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Originally published as JCO Early Release 10.1200/JCO.2005.02.093 on November 15 2004 © 2005 American Society of Clinical Oncology. KIT and Platelet-Derived Growth Factor Receptor Alpha Tyrosine Kinase Gene Mutations and KIT Amplifications in Human Solid TumorsFrom the Departments of Oncology and Pathology, Helsinki University Central Hospital, Helsinki; and Department of Oncology, Tampere University Hospital, Tampere, Finland Address reprint requests to Heikki Joensuu, MD, Department of Oncology, Helsinki University Central Hospital, Haartmaninkatu 4, PO Box 180, FIN-00029 Helsinki, Finland; e-mail: heikki.joensuu{at}hus.fi
PURPOSE: Mutated KIT and platelet-derived growth factor receptor alpha (PDGFR  ) tyrosine kinases are the principal targets for imatinib mesylate in the treatment of gastrointestinal stromal tumors (GISTs). The frequency of activating KIT and PDGFRA gene mutations in most other histologic types of human cancer is not known. MATERIALS AND METHODS: KIT exons 9, 11, 13, and 17 and PDGFRA exons 11 and 17 of 334 human cancers were screened for mutations using sensitive denaturing high-performance liquid chromatography (DHPLC). In addition, all KIT exons from 9 to 21 of 115 tumors were screened. Thirty-two histologic tumor types were examined. Samples with abnormal findings in DHLPC were sequenced. Immunostaining for the KIT protein (CD117) was performed in 322 (96.4%) of the 334 cases. RESULTS: Of the 3,039 exons screened, only 17 had mutation. All 17 cases with either mutated KIT (n = 15) or PDGFRA (n = 2) were histologically GIST tumors, whereas none of the other histologic types of cancer (n = 316) harbored KIT or PDGFRA mutation. KIT immunostaining was rarely positive except in GISTs (18 of 18), small-cell lung cancer (10 of 30; 33%), and testicular teratocarcinoma (four of 17; 24%). Wild-type KIT gene amplification or chromosome 4 aneuploidy was common (seven of 12) in non-GIST tumors with strong KIT protein expression when studied with fluorescence in situ hybridization. CONCLUSION: Despite frequent KIT protein expression in some tumor types, KIT and PDGFRA gene mutations are uncommon in most human cancers. Cancer KIT expression is frequently associated with multiple copies of the wild-type KIT gene.
Imatinib mesylate is a selective inhibitor of certain tyrosine kinases, including ABL, BCR-ABL, ARG, KIT, and the platelet-derived growth factor receptors (PDGFRs).1 Imatinib is highly active in the treatment of chronic myeloid leukemia, where it inhibits the kinase activity of the BCR-ABL fusion protein.2 Other target diseases include chronic myelomonocytic leukemia, where imatinib may act by inhibiting the TEL-PDGFR beta (PDGFRß) fusion protein produced as a result of the 5;12(q31-33,p13) translocation,3 and idiopathic hypereosinophilic syndrome with the FIP1L1-PDGFR fusion protein.4 Imatinib therapy may also be effective in the treatment of dermatofibrosarcoma protuberans, where it inhibits PDGFR activation related to the COL1/PDGFB fusion gene resulting from translocation between the chromosomes 17 and 22,5 and of some desmoid tumors, where the exact mechanism of action is not well understood.6 Imatinib is also effective in the treatment of gastrointestinal stromal tumors (GISTs).7,8 The great majority of GISTs express the KIT receptor tyrosine kinase, which can be detected by immunostaining for the CD117 antigen.9 A majority of GISTs have a gain-of-function mutation in the KIT proto-oncogene that encodes the KIT protein. Most mutations occur in the KIT exon 11, but mutations may also be found in exon 9 and rarely in exons 13 and 17.10 Gain-of-function mutations of KIT result in ligand-independent activation of KIT signaling, leading to growth and antiapoptotic signals. Many GISTs that lack KIT mutation have PDGFRA mutations, but only two PDGFRA exons have thus far been found to harbor mutations in GIST.11,12 KIT and PDGFRA genes belong to the family of class III receptor protein tyrosine kinases (RTKs), which also includes the colony-stimulating factor I receptor, PDGFRß, and FMS-related tyrosine kinase 3.13 KIT and PDGFRA are both located on chromosome 4q12 and have structural similarities with the other PDGFR family members.14,15 Class III RTKs have five extracellular immunoglobulin-like domains, a single transmembrane region, an intracellular juxtamembrane domain, and an intracellular kinase domain split by a kinase insert segment.16 Apart from GISTs, activating KIT mutations are associated with mast-cell neoplasms,17-19 and KIT mutations have now been detected in testicular and mediastinal seminomas in several studies.20-23
Because inhibition of KIT and PDGFR
Archival Tissue Material Three hundred thirty-four formalin-fixed, paraffin-embedded tumor samples were retrieved from the archives of the Department of Pathology, Helsinki University Central Hospital. Permission to analyze tissue samples containing different histologic types of human cancers was provided by the National Authority for Medicolegal Affairs of Finland. Thirty-two different histologic types of cancer were selected for the study. Our strategy was to select tumor types that have only rarely or never been investigated for the presence of KIT or PDGFRA mutations in the study. Therefore, we excluded seminomas, as these have been extensively studied,20-23,27 but included 18 GISTs to control for the mutation detection sensitivity of the assays.
