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Pediatric KIT–Wild-Type and Platelet-Derived Growth Factor Receptor –Wild-Type Gastrointestinal Stromal Tumors Share KIT Activation but not Mechanisms of Genetic Progression with Adult Gastrointestinal Stromal Tumors

Departments of ¹ Medicine and ² Pathology, Children's Hospital Boston, ³ Pediatric Oncology, Dana-Farber Cancer Institute; ⁴ Department of Pathology, Bringham and Women's, Hospital, Boston, Massachusetts; ⁵ Department of Pathology, Medical University, Graz, Austria; and Departments of ⁶ Medicine, and ⁷ Cell and Developmental Biology, Oregon Health and Science University and ⁸ Portland VA Medical Center, Portland, Oregon

Requests for reprints: Katherine A. Janeway, Department of Pediatrics, Dana Farber Cancer Institute, 44 Binney St., Boston, MA 02115 or Jonathan A. Fletcher, Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Phone: 617-632-4994; Fax: 617-278-6921; E-mail: katherine.janeway{at}childrens.harvard.edu.

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Fewer than 15% of gastrointestinal stromal tumors (GIST) in pediatric patients harbor KIT or platelet-derived growth factor receptor (PDGFRA) mutations in contrast to a mutation rate of 80% in adult GISTs. However, some therapeutic inhibitors of KIT have efficacy in pediatric GIST, suggesting that KIT may, nevertheless, play an important role in oncogenesis. In adult GIST, characteristic cytogenetic changes occur during progression to malignancy. A better understanding of mechanisms of genetic progression and KIT and PDGFRA transforming roles in pediatric GIST might facilitate treatment advances. KIT and PDGFRA mutation analysis was done in 27 pediatric GISTs. The activation status of KIT, PDGFRA, and downstream signaling intermediates was defined, and chromosomal aberrations were determined by single nucleotide polymorphism assays. Mutations in KIT or PDGFRA were identified in 11% of pediatric GISTs. KIT and the signaling intermediates AKT and mitogen-activated protein kinase were activated in pediatric GISTs. In particular, most pediatric KIT–wild-type GISTs displayed levels of KIT activation similar to levels in adult KIT-mutant GISTs. Pediatric KIT–wild-type GISTs lacked the typical cytogenetic deletions seen in adult KIT-mutant GISTs. Notably, most pediatric KIT–wild-type GISTs progress to malignancy without acquiring large-scale chromosomal aberrations, which is a phenomenon not reported previously in malignant solid tumors. KIT activation levels in pediatric KIT–wild-type GISTs are comparable with those in KIT-mutant GISTs. Therapies that inhibit KIT activation, or crucial KIT signaling intermediates, should be explored in pediatric KIT–wild-type GIST. [Cancer Res 2007;67(19):9084–8]

	Introduction

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Gastrointestinal stromal tumor (GIST) is a neoplasm of mesenchymal origin in the gastrointestinal tract of adults and children. A key, early transforming event in 80% of adult GISTs is mutation, leading to ligand-independent activation of KIT or, less commonly, platelet-derived growth factor receptor (PDGFRA; ref. 1). In adult GIST, oncogenic KIT or PDGFRA mutations are likely sufficient for transformation, but progression from benign to malignant GIST is characterized by sequential acquisition of chromosomal deletions at 14q, 22q, 1p, and 9p (1). Whereas pediatric GIST expresses KIT at levels comparable with adult GIST, only 15% of the pediatric tumors harbor activating mutations in KIT or PDGFRA (2).

GIST in both pediatric and adult patients is resistant to standard chemotherapeutic agents. However, therapeutic KIT and PDGFRA inhibitors, such as imatinib and sunitinib, have prolonged survival in adult patients with metastatic GIST (3–5). Although case reports suggest only limited therapeutic benefit of imatinib in metastatic pediatric GIST (6–8), there is recent evidence that sunitinib, a more potent inhibitor of wild-type KIT, can slow progression in pediatric GIST (9). A rational approach to investigation and use of drugs that inhibit receptor tyrosine kinases (RTK) in pediatric GIST requires a better understanding of the KIT and PDGFRA transforming roles in these tumors. To this end, we report herein the KIT and PDGFRA genotype in 27 pediatric GISTs and correlate genotype results with the activation status of KIT, PDGFRA, and downstream signaling intermediates.

