Type Of KIT Mutation Research Articles

Outcomes in late-line systemic treatment in GISTs: Does sequence matter?

11542 Background: Ripretinib (R) is approved for 4th line treatment of GIST based on superior PFS and OS compared to placebo in a phase 3 study, with RR of 11.8% and PFS of 6.3 months (mo). In addition to having high potency against PDGFRA D842V, avapritinib (A) showed activity in 4th or later lines for KIT mutated patients (pts). The RR was 17% and median duration of response was 10.2 mo from a phase 1 study. It is not known if pts receiving R benefit from A after progression or vice-versa. We retrospectively reviewed outcomes of R and A to determine if sequence affects outcomes. Methods: Pts diagnosed with GISTs and treated with both R and A at UTMDACC from Jan 2016 to Dec 2021 were included. Pts were separated into R-A (RA) or A-R sequence (AR) and outcomes were tabulated. Descriptive statistics were used to summarize characteristics and genetic profiles. Differences between RA and AR groups were calculated using Fisher’s exact. Response was evaluated using RECIST. Kaplan-Meier and Log-rank test were used to estimate and compare PFS and OS between groups. Results: Twenty pts were included in the study; 12 in RA and 8 in AR. Median age was 55 years (R:29.7-76.3). Most pts had small bowel primary (11/20, 55%) followed by stomach (4/20, 20%). All baseline characteristics and mutations were equitably distributed between RA and AR. RR of R was 17% and 14% in RA and AR groups, respectively and RR of A was 33% and 29% in RA and AR, respectively (Table). None of the pts with secondary exon 13 mutations responded to R or A. The drug administration sequence did not affect RR (p = 0.7, 0.62 in R, A). The PFS of the second drug administered, was shortened. PFS did not differ based on type of KIT mutation. Median OS from diagnosis in RA and AR groups were 121.8 (58.2-NR) and 171.3 (73.3-NR) mo, respectively and median OS from start of RA and AR was 43.9 (23.0-NR) and NR (11.5-NR) mo, respectively. Neither difference was statistically significant. Conclusions: Both R and A are efficacious in later lines of treatment, with greater benefit from the agent used first. Although, the combined PFS was numerically higher in AR compared to RA (20.5 vs 15.2 mo), the OS was not different. Currently, R is the only drug approved in the 4th or later lines in KIT-mutated GIST. [Table: see text]

AML-282: Prognostic Values of D816V KIT Mutation and Peri-Transplant CBFB-MYH11 MRD Monitoring on Acute Myeloid Leukemia with CBFB-MYH11

<h3>Context:</h3> Controversies exist in the prognostic value of KIT mutations and the optimal thresholds and time points for measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with CBFB-MYH11. <h3>Objective:</h3> This study aimed to evaluate the prognostic value of different types of KIT mutations and CBFB-MYH11 quantification in AML patients with CBFB-MYH11 who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) or autologous HSCT (auto-HSCT) and the clinical relevance of each transplant strategy in each risk group. <h3>Design:</h3> We retrospectively evaluated 88 patients who underwent allo-HSCT (n=60) or auto-HSCT (n=28). <h3>Setting:</h3> A referral center. <h3>Patients:</h3> Ninety-six consecutive AML patients with CBFB-MYH11 in remission who underwent HSCT at the Catholic Hematology Hospital between 2009 and 2019. After excluding two patients who underwent second HSCT and four patients without data for KIT mutations or pre-transplant CBFB-MYH11 MRD data, 88 patients were finally included in this study. <h3>Interventions:</h3> Not applicable. <h3>Main Outcome Measures:</h3> We retrospectively compared survival outcomes according to different types of KIT mutations and CBFB-MYH11 MRD levels. <h3>Results:</h3> The D816V KIT mutation was significantly associated with post-transplant relapse, contrasting with other types of mutations in KIT. Pre- and post-transplant (3 months after transplant) CBFB-MYH11 MRD assessments were useful for predicting post-transplant relapse and poor survival. The optimal threshold was determined as a 2-log reduction at both time points. In multivariate analysis, the D816V KIT mutation and CBFB-MYH11 MRD assessments were independently associated with post-transplant relapse and survival. Stratification by D816V KIT and pre-transplant CBFB-MYH11 MRD status further distinguished the risk of relapse and survival. Auto-HSCT was superior to allo-HSCT in MRD-negative patients without D816V KIT, while allo-HSCT trended to be superior to auto-HSCT in patients with MRD positivity or the D816V KIT mutation. <h3>Conclusions:</h3> This study demonstrated the differentiated prognostic value of the D816V KIT mutation in AML with CBFB-MYH11 and clarified the optimal time points and thresholds for CBFB-MYH11 MRD monitoring in the setting of HSCT.

