Molecular Characterization of Pediatric Gastrointestinal Stromal Tumors

Abstract

Purpose: Pediatric gastrointestinal stromal tumors (GIST) are rare and occur preferentially in females as multifocal gastric tumors, typically lacking mutations in KIT and PDGFRA. As KIT oncoprotein is consistently overexpressed in pediatric GIST, we sought to investigate the activation of KIT downstream targets and alterations of KIT/PDGFRA gene copy number, mine novel therapeutic targets by gene expression, and test tyrosine kinase receptor activation by proteomic profiling. Experimental Design: Seventeen pediatric GISTs were investigated for KIT/PDGFRA genotype and biochemical activation of KIT downstream targets. The transcriptional profile of 13 nodules from 8 pediatric patients was compared with 8 adult wild-type (WT) GISTs, including 3 young adults. The drug sensitivity of second-generation kinase inhibitors was tested in murine Ba/F3 cells expressing human WT KIT, as well as in short-term culture of explants of WT GIST cells. Results: A KIT/PDGFRA WT genotype was identified in all 12 female patients, whereas two of five males had either a KIT exon 11 or PDGFRA exon 18 mutation. KIT downstream targets were consistently activated. Pediatric GISTs showed a distinct transcriptional signature, with overexpression of BAALC, PLAG1, IGF1R, FGF4, and NELL1. In vitro studies showed that nilotinib, sunitinib, dasatinib, and sorafenib are more effective than imatinib against WT KIT. Conclusions: Rare cases of pediatric GIST may occur in male patients and harbor activating KIT/PDGFRA mutations. Pediatric GISTs show distinct transcriptional signature, suggesting a different biology than WT GIST in adults. In vitro drug screening showed that second-generation kinase inhibitors may provide greater clinical benefit in pediatric GIST.Gastrointestinal stromal tumors (GIST), the most common mesenchymal tumors of the gastrointestinal tract, typically occur in adults over the age of 40 years. GISTs in the pediatric age group are rare and account for 1% to 2% of all GIST cases (1, 2). Pediatric GISTs are preferentially located in the stomach as multiple nodules and histologically have either an epithelioid or a mixed spindle and epithelioid morphology (1, 2). Of interest is that unlike in adults, the majority of GISTs in pediatric patients follow an indolent course, in spite of the high rate of metastasis to the peritoneal cavity and liver. Furthermore, metastasis to locoregional lymph nodes is common in pediatric GIST patients and rare in adults (2). Also, in contrast with adult GISTs, tumors in the pediatric age group often lack activating mutations in KIT or PDGFRA. In spite of the wild-type (WT) genotype, KIT oncoprotein is consistently overexpressed in these tumors. Certain clinicopathologic features, such as female predisposition, multifocal gastric location, and WT genotype suggest a relationship with Carney's triad.Although imatinib mesylate achieves a clinical response in >80% of adult patients with metastatic or advanced GIST, the efficacy of selective kinase inhibition in pediatric GIST population has not b...

Gastrointestinal stromal tumors: what do we know now?

“…These tumors, which often metastasize but tend to grow slowly, have a different gene expression signature from KIT/PDGFRA-mutant GISTs. [69][70][71] Some pediatric-type GISTs are accompanied by pulmonary chondromas and/or paragangliomas, referred to as Carney triad, a non-heritable syndrome, the genetic cause for which has yet to be determined. 72 The origin of GISTs…”

Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors

“…3,4 Approximately 15% of GISTs in adults, and 490% of GISTs in children, do not contain identifiable mutations in KIT or PDGFRA and were previously lumped into one group referred to as 'wild-type GIST'. [5][6][7] More recently, these tumors have been subcategorized into genetically defined subgroups, including tumors with activating mutations in BRAF, [8][9][10] loss-offunction mutations in NF1, or loss-of-function mutations in components of the inner mitochondrial membrane Krebs cycle enzyme complex succinate dehydrogenase (SDH). 11,12 This latter group of tumors has been designated 'SDH-deficient GIST'.…”

Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis

“…3,4 In contrast, approximately 15% of GISTs in adults and 490% of GISTs in children are categorized as 'wild-type' GISTs because they lack KIT and PDGFRA mutations. [5][6][7] In recent years, a defined set of genetic changes in these so-called wild-type GISTs have begun to be characterized, including activating mutations in BRAF, [8][9][10] loss of function mutations in NF1, 11 and mutations leading to loss of function of the succinate dehydrogenase (SDH) enzyme complex. 12 The SDH enzyme complex is localized to the inner mitochondrial membrane, where it functions both as complex II of the electron transport chain and as a member of the Krebs cycle, converting succinate to fumarate.…”