Succinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors.
Succinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors.
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DOI：
10.3389/fonc.2013.00117
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发表时间：
2013
影响因子：
4.7
通讯作者：
von Mehren M
中科院分区：
文献类型：
--
作者：
Belinsky MG;Rink L;von Mehren M
成人胃肠道间质瘤（gist）通常是由KIT或PDGFRA的体细胞功能获得性突变驱动的，针对这些受体酪氨酸激酶的生物治疗是转移性和不可手术性胃肠道间质瘤治疗方案的一部分。少数成人（10-15%）的胃肠道间质瘤患者，以及约85%的儿科胃肠道间质瘤患者，在KIT和PDGFRA中缺乏致癌突变。毫不奇怪，这些野生型（WT） gist对激酶抑制剂治疗反应不佳。WT gist的一个子集共享一组独特的临床和病理特征，最近的一系列报告令人信服地证明了共享的分子特征。这些gist具有独特的转录谱，包括胰岛素样生长因子-1受体的过度表达，以及琥珀酸脱氢酶（SDH）酶复合物的缺乏。后者通常但并不总是与SDH亚基基因的双等位基因失活有关，特别是SDHA。这篇综述将总结这组sdh缺陷肿瘤的分子、病理和临床联系，并为理解该疾病的潜在生物学和隐含的治疗挑战提供观点。
Gastrointestinal stromal tumors (GISTs) in adults are generally driven by somatic gain-of-function mutations in KIT or PDGFRA, and biological therapies targeted to these receptor tyrosine kinases comprise part of the treatment regimen for metastatic and inoperable GISTs. A minority (10–15%) of GISTs in adults, along with ∼85% of pediatric GISTs, lacks oncogenic mutations in KIT and PDGFRA. Not surprisingly these wild type (WT) GISTs respond poorly to kinase inhibitor therapy. A subset of WT GISTs shares a set of distinguishing clinical and pathological features, and a flurry of recent reports has convincingly demonstrated shared molecular characteristics. These GISTs have a distinct transcriptional profile including over-expression of the insulin-like growth factor-1 receptor, and exhibit deficiency in the succinate dehydrogenase (SDH) enzyme complex. The latter is often but not always linked to bi-allelic inactivation of SDH subunit genes, particularly SDHA. This review will summarize the molecular, pathological, and clinical connections that link this group of SDH-deficient neoplasms, and offer a view toward understanding the underlying biology of the disease and the therapeutic challenges implicit to this biology.