Protein tyrosine phosphatase receptor type E (PTPRE) regulates the activation of wild-type KIT and KIT mutants differently

Activation of receptor tyrosine kinases needs tight control by tyrosine phosphatases to keep their normal function. In this study, we investigated the regulation of activation of the type III receptor tyrosine kinase KIT by protein tyrosine phosphatase receptor type E (PTPRE). We found that PTPRE can associate with wild-type KIT and inhibit KIT activation in a dose-dependent manner, although the activation of wild-type KIT is dramatically inhibited even when PTPRE is expressed at low level. The D816V mutation of KIT is the most frequently found oncogenic mutation in mastocytosis, and we found that PTPRE can associate and inhibit the activation of KIT/D816V in a dose dependent manner, but the inhibition is much weaker compared with wild-type KIT. Similar to mastocytosis, KIT mutations are the main oncogenic mutations in gastrointestinal stromal tumors (GISTs) although GISTs carry different types of KIT mutations. We further studied the regulation of the activation of GISTs-type KIT mutants and other mastocytosis-type KIT mutants by PTPRE. Indeed, PTPRE can almost block the activation of GISTs-type KIT mutants, while the activation of mastocytosis-type KIT mutants is more resistant to the inhibition of PTPRE. Taken together, our results suggest that PTPRE can associate with KIT, and inhibit the activation of both wild-type KIT and GISTs-type KIT mutants, while the activation of mastocytosis-type KIT mutants is more resistant to PTPRE.

Prognostic Impacts of D816V KIT Mutation and Peri-Transplant RUNX1-RUNX1T1 MRD Monitoring on Acute Myeloid Leukemia with RUNX1-RUNX1T1.

Simple SummaryAcute myeloid leukemia (AML) with RUNX1-RUNX1T1 is a heterogeneous disease entailing different prognoses. Patients with high-risk features can benefit from allogeneic hematopoietic stem cell transplantation (HSCT) or autologous HSCT. However, insufficient data about major risk factors, such as KIT mutations and measurable residual disease (MRD) status for relapse, make it difficult to clarify the benefit of each transplant strategy. Moreover, limited data are available to elucidate the exact prognostic impacts of different types of KIT mutations and optimal thresholds or time points for RUNX1–RUNX1T1 MRD assessment, particularly in the setting of HSCT. Given the lack of prospective study, the current retrospective study, including a large cohort of high-risk AML patients with RUNX1–RUNX1T1, firstly demonstrated the differentiated prognostic impact of D816V KIT mutation among various KIT mutations and clarified optimal time points and thresholds for RUNX1–RUNX1T1 MRD monitoring in the setting of HSCT.The prognostic significance of KIT mutations and optimal thresholds and time points of measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with RUNX1-RUNX1T1 remain controversial in the setting of hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated 166 high-risk patients who underwent allogeneic (Allo-HSCT, n = 112) or autologous HSCT (Auto-HSCT, n = 54). D816V KIT mutation, a subtype of exon 17 mutations, was significantly associated with post-transplant relapse and poor survival, while other types of mutations in exons 17 and 8 were not associated with post-transplant relapse. Pre- and post-transplant RUNX1–RUNX1T1 MRD assessments were useful for predicting post-transplant relapse and poor survival with a higher sensitivity at later time points. Survival analysis for each stratified group by D816V KIT mutation and pre-transplant RUNX1–RUNX1T1 MRD status demonstrated that Auto-HSCT was superior to Allo-HSCT in MRD-negative patients without D816V KIT mutation, while Allo-HSCT was superior to Auto-HSCT in MRD-negative patients with D816V KIT mutation. Very poor outcomes of pre-transplant MRD-positive patients with D816V KIT mutation suggested that this group should be treated in clinical trials. Risk stratification by both D816V KIT mutation and RUNX1–RUNX1T1 MRD status will provide a platform for decision-making or risk-adapted therapeutic approaches.

