Role of succinate dehydrogenase deficiency and oncometabolites in gastrointestinal stromal tumors  

作　　者：Yue Zhao Fei Feng Qing-Hong Guo Yu-Ping Wang Rui Zhao 

机构地区：[1]Department of Gastroenterology,the First Hospital of Lanzhou University,Key Laboratory for Gastrointestinal Disease of Gansu Province,Lanzhou 730000,Gansu Province,China [2]Department of Ultrasound,the First Hospital of Lanzhou University,Lanzhou 730000,Gansu Province,China [3]Department of Biochemistry and Molecular Genetics,School of Medicine,the University of Alabama at Birmingham,Birmingham,AL 35294,United States

出　　处：《World Journal of Gastroenterology》2020年第34期5074-5089,共16页世界胃肠病学杂志（英文版）

基　　金：Science and Technology Program of Gansu Province Grant,No.18JR3RA339 and No.18JR3RA363;Fund of the First Hospital of Lanzhou University Grant,No.ldyyyn2018-63;Teaching and Research Project of the First Clinical Medical College of Lanzhou University in 2018 Grant,No.2018007;NIH awards,No.R21NS106430 and No.R01OD026594;Cystic Fibrosis Foundation Research Grant,No.ZHAO19G0;an American Cancer Society-IRG Junior Faculty Development Grant,a UAB CCC Neuro-oncology Research Acceleration Grant,and a UAB Faculty Development Grant Program Award.

摘　　要：Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract.At the molecular level,GISTs can be categorized into two groups based on the causative oncogenic mutations.Approximately 85%of GISTs are caused by gain-of-function mutations in the tyrosine kinase receptor KIT or platelet-derived growth factor receptor alpha(PDGFRA).The remaining GISTs,referred to as wild-type(WT)GISTs,are often deficient in succinate dehydrogenase complex(SDH),a key metabolic enzyme complex in the tricarboxylic acid(TCA)cycle and electron transport chain.SDH deficiency leads to the accumulation of succinate,a metabolite produced by the TCA cycle.Succinate inhibitsα-ketoglutarate-dependent dioxygenase family enzymes,which comprise approximately 60 members and regulate key aspects of tumorigenesis such as DNA and histone demethylation,hypoxia responses,and m6A mRNA modification.For this reason,succinate and metabolites with similar structures,such as D-2-hydroxyglutarate and fumarate,are considered oncometabolites.In this article,we review recent advances in the understanding of how metabolic enzyme mutations and oncometabolites drive human cancer with an emphasis on SDH mutations and succinate in WT GISTs.

关 键 词：Gastrointestinal stromal tumors Succinate dehydrogenase Oncometabolite SUCCINATE α-ketoglutarate-dependent dioxygenase EPIGENETICS 

分 类 号：R735[医药卫生—肿瘤]