Cytogenetic aberrations in adult GIST are similar, irrespective of whether the tumor contains a KIT or PDGFRA oncogenic mutation (10). Therefore, the mechanisms of genetic progression seem to be the same in adult GISTs with various activating RTK mutations. However, it is unknown whether similar chromosomal aberrations predominate in pediatric GIST. Evaluations of pediatric GIST have shown only normal (diploid) karyotypes (11), but such findings, in malignant solid tumors generally, are apt to result from overgrowth of the neoplastic population by reactive cells, such as normal myofibroblasts, during the cytogenetic analysis (12). To determine whether chromosomal aberrations in pediatric GIST are different from those in adult GIST, we investigated genomic alterations in 15 pediatric GISTs using 10K single nucleotide polymorphism (SNP) arrays.

	Materials and Methods

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Patient materials. Twenty-seven GISTs from patients <25 years at diagnosis were analyzed after Institutional Review Board (IRB) review and approval. All 27 cases were histologically reviewed and confirmed to be GIST by one of the authors (C.C.) and were tested for KIT and PDGFRA mutations. Fifteen cryopreserved tumor samples were available, and this subset was analyzed for KIT activation and KIT signaling by Western blotting and genomic changes by SNP assays. Normal tissue or peripheral blood from three of the patients and from three healthy control subjects was also analyzed by SNP assays after IRB approval.

Reagents. Polyclonal rabbit antibody to KIT was from DAKO. Polyclonal rabbit antibody to mitogen-activated protein kinase (MAPK) p42/44 was from Zymed Laboratories. Polyclonal rabbit antibodies to phosphorylated KIT Y721, phosphorylated AKT S473, total AKT, and phosphorylated MAPK T202/Y204 were from Cell Signaling. Polyclonal goat antibody to PKC was from Santa Cruz Biotechnology. Mouse monoclonal antibody to actin was from Sigma.

Western blotting. Whole cell lysates of cryopreserved tumors were prepared as previously described (13). The lysates were separated by gel electrophoresis using NuPAGE 4% to 12% Bis-Tris gels (Invitrogen) and blotted to nitrocellulose membranes. Immunostains were detected using enhanced chemiluminescence (ECL Amersham Pharmacia Biotech) and captured and quantified using a Fuji LAS1000-plus imaging system. A standard lane (GIST882 cell line lysate; ref. 14) was used to equalize the staining between gels.

KIT and PDGFRA mutational analyses. Genomic DNA was isolated from paraffin-embedded or cryopreserved tumor. KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 were amplified by PCR and screened for mutations by denaturing high-performance liquid chromatography. Primers, PCR conditions, and sequencing methods have been described previously (1). cDNA sequencing of the entire KIT coding sequence was also done in four pediatric GISTs lacking KIT or PDGFRA genomic mutations. The SuperScript one-step reverse transcription-PCR system with Platinum Taq (Invitrogen) was used for cDNA synthesis and PCR. KIT cDNA was synthesized in eight overlapping segments. Primer sequences used for PCR and sequencing are given in Supplementary Table S1. Sequencing was done with an ABI 3730 xl sequencer after gel purification of the PCR products.

SNP assay. DNAs were isolated from cryopreserved tumor using a standard phenol-chloroform method. The DNAs were analyzed using an Affymetrix 10K SNP array at the Dana-Farber Cancer Institute Microarray Core Facility. DNA (250 ng) was digested with XbaI, and linkers were ligated to the restriction fragments to permit PCR amplification. The PCR products were then purified and fragmented by treatment with DNase I. The fragmented PCR products were labeled and hybridized to microarray chips. The positions and intensities of the fluorescent emissions were analyzed using dCHIPSNP software.⁹ Array intensity was normalized to the array with median intensity. Median smoothing was used to infer copy number. Loss of heterozygosity (LOH) analysis was done using a Hidden Markov Model (15).