Immunohistochemistry and Tissue Microarray Immunostaining for CD117 was performed with a polyclonal rabbit antibody (A 4502; Dako, Glostrup, Denmark) diluted as 1:300. Staining was analyzed with a detection kit (Envision Detection KIT, Peroxidase/DAB, rabbit/mouse; Dako) designed for use with an automated immunostaining system, Labvision (LAB VISION Corp, Fremont, CA). The samples were graded either as strongly positive (+++, where more than 50% of tumor cells expressed KIT), moderately positive (++, 10% to 50% positive), or weakly positive (< 10% expressed KIT; Fig 1). Negative and positive controls were included in each batch.
DNA Extraction and Polymerase Chain Reaction The genomic DNA was extracted from the formalin-fixed paraffin-embedded tissue blocks using standard methods. Fifty nanograms of the genomic DNA was amplified in a polymerase chain reaction (PCR) reaction containing 0.6 x Platinium PCR Buffer (Invitrogen, Carlsbad, CA), 1.4 to 2.4 mmol/L of MgCl2, 160 µmol/L of dNTPs (Clontech, Palo Alto, CA), 0.3 µmol/L of forward and reverse primers, and DNA polymerases AmpliTaq Gold (1.25 U; Applied Biosystems, Branchburg, NJ), and Platinium Taq (1.25 U; Invitrogen) in a volume of 50 µL. The forward and reverse oligonucleotide primers used to amplify KIT exons 9 to 21 and PDGFRA exons 11 and 17 are listed in Table 1 (PDGFRA exons are numbered according to the human genome project available at http://www.ensembl.org; exons 11 and 17 correspond to PDGFRA exons 12 and 18 of GenBank accession No. D50013, http://www.ncbi.nlm.nih.gov:80/entrez/, respectively).
The PCR cycling conditions consisted of an initial denaturation step at 94°C for 14 minutes, after 35 cycles at 94°C for 30 seconds, annealing at 56°C for 45 seconds and 2 minutes at 72°C, and final extension for 10 minutes at 72°C. Heteroduplex formation was created by denaturating the PCR products for 5 minutes at 95°C and then allowing the samples to reanneal by decreasing the temperature 1°C per minute from 95°C to 40°C.
DHPLC All 334 tumors were screened for known mutational hot spots of KIT and PDGFRA (ie, for KIT exons 9, 11, 13 and 17) and for PDGFRA exons 11 and 17. A part of the tumors (n = 117) we screened for KIT exons 9 to 21, which span the proximal part of the extracellular domain, the transmembrane domain, and the entire intracellular kinase domain. The tumors that were screened for the entire transmembrane and intracellular domains included small-cell lung carcinomas (n = 28), synovial sarcomas (n = 10), melanomas (n = 2), Merkel cell carcinomas (n = 3), neuroblastomas (n = 8), testicular carcinomas (n = 5), adenocarcinomas of the colon (n = 8), renal cell adenocarcinomas (n = 7), adenocarcinomas of the lung (n = 10), bronchioloalveolar carcinomas (n = 9), squamous cell lung carcinomas (n = 10), lymphoepitheliomas (n = 2), and adenocarcinomas of the pancreas (n = 4) and stomach (n = 9). Thus a total of 2,371 exons were screened for KIT mutations and 668 exons for PDGFRA mutations.
