Agaram NP, Laquaglia MP, Ustun B, et al. Molecular characterization of pediatric gastrointestinal stromal tumors

Department of Pathology, Sloan-Kettering Institute, New York, New York 10021, USA.
Clinical Cancer Research (Impact Factor: 8.72). 06/2008; 14(10):3204-15. DOI: 10.1158/1078-0432.CCR-07-1984
Source: PubMed


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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    • "PLAG1 is developmentally regulated and highly expressed in certain fetal tissues [17], [18]. Oncogenic activation of PLAG1 plays a key role in the development of lipoblastomas [19], hepatoblastomas [20], chronic lymphocytic leukemia [21] as well as in pediatric gastro-intestinal stromal tumors [22]. PLAG1 has been found to bind the insulin-like growth factor gene (IGF-II) promoter and to stimulate its activity [23]–[25]. "
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    ABSTRACT: In pleomorphic adenomas of the salivary glands (PASG) recurrent chromosomal rearrangements affecting either 8q12 or 12q14∼15 lead to an overexpression of the genes of the genuine transcription factor PLAG1 or the architectural transcription factor HMGA2, respectively. Both genes are also affected by recurrent chromosomal rearrangements in benign adipocytic tumors as e. g. lipomas and lipoblastomas. Herein, we observed a strong correlation between the expression of HMGA2 and PLAG1 in 14 benign and 23 malignant thyroid tumors. To address the question if PLAG1 can be activated by HMGA2, the expression of both genes was quantified in 32 uterine leiomyomas 17 of which exhibited an overexpression of HMGA2. All leiomyomas with HMGA2 overexpression also revealed an activation of PLAG1 in the absence of detectable chromosome 8 abnormalities affecting the PLAG1 locus. To further investigate if the overexpression of PLAG1 is inducible by HMGA2 alone, HMGA2 was transiently overexpressed in MCF-7 cells. An increased PLAG1 expression was observed 24 and 48 h after transfection. Likewise, stimulation of HMGA2 by FGF1 in adipose tissue-derived stem cells led to a simultaneous increase of PLAG1 mRNA. Altogether, these data suggest that HMGA2 is an upstream activator of PLAG1. Accordingly, this may explain the formation of tumors as similar as lipomas and lipoblastomas resulting from an activation of either of both genes by chromosomal rearrangements.
    Full-text · Article · Feb 2014 · PLoS ONE
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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.
    Full-text · Article · Oct 2013 · Histology and histopathology
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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.
    Full-text · Article · May 2013 · Frontiers in Oncology
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