Article

Molecular Characterization of Pediatric Gastrointestinal Stromal Tumors

Department of Pathology, Sloan-Kettering Institute, New York, New York 10021, USA.
Clinical Cancer Research (Impact Factor: 8.19). 06/2008; 14(10):3204-15. DOI: 10.1158/1078-0432.CCR-07-1984
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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    • "Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract, commonly characterized in most cases by KIT and PDGFRA gain mutations. Beyond to the well recognized KIT and PDGFRA gain mutations, in the last years other molecular aberrations have been investigated, especially in that subset of GIST wild-type (WT) for known driver mutations, defined as KIT/PDGFRA WT GIST (Agaram et al., 2008a; Astolfi et al., 2010; Pantaleo et al., 2011, 2013). The evidence about the involvement of IGF system in GIST recently accumulated could be separated into four main fields of interest (Fig. 2): -IGF1R over-expression (Prakash et al., 2005; Agaram et al., 2008b; Tarn et al., 2008; Pantaleo et al., 2009, 2010; Janeway et al., 2010; Italiano et al., 2012; Chou et al., 2012; Belinsky et al., 2013; Lasota et al., 2013; Nannini et al., 2013); -the correlation between IGF system deregulation and survival (Braconi et al., 2008; Rikhof et al., 2009; Kwon et al., 2012); -the correlation between IGF system and response to imatinib treatment (Trent et al., 2006; Dupart et al., 2009; Valadao et al., 2012); -the non-islet cell tumour-induced hypoglycemia in GIST patients (Beckers et al., 2003; Pink et al., 2005; Rikhof et al., 2005, 2009; Hamberg et al., 2006; Singh et al., 2006; Escobar et al., 2007; Davda and Seddon, 2007; Tan et al., 2011). "
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    • "The natural history of these tumors nevertheless appears to be more indolent than adult GISTs, as patients can survive for many years with metastatic disease (Miettinen et al., 2005a). Interestingly, many of the characteristics of GISTs in the pediatric population (e.g., female predilection, predominance of gastric, multi-focal tumors of epithelioid morphology ) are not as clearly defined in the more heterogeneous group of young adult (i.e., 21–30 years) GIST patients (Miettinen et al., 2005a; Prakash et al., 2005; Agaram et al., 2008a; Rink and Godwin, 2009), suggesting that some but not all of the patients in this age group may more properly be considered with the pediatric group. "
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