Paediatric mastocytosis: long-term follow-up of 53 patients with whole sequencing of KIT. A prospective study.

Mastocytosis is a heterogeneous group of clinical disorders characterized by the abnormal accumulation of mast cells. The adult and paediatric forms differ in their clinical and genetic features and outcomes. To describe the clinical evolution of a well-characterized cohort of paediatric mastocytosis (PM), and to analyse the relationship between KIT mutation and the clinical course. This was a prospective cohort study performed at the National Clinical Reference Center for Mastocytosis. Diagnosis was confirmed by identification of KIT mutation on lesional skin biopsy. Mastocytosis subtype, mast cell mediator-related symptoms (MC MRS) and clinical course were recorded. Fifty-three patients with PM and >4years of disease course were enrolled. The mean±SD age at the final evaluation was 13·2±4·8years. The main outcome was the type of KIT mutation as a predictor of evolution and clinical characteristics. Patients presented with maculopapular cutaneous mastocytosis (n=44), diffuse cutaneous mastocytosis (n=6) or mastocytoma (n=3). The mean duration of disease was 12·1years. Substantial or partial cutaneous regression (18 of 53 and 16 of 53), stabilization or aggravation (16 of 53) and complete cutaneous regression (three of 53) were noted. MC MRS mainly regressed (21 of 53). For 22 patients, evolution of MC MRS and evolution of cutaneous lesions were different. No significant association between evolution and KIT mutation or between evolution and type of cutaneous mastocytosis was found. A late onset of the disease (after 2years) is associated with worse evolution. PM is not systematically self-regressive. MC MRS manifestations and cutaneous lesions can persist or increase overtime. KIT mutation is not a predictor of evolution.

The Prognostic Impact of KIT D816 Mutations in Core Binding Factor Acute Myeloid Leukemia