DNA Sequencing
Fluorescence In Situ Hybridization Interphase nuclei were prepared as described previously.29 The KIT and chromosome 4 centromere probes were cohybridized, and after hybridization, the probes were detected with avidin-fluorescein isothiocyanate and antidigoxigenin rhodamine as described earlier, counterstained with 4,6-diamidino-2-phenylindole, and viewed under a fluorescence microscopy equipped with an ISIS digital image analysis system (MetaSystems, Altlussheim, Germany). Approximately 50 interphase nuclei were analyzed from each sample.
Statistical Analysis
KIT and PDGFRA Mutations Of the total of 3,039 KIT or PDGFR exons and 334 tumors screened, only 17 tumors (5.1%) were found to have a mutation in either of these genes. All 17 tumors with a mutation were histologically GISTs. Seventeen (94%) of the 18 GISTs investigated had mutation (Table 2). All 15 KIT mutations in GISTs were found in exon 11, and PDGFRA exon 17 mutation was found in two GISTs that did not harbor KIT mutation. No mutations were detected in any of the 2371 KIT exons or in the 668 PDGFRA exons investigated in the histologic tumor types other than GIST (n = 316).
All except one of the KIT exon 11 mutations present in GISTs were in-frame deletions leading to deletions of one to eight amino acid residues from the KIT protein, and in the remaining case a missense mutation Val560Asp was found (case No. 6, Table 3). Both PDGFRA mutations were in-frame deletions in exon 17, resulting in a loss of amino acid residues 842 to 845.
Although no mutations leading to a change in the amino acid sequence were found in nonseminoma testicular cancer, two testicular embryonal carcinomas that did not express the KIT protein in immunohistochemistry had alterations in the nucleotide sequence. In one tumor, a silent single nucleotide polymorphism in the KIT exon 17 (N819N) was identified. In the other case, both a silent single nucleotide polymorphism in the PDGFRA exon 11 (P567P) was found, and an earlier unreported polymorphism located at the nucleotide position 73805T>A (51 bp upstream from the first codon of exon 16) of KIT was also present.
KIT Protein Expression
KIT Gene Copy Number
Tumors that harbor activating KIT or PDGFRA mutations are potential targets for imatinib and other selective tyrosine kinase inhibitors. We found mutated KIT or PDGFRA only in GISTs, whereas none of the cancers of the other histologic types investigated contained such mutations. Although gene mutation is merely one of the mechanisms that may result in RTK activation,10 the present results do not lend support for routine use of imatinib in the treatment of most human solid tumors outside clinical trials. DHPLC is regarded as one of the most sensitive screening methods for mutation detection in clinical tumor materials, with sensitivity approaching to 100%.30 Mutation detection sensitivity is of prime importance, especially when archival paraffin-embedded tumor tissue is used as the starting material. Many tumor samples may contain large numbers of stromal, inflammatory, and other host cells, which may result in a false-negative mutation analysis unless special efforts are made to enrich the relative proportion of cancer cells in the sample and unless a sensitive mutation detection method is used. We found either KIT or PDGFRA mutation in as many as 17 (94.4%) of the 18 GISTs investigated, which is a high frequency31-34 and suggests that the combination of DHPLC and DNA sequencing used by us was sensitive enough for detection of most KIT and PDGFRA mutations. The frequency and type of KIT mutations have not been systematically explored in human solid tumors, and most studies carried out have focused only on one or two exons of the 21 exons of the gene. In a recent study, 26 small-cell carcinomas were screened for KIT exon 11 mutations, but no mutations were found despite frequent (64%) KIT expression in the same tumors when studied with immunohistochemistry.35 Similarly, none of the total of 53 adenocystic carcinomas investigated in two studies had KIT exon 11 and 17 mutations, despite frequent KIT expression in immunohistochemistry.36,37 However, KIT mutations were found in 10 of the 14 Chinese patients and in two of the nine Japanese patients with sinonasal natural killer/T-cell lymphoma investigated.38 Eight of these mutations were located in KIT exon 17, and four were located in exon 11. KIT exon 11 mutations are rarely present in patients with mastocytosis.39 Ninety percent to 100% of seminomas express the KIT protein, whereas nonseminomas rarely express it.20,24 In seminomas, KIT mutations usually occur in exon 17, the most commonly mutated codon being 816 (D816V, D816H, D816Y).20,23,27 KIT mutation may be associated with constitutive activation of the KIT kinase in seminoma, but the mutated kinases