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Patients. Patients were 6 to 22 years at diagnosis with a mean age of 14 years. Twenty-three (85%) patients were female. Two patients had Carney Triad (cases 8 and 13). The age and gender distribution of the patients in this report are representative of previously published series of pediatric GIST (7, 16).

KIT and PDGFRA mutation analyses. Three of twenty-seven GISTs (11%) had KIT or PDGFRA mutations that included a homozygous KIT exon 11 mutation, resulting in deletion VV559-560 (case 1), a heterozygous KIT exon 9 mutation resulting in AY502-503 insertion (case 2), and a heterozygous PDGFRA exon 18 mutation resulting in D842V substitution. Patients with KIT-mutant GISTs were 17 and 22 years at diagnosis, and the patient with PDGFRA-mutant GIST was 14 years at diagnosis. To investigate the possibility that novel KIT mutations are present in pediatric GIST, cDNA sequencing of the entire KIT coding sequence was done. cDNA sequencing did not reveal mutations in four cases (cases 5, 6, 8, and 10) wherein the KIT and PDGFRA genomic mutation screening had been wild-type.

The PDGFRA-mutant GIST did not have sufficient tumor material for inclusion in the subset analyzed by Western blotting and SNP assays. However, it is known that, in Chinese hamster ovary cells, the D842V PDGFRA variant leads to constitutive activation of PDGFRA in the absence of ligand stimulation. The D842V PDGFRA mutation is present in over half of adult GISTs with PDGFRA mutations (10).

KIT and PDGFRA genotyping in these 27 cases, together with data published previously for 31 pediatric GISTs, provides strong evidence that oncogenic KIT and PDGFRA mutations are found in only 15% of pediatric GISTs (2, 8). By contrast, >80% of adult GISTs feature KIT or PDGFRA mutations, with KIT exon 11, KIT exon 9, and PDGFRA mutations found in 66%, 10%, and 7%, respectively (1). These findings also suggest that the distribution of KIT and PDGFRA mutations differ between pediatric and adult GISTs, with KIT exon 11, KIT exon 9, and PDGFRA mutations found in 5%, 9%, and 3% of pediatric GISTs, respectively.

KIT and KIT signaling. KIT and PKC expression are highly specific characteristics of GIST with the exception of PDGFRA mutant tumors, in which KIT expression is often nearly undetectable (13). All 15 cryopreserved pediatric GISTs variably expressed KIT, and 14 coexpressed PKC, confirming the diagnosis of GIST (Fig. 1 ). Twelve of thirteen KIT–wild-type pediatric GISTs expressed tyrosine phosphorylated KIT, consistent with a nonmutational mechanism of KIT activation (Fig. 1). In general, the level of KIT activation in pediatric KIT–wild-type GISTs was similar to that in adult and pediatric KIT-mutant GISTs. The AKT and MAPK downstream signaling intermediates were expressed and activated in all pediatric GISTs, except for case 8 which did not have MAPK activation. The level of total KIT expression was similar to adult KIT-mutant GISTs in all pediatric GISTs with the exception of slightly lower levels in one pediatric KIT–wild-type and one pediatric KIT-mutant case. None of the pediatric KIT–wild-type GISTs expressed PDGFRA (data not shown). The specificity of the phosphorylated KIT antibody used is underscored by the lack of phosphorylated KIT staining in case 12, which does express total KIT. The antibodies detecting phosphorylated downstream signaling intermediates have been validated in GIST cell lines treated with Imatinib (17).

View larger version (78K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Expression and activation of KIT (A) and KIT signaling intermediates (B) shown by immunoblotting in KIT–wild-type pediatric GIST (n = 13), KIT-mutant pediatric GIST (n = 2), and KIT-mutant adult GIST (n = 3).