Background: Core binding factor acute myeloid leukemia (CBF-AML) is a form of AML associated with the chromosomal abnormalities t(8;21)(q22;q22) (t(8;21)AML) and inv(16)(p13.1q22)/t(16;16)(p13.1;q22) (inv16 AML). It accounts for approximately 8% of AML cases and is considered to be a karyotype with a favorable prognosis. Mutations of c-kit gene which constitute type III tyrosine kinase receptor were found in approximately 30% of patients with CBF-AML. In CBF-AML, KIT mutation is observed mainly in two domains: the extracellular domain (exon8), and the tyrosine kinase domain (exon17), and has frequently been reported to be an unfavorable prognostic factor for early relapse and for shorter survival. On the other hand, some reports conclude that KIT mutation has no prognostic impact in CBF-AML, and in 2016's guidelines of NCCN, CBF-AML with KIT gene mutation was not assigned to the intermediate prognosis group. One potential reason why the reported prognostic impact of KIT mutation in CBF-AML differs between studies is that CBF-AML cases with t(8;21) and those with inv(16) have differing clinical profiles. Another reason is that KIT mutation occurs at various locations on the gene. We have previously reported that KIT D816 in CBF-AML is associated with a higher relapse rate than KIT N822K and has unfavorable prognosis. The aim of the present study was to clarify that these two types of KIT mutations have differing prognostic impacts in CBF-AML.Methods: We analyzed 138 cases of CBF-AML who achieved complete remission (CR), retrospectively. Mutation analyses were performed by direct sequence analysis Mutation Biased PCR, direct sequence analysis, and the next-generation sequencer Ion PGMTM.Results: Average age was 45 years (15-80 years). The inv16 AMLand t(8;21) AMLwere28 cases and 110 cases, respectively. KIT mutations were found in 62 (45%) cases of patients with CBF-AML. Patients with KIT mutations were significantly more frequently associated with male gender (p=0.029) and higher white blood cell count (>1×104/μl) (p=0.002) compared to KIT wild type cases. No significant differences were found in other clinical characteristics between those with and without KIT mutations. Analyzing all CBF-AML patients and inv16 AML, rates of relapse free survival (RFS) and overall survival (OS) in those with KIT mutations were significantly lower than those in patients without c-kit mutations (All patients: RFS, 38% vs 58% at 3 years after CR1, p=0.040; OS, 61% vs 77%, p=0.033; inv16 AML: RFS, 46% vs 82%, p=0.044; OS, 75% vs 100%, p=0.045). However, there was no significant difference between t(8;21)AML with and without KIT mutations (RFS, 35% vs 51%, p=0.219, OS, 58% vs 70%, p=0.161). Next, we analyzed prognosis of CBF-AML according to the types of c-kit mutations. D816, N822K, co-expression of D816 and N822K, and other mutations of KIT gene were detected in 29 cases (21%, D816A:1 case, D816Y:2 cases, D816V:26 cases), 20 (14%), 7 (5%, D816H:1 case, D816V:6 cases), and 6 cases (4%), respectively. (RFS, 58.2% vs 21.6% vs 58.9% vs 14.3% vs 60.0%, p=0.005; OS,77.2% vs 40.0% vs 78.9% vs 60.0% vs 100.0%, p<0.001) Rates of RFS and OS in patients with D816 or both of D816 and N822K (D816-positive) were significantly lower than those in patients with KIT wild type or other KIT mutations (D816-negative) (RFS, 20% vs 59%, p<0.001; OS, 43% vs 79%, p<0.001). In stratified analysis of inv16 AML and t(8;21)AML, rates of RFS and OS in the D816-positive patients were significantly lower than those in D816-negative patients (inv16 AML: RFS, 25% vs 85%, p=0.001; OS, 60% vs 100%, p=0.005; t(8;21)AML: RFS, 18% vs 52%, p=0.019; OS, 38% vs 73%, p<0.001). Multivariate analyses for RFS and OS showed that D816 was an independent unfavorable prognostic factor (RFS, HR 2.06, p=0.014; OS, HR 3.12, p=0.003). Consolidation using high-dose AraC was shown to be independently associated with improved RFS.Conclusions: In ASH meeting of 2014, we showed that the D816V confers higher proliferation activity by JAK-STAT and Src family kinase compared to N822K by in vitro assay. In this study, we showed that patients with D816 had a significantly poorer prognosis than those with N822K or other mutations of KIT in CBF-AML. Going forward, a study is needed in which a trial of autologous stem cell transplantation in first CR or conventional chemotherapy with dasatinib or novel molecular target drug such as PKC 412 for CBF-AML with D816. DisclosuresNo relevant conflicts of interest to declare.

Clinicopathological significance of c-KIT mutation in gastrointestinal stromal tumors: a systematic review and meta-analysis.

Many types of KIT mutations have been observed in gastrointestinal stromal tumors (GISTs), but their prognostic and predictive significance are still unclear. A meta-analysis and literature review were conducted to estimate the contribution of KIT mutations in prognostic parameters and clinic-pathological significance of GISTs. A total of 18 relevant articles from PubMed, EMBASE and Web of Science databases were included in this study. The frequency of KIT mutation was significantly increased in the GIST patients with higher mitosis (≥5/50 high-power fields (HPFs) and larger size (≥5 cm) of tumors than in those with lower MI (≤5/50HPFs) and smaller size (≤5 cm) of GISTs respectively. The rate of KIT mutation was not significantly changed between GISTs in stomachs and in small intestines. KIT mutational status has prognostic significance for patients’ outcome. GIST patients with KIT exon 9 mutations have higher risk of progression than those with exon 11 mutations. 5 year relapse-free survival (RFS) rate was significantly higher in patients with KIT exon 11 deletion than in those with other type of KIT exon 11 mutations. The deletion involving KIT exon 11, particularly codons 557–558, is a valuable predictor of prognosis for patients with GISTs.