are usually not inhibited by imatinib.23 In line with our findings, no KIT mutations were found in nonseminoma testicular tumors in two series.20,23 In addition to germ cell tumors, KIT codon 816 mutations have been identified in human mastocytosis (D816V, D816Y, D816F), acute myeloid leukemia (D816V, D816Y), and sinonasal natural killer/T-cell lymphoma (D816N, reviewed in Heinrich et al10). These data support the present findings, which suggest that KIT mutations are uncommon in most histologic types of solid tumors despite the fact that some tumor types frequently express the KIT protein. Besides GISTs, we found frequent KIT expression in small-cell lung carcinomas, of which 33% had weak to strong KIT protein expression; this figure is in agreement with the 36% frequency reported by Tsuura et al.24 Other tumors that may occasionally express KIT include melanomas, lymphomas, neuroblastoma, acute myelogenous leukemia, breast cancer, ovarian carcinoma, adenoid cystic carcinoma, thyroid carcinoma, and mastocytoma.10,24 The role of KIT in the molecular pathogenesis of these neoplasms is unknown, but the present findings suggest that in the absence of KIT mutation, marked KIT protein expression is frequently associated either with KIT gene amplification or the presence of multiple copies of chromosome 4. These amplicons may contain PDGFRA, because KIT and PDGFRA are tightly linked on chromosome 4q12.14
The frequency of PDGFRA mutations has been infrequently studied in human cancer.40 One study found activating PDGFRA mutations in 14 of 40 GISTs that did not contain KIT mutation,11 and another study in five of eight such cases.12 A single glioblastoma-derived PDGFRA deletion mutant with a loss of the extracellular exons 8 and 9 has also been described.41 As most investigators, we did not study tumor PDGFR In GIST, presence of mutated KIT or PDGFRA is predictive for disease responsiveness to imatinib, although imatinib inhibits effectively also wild-type KIT and PDGF receptors.42 Patients with GIST that lacks KIT or PDGFRA mutation rarely respond to imatinib, whereas those with GIST with mutated KIT often achieve a durable response.43 Yet absence of mutation should be used with caution in selection of therapy, because the number of wild-type GISTs evaluated for response to imatinib is still small, and any mutation detection method may occasionally produce a false-negative result. Of note, neurofibromatosis type I patients rarely have GIST tumors with KIT mutation, but these GISTs may harbor NF1 mutation instead.44
Although KIT and PDGFRA mutations seem to be uncommon in most malignant solid tumors, such mutations might still rarely exist within a single histologic cancer type. Identification of rare mutated tumors would require screening of large numbers of tumors, which is costly and time-consuming. KIT or PDGFRA mutational hot-spots may also be located in various exons in different histologic tumor types. However, we found no mutations among the 115 cases where we screened the entire transmembrane and intracellular domains of the KIT gene. We also screened 91 human solid tumors of various histologic types for PDGFRA exons 8 to 21 but found no mutations (data not shown). Importantly, KIT, PDGFR Imatinib may have a role in cancer chemotherapy in the absence of KIT or PDGFR mutation. PDGFRs are abundant in tumor stroma and vasculature, and PDGFß receptors are involved in pericyte recruitment to capillaries and development of smooth muscle cells in vessels, and PDGF signaling also contributes to wound healing, suggesting that imatinib has antiangiogenic properties.40 Imatinib decreases ovarian carcinoma microvessel density when given with paclitaxel and pancreatic carcinoma vessel density when used with gemcitabine in mice,45,46 reduces vascular endothelial growth factor expression of neuroblastoma cells and Bcr-Abl-expressing cells,47,48 and inhibits in vitro angiogenesis in fibrinogen-embedded mouse aorta.49 PDGFß receptors regulate tumor interstitial fluid pressure, and coadministration of PDGFR inhibitors and other anticancer drugs may improve drug delivery into tumors by lowering the intratumoral pressure. In a mouse model, administration of imatinib improved tumor paclitaxel and epothilone B uptake and enhanced antitumor efficacy.50,51 The clinical value of these findings remains to be evaluated.
In conclusion, only GISTs were found to harbor KIT or PDGFRA mutations, suggesting that mutations of these genes are uncommon in most types of human cancer. KIT and PDGFR
The authors indicated no potential conflicts of interest.
Supported by grants from the Cancer Society of Finland, Foundation for the Finnish Cancer Institute, Helsinki University Research Grants, and the Sigrid Juselius Foundation. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
INTRODUCTION