There are several mechanisms by which KIT might be activated in KIT–wild-type pediatric GISTs. One possibility is an autocrine/paracrine loop involving overexpression of the KIT ligand stem cell factor. There is precedent for such a mechanism in dermatofibrosarcoma protuberans, wherein PDGFRB activation results from a genomic mutation, causing overexpression of PDGFB (19). Alternatively, KIT activation in KIT–wild-type pediatric GIST could be due to impaired degradation, as can result from mutation of a Cbl ubiquitin-protein ligase or the adaptor containing PH and SH2 domains protein (20). Or, unchecked KIT activation could result from a phosphatase mutation, such as has been reported in juvenile myelomonocytic leukemia (21). Finally, tyrosine kinase heterooligomerization could result in KIT cross-phosphorylation by another RTK family member. This type of heterooligomerization is well-described in the epidermal growth factor receptor family. In addition, forced interaction between KIT and FLT-3 has been shown to result in KIT activation and cell proliferation (22).

In vitro and in vivo data confirm that activation of MAPK and AKT is dependent upon KIT activation in KIT-mutant GIST. In GIST cell lines, treatment with the selective KIT inhibitor imatinib abolishes KIT, AKT, and MAPK activation. Furthermore, analysis of GIST biopsies show complete inhibition of KIT, AKT, and MAPK shortly after initiation of imatinib (18). The KIT-dependent nature of AKT and MAPK activation in most adult GISTs suggests that AKT and MAPK activation in pediatric wild-type GISTs might also be regulated by KIT. Alternatively, AKT and MAPK activation in some pediatric GISTs might not be entirely regulated by KIT or PDGFRA signaling. Such possibilities are underscored by our immunoblotting data, which suggest that signaling relationships vary in pediatric GISTs. Case 8, with a moderate level of KIT phosporylation, had minimal AKT and no MAPK phosphorylation, whereas case 12, with no KIT phosphorylation, had a moderate level of AKT and MAPK phosphorylation. One explanation for this observation is the variable participation of additional upstream kinases. A subset of the KIT–wild-type GISTs reported herein were screened with a proteomic technique (10) for strongly activated RTKs. However, other than KIT, no strongly activated RTKs were identified.¹¹

SNP analysis. SNP analyses of three adult KIT-mutant GISTs showed typical cytogenetic alterations, including LOH at 1p and LOH and decreased copy number at 14q and 22q (Fig. 2 ). Each of these adult KIT-mutant GISTs had additional regions of LOH and copy number change, spanning large numbers of SNPs. The two pediatric KIT-mutant GISTs had chromosomal changes typical of adult KIT-mutant GIST. Case 1 had loss of 1p, 9p, and 14q, whereas case 2 had loss of 1p and 22q. Both of these pediatric KIT-mutant cases, like the adult KIT-mutant cases, had multiple additional large chromosomal regions with LOH and copy number change. In contrast, the pediatric KIT–wild-type cases lacked the typical cytogenetic deletions (1p, 14q, and 22q) seen in KIT-mutant GISTs, and indeed had minimal areas of LOH or copy number change. Large chromosomal region(s) with LOH or copy number change were seen in only three KIT–wild-type pediatric GISTs. Case 9 had 5p LOH with apparent trisomy in this region, consistent with allelic duplication and retention of heterozygosity rather than true LOH. Case 14 had 11q LOH without associated copy number change, consistent with true LOH, followed by allelic duplication. Case 5 had multiple regions of apparent LOH, including 1p, 3q, 5q, and chromosomes 13 and 18. There was also 1p LOH but without a decrease in copy number.

View larger version (41K): [in this window] [in a new window] [Download PPT slide]   Figure 2. SNP LOH display shows few LOH regions in KIT–wild-type pediatric GISTs compared with KIT-mutant pediatric or adult GISTs. Cases in bold have companion normal DNAs. Blue, LOH; yellow, retained heterozygosity.

Notably, our present findings show that pediatric malignant GISTs are the first clinically aggressive solid tumor, in which cytogenetic aberrations, even when queried by high-resolution SNP assays, are undetectable in most cases. The normal genomic profiles in these malignant pediatric GISTs are representative of the neoplastic population based on pathologic examination of cryopreserved specimen regions, showing 10% or less nonneoplastic cells, from which DNAs for SNP assays were extracted (further details available in Supplementary Material). In addition, protein and DNA isolates were prepared from the exact same tumor aliquot in each case, and immunoblotting studies showed variable expression of the GIST-specific biomarkers KIT and PKC in all but one of these samples. Further, concurrent SNP analyses in the adult GISTs and pediatric KIT-mutant GISTs (which, like pediatric KIT–wild-type GISTs, are composed primarily of neoplastic cells) showed numerous large-scale chromosomal deletions in all cases.