KIT and PDGFRA mutations and PDGFRA immunostaining in gastrointestinal stromal tumors

In the present study, we investigated the association of PDGFRA and KIT mutations as well as PDGFRA immunohistochemical expression with clinicopathologic features and prognosis in a series of gastrointestinal stromal tumors (GISTs). Tumor DNA from 40 GISTs was sequenced for the presence of mutations in KIT exons 9, 11, 13 and 17, and in PDGFRA exons 12 and 18. Tissue sections were stained with polyclonal anti-PDGFRA antibody. KIT mutations occurred in 26 cases. There were 13 deletions, 6 substitutions, 3 deletion-substitutions, 3 duplications and 1 insertion. Tumors with KIT deletions/insertion were large with a high mitotic index (MI), and were associated with a high rate of symptoms at diagnosis, invasion into adjacent organs, distant metastasis, relapse and a short disease-free survival (DFS). PDGFRA mutations occurred in 6 gastric GISTs. There were 4 deletions and 2 substitutions. Tumors with PDGFRA mutations were small, with a low MI and Ki67 score, and were associated with a very low rate of symptoms at diagnosis, invasion into adjacent organs and distant metastasis. PDGFRA immunopositivity was found in 23 cases: a peculiar 'dotlike' staining was found in 5 out of 6 PDGFRA mutated cases. Patients with positive PDGFRA immunostaining had a longer DFS than those with negative staining. Our data confirm that the type of KIT mutation is associated with various clinicopathologic features of GISTs, and indicate that PDGFRA mutations are associated with rather indolent tumors. PDGFRA immunopositivity reflects PDGFRA mutational status and is associated with a favorable outcome.

KIT polymorphisms and mutations determine responses of neoplastic mast cells to bafetinib (INNO-406)

Advanced systemic mastocytosis (SM) is characterized by uncontrolled growth of neoplastic mast cells (MC) and drug resistance. The tyrosine kinase receptor KIT is often mutated and activated and thus contributes to malignant growth of MC. Therefore, KIT-targeting drugs are currently tested for their ability to block growth of malignant MC. We determined the effects of the multikinase inhibitor INNO-406 (bafetinib) on primary neoplastic MC, the canine mastocytoma cell line C2, the human MC leukemia cell line HMC-1.1 bearing the KIT mutant V560G, and HMC-1.2 cells harboring KIT V560G and KIT D816V. INNO-406 was found to inhibit proliferation in HMC-1.1 cells (IC(50): 30-40 nM), but not in HMC-1.2 cells or primary neoplastic cells in patients with KIT D816V-positive SM. In canines, growth-inhibitory effects of INNO-406 were seen in C2 cells (IC(50): 50-100 nM) exhibiting a KIT exon 11 internal tandem-duplication and in primary neoplastic MC harboring wild-type exon 11, whereas no effects were seen in MC exhibiting a polymorphism at amino acid 581 in exon 11. INNO-406 was found to block KIT phosphorylation and expression in HMC-1.1 cells and C2 cells, but not in HMC-1.2 cells, whereas Lyn-phosphorylation was blocked by INNO-406 in all types of MC. In neoplastic MC, the major target of INNO-406 appears to be KIT. Drug responses may depend on the presence and type of KIT mutation. In human MC, the KIT D816V mutant introduces resistance, and in canine mastocytomas, an exon 11 polymorphism may be indicative of resistance against INNO-406.

Anti–leukemia Activity of a Novel KIT Selective Inhibitor KI–328.

Abstract 4146 IntroductionKIT is a type III receptor tyrosine kinase together with FLT3, PDGFR and FMS. The interaction of KIT and its ligand stem cell factor (SCF) plays an important role in the cell survival, proliferation and differentiation. Activating mutations of KIT have been demonstrated in several kinds of human malignancies, such as mastocytoma, gastrointestinal stromal tumor, and acute myeloid leukemia (AML). Since KIT mutation seems a poor prognostic factor in CBF leukemia and the KIT expression is observed in most AML cells, KIT serves a molecular target for the treatment of AML. To date, several small molecules have been demonstrated to have a potency against KIT kinase, while KIT selective inhibitors are not yet developed for the clinical use. We recently developed a novel KIT selective inhibitor KI-328, and evaluated here its inhibitory effect on wild-type (Wt) and mutant KIT kinases. MethodsWe identified 5 types of KIT mutations (D816V, M541L, V540L, T417F/del418-419 and N822K) in AML cells, and established these mutant-KIT, as well as Wt-KIT, expressing IL-3-dependent mouse myeloid precursor 32