advances in Research on Genotyping and the Molecular Mechanism of Pancreatic Neuroendocrine Neoplasias

作　　者：韩序[1] 楼文晖[1] HAN Xu;LOU Wen-hui(Department of General Surgery,Zhongshan Hospital,Fudan University,Shanghai 200032,China)

机构地区：[1]复旦大学附属中山医院普通外科,上海200032

出　　处：《协和医学杂志》2020年第4期377-382,共6页Medical Journal of Peking Union Medical College Hospital

基　　金：国家自然科学基金(81702304、81773068)。

摘　　要：大量研究发现,染色体重塑相关基因(ATRX/DAXX、ARID1A)、MEN-1基因、DNA损伤修复基因(MUTYH)和哺乳动物雷帕霉素靶蛋白信号通路相关基因的异常改变共同参与了无功能性胰腺神经内分泌肿瘤(pancreatic neuroendocrine neoplasia,pNEN)的发生发展。作为功能性pNEN的代表,胰岛素瘤常出现拷贝数异常,伴随转录因子YY1的热点突变。驱动基因突变、DNA损伤修复、DNA甲基化、组蛋白修饰、染色体重塑和端粒替代延长机制激活等表观遗传学的异常改变以及相关信号通路的异常激活协同引起pNEN增殖和侵袭。这些分子机制及基因分型具有十分重要的意义,可为临床个体化综合治疗和预后判断提供依据,使更多的pNEN患者从精准医学中获益。Genomic sequencing studies have led to an increased understanding of the genotyping and molecular biology of pancreatic neuroendocrine neoplasias(pNENs). Recent studies reported that ATRX(α-thalassaemia/mental retardation syndrome X-linked)/DAXX(death-domain associated protein), ARID1 A(AT-rich interactive domain-containing protein 1 A, BAF250 A), MUTYH(mutY homolog), and MEN-1(multiple endocrine neoplasia type 1) genes are remarkably mutated in non-functional pNENs, as well as genes encoding core components of the mammalian target of rapamycin(mTOR) signaling pathway. As a representative of functional pNENs,insulinomas had CNV amplifications and copy neutral with YY1(Yin Yang 1) gene mutations. These mutated genes are involved in aberrations of chromatin remodeling, DNA damage repair, histone modification, and telomere maintenance, and thus might contribute to tumorigenesis and ultimately to the progression of pNENs characterized by divergent phenotypes. Differentiating genotypic subtypes of pNENs plays an important role in prognostication. Future therapies might be based on recent advances in molecular genotyping and mechanism.

关 键 词：神经内分泌肿瘤 胰腺 分子机制 基因突变 表观遗传学 

分 类 号：R58[医药卫生—内分泌]