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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    ABSTRACT: In the last decades, the concept that Insulin-like Growth Factor (IGF) axis plays a key role in several steps of tumorigenesis, cancer growth and metastasis has been widely documented. The aberration of the IGF system has been described in many kinds of tumours, providing several lines of evidence in support of IGF receptor type 1 (IGF1R) as molecular target in cancer treatment. 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. Recently, several lines of evidence about the involvement of the IGF system in GIST have been accumulated. The aim of this review is to report all current data about the IGF system involvement in GIST, focusing on the current clinical implication and future perspectives.
    Histology and histopathology 10/2013; · 2.24 Impact Factor
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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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    ABSTRACT: 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.
    Frontiers in Oncology 05/2013; 3:117. DOI:10.3389/fonc.2013.00117
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    • "DNA from individual BACs was isolated according to the manufacturer's instructions, labeled with different fluorochromes in a nick translation reaction, denatured, and hybridized to pretreated slides. Slides were then incubated, washed, and mounted with DAPI in an antifade solution, as previously described (Agaram et al., 2008). The genomic location of each BAC set was verified by hybridizing them to normal metaphase chromosomes . "
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    ABSTRACT: The diagnosis of myoepithelial (ME) tumors outside salivary glands remains challenging, especially in unusual clinical presentations, such as bone or visceral locations. A few reports have indicated EWSR1 gene rearrangement in soft tissue ME tumors, and, in one case each, the fusion partner was identified as either PBX1 or ZNF444. However, larger studies to investigate whether these genetic abnormalities are recurrent or restricted to tumors in soft tissue locations are lacking. Sixty-six ME tumors mainly from soft tissue (71%), but also from skin, bone, and visceral locations, characterized by classic morphological features and supporting immunoprofile were studied. Gene rearrangements in EWSR1, FUS, PBX1, and ZNF444 were investigated by fluorescence in situ hybridization. EWSR1 gene rearrangement was detected in 45% of the cases. A EWSR1-POU5F1 fusion was identified in a pediatric soft tissue tumor by 3'Rapid Amplification of cDNA Euds (RACE) and subsequently confirmed in four additional soft tissue tumors in children and young adults. An EWSR1-PBX1 fusion was seen in five cases, whereas EWSR1-ZNF444 and FUS gene rearrangement was noted in one pulmonary tumor each. In conclusion, EWSR1 gene rearrangement is a common event in ME tumors arising outside salivary glands, irrespective of anatomical location. EWSR1-negative tumors were more often benign, superficially located, and showed ductal differentiation, suggesting the possibility of genetically distinct groups. A subset of soft tissue ME tumors with clear cell morphology harbor an EWSR1-POU5F1 fusion, which can be used as a molecular diagnostic test in difficult cases. These findings do not support a pathogenetic relationship between soft tissue ME tumors and their salivary gland counterparts.
    Genes Chromosomes and Cancer 12/2010; 49(12):1114-24. DOI:10.1002/gcc.20819 · 3.84 Impact Factor
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