The methods used for analysis of the SNP data do not require matched normal DNA to identify large-scale genetic changes in heterozygosity or copy number. As a demonstration of this point, the cases in which SNP analysis identified the greatest extent of LOH and copy number change were those that lacked matched normal DNA (see Fig. 2), whereas one case (case 8) with matched normal DNA had no large-scale genetic changes. SNP (10K) analysis, without the use of matched normal controls, has been validated as a highly sensitive method for detecting regions of copy number change compared with genomic hybridization (CGH) or karyotyping (24).

Data from CGH array analyses and karyotypes (23, 25) of adult GIST strongly support the conclusion that chromosomal changes contribute to clinical progression. Similar chromosomal regions are affected in most GISTs, and the pattern of genetic changes is similar in KIT-mutant and PDGFRA-mutant GISTs (10). Finally, there is similarity between GIST and other oncogene-driven malignancies, such as chronic myologenous leukemia, in which cytogenetic abnormalities, after the acquisition of an oncogene, are progressively acquired during disease progression.

The markedly different pattern of chromosomal aberrations in pediatric KIT–wild-type versus pediatric and adult KIT-mutant GIST suggests that, despite sharing KIT activation, these tumors likely have quite distinct mechanisms of genetic progression. In that sense, our findings show that pediatric and adult GISTs differ genetically and biologically. By CGH analysis, the genetic pattern of one pediatric GIST in a Carney Triad patient also differed from the pattern seen in adult tumors (2). Similarly, a cDNA profiling study has shown that pediatric GISTs cluster separately from adult GISTs (7). The paucity of chromosomal changes in most KIT–wild-type malignant pediatric GISTs suggests that substantial accumulation of additional genetic events does not occur or more likely occurs via highly localized genetic alterations, such as intragenic point mutations or balanced cytogenetic rearrangements, which are undetected by conventional high-density SNP assays. It is also possible that GIST genetic progression in pediatric patients results, at least in part, from epigenetic phenomena, such as gene promoter methylation, which are undetected by the genomic evaluations used in this study.

In summary, this study shows that pediatric KIT–wild-type GISTs exhibit KIT activation at levels comparable with KIT-mutant pediatric and adult GISTs although they do not have KIT (or PDGFRA) mutations. In addition, genetic progression seems to be very different in KIT-mutant versus KIT–wild-type pediatric GISTs. KIT-mutant pediatric GISTs have large-scale chromosomal aberrations similar to those seen in KIT-mutant adult GISTs, whereas KIT–wild-type pediatric GISTs have few large-scale chromosomal aberrations. Our findings suggest that targeted therapies for pediatric GIST should focus on inhibitors of KIT activation or signaling molecules downstream of KIT with an emphasis on those agents that strongly inhibit wild-type KIT.

	Acknowledgments

 
Grant support: An anonymous donor, Department of Veterans Affairs merit review grant (M.C. Heinrich), Life Raft Group (M.C. Heinrich, C.L. Corless, and J.A. Fletcher), and Virginia and Daniel K. Ludwig Trust for Cancer Research and GI SPORE 1P50CA12703-01 (J.A. Fletcher) and NIH grant 5732HL007574.25 (K.A. Janeway).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	Footnotes

 
Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

⁹ http://biosun1.harvard.edu/complab/dchip/snp

¹⁰ K.A. Janeway, personal communication.

¹¹ Unpublished data.

Received 5/25/07. Revised 6/25/07. Accepted 7/25/07.

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This Article Abstract Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Janeway, K. A. Articles by Fletcher, J. A. Search for Related Content PubMed PubMed Citation Articles by Janeway, K. A. Articles by Fletcher, J. A.