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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 28, 2015; 21(8): 2303-2314
Published online Feb 28, 2015. doi: 10.3748/wjg.v21.i8.2303
Succinate dehydrogenase-deficient gastrointestinal stromal tumors
Ya-Mei Wang, Meng-Li Gu, Feng Ji
Ya-Mei Wang, Meng-Li Gu, Feng Ji, Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University, Hangzhou 310009, Zhejiang Province, China
Author contributions: All of the authors generated the ideas. Wang YM was responsible for collating the data and writing the manuscript, which were verified by Gu ML and Ji F, who also acts as a guarantor for the manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Feng Ji, MD, PhD, Professor, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qing Chun Road, Hangzhou 310003, Zhejiang Province, China. wym910319@126.com
Telephone: +86-571-87236586 Fax: +86-571-87236611
Received: July 24, 2014
Peer-review started: July 25, 2014
First decision: August 27, 2014
Revised: October 29, 2014
Accepted: December 16, 2014
Article in press: December 16, 2014
Published online: February 28, 2015
Processing time: 219 Days and 5.5 Hours
Abstract

Most gastrointestinal stromal tumors (GISTs) are characterized by KIT or platelet-derived growth factor alpha (PDGFRA) activating mutations. However, there are still 10%-15% of GISTs lacking KIT and PDGFRA mutations, called wild-type GISTs (WT GISTs). Among these so-called WT GISTs, a small subset is associated with succinate dehydrogenase (SDH) deficiency, known as SDH-deficient GISTs. In addition, GISTs that occur in Carney triad and Carney-Stratakis syndrome represent specific examples of SDH-deficient GISTs. SDH-deficient GISTs locate exclusively in the stomach, showing predilection for children and young adults with female preponderance. The tumor generally pursues an indolent course and exhibits primary resistance to imatinib therapy in most cases. Loss of succinate dehydrogenase subunit B expression and overexpression of insulin-like growth factor 1 receptor (IGF1R) are common features of SDH-deficient GISTs. In WT GISTs without succinate dehydrogenase activity, upregulation of hypoxia-inducible factor 1α may lead to increased growth signaling through IGF1R and vascular endothelial growth factor receptor (VEGFR). As a result, IGF1R and VEGFR are promising to be the novel therapeutic targets of GISTs. This review will update the current knowledge on characteristics of SDH-deficient GISTs and further discuss the possible mechanisms of tumorigenesis and clinical management of SDH-deficient GISTs.

Keywords: Gastrointestinal stromal tumors; Succinate dehydrogenase; Insulin-like growth factor 1 receptor; Vascular endothelial growth factor receptor; Hypoxia-inducible factor 1α

Core tip: Succinate dehydrogenase (SDH) deficiency occurs in about 5%-7.5% of gastrointestinal stromal tumors (GISTs). These so-called SDH-deficient GISTs lack KIT and PDGFRA mutations. Such type of GISTs has its own clinical, morphological and molecular characteristics. The accumulation of hypoxia-inducible factor 1α and the upregulation of its downstream molecules, such as insulin-like growth factor 1 and vascular endothelial growth factor receptor, may play important roles in the tumorigenesis of SDH-deficient GISTs. They are promising to be the novel therapeutic targets of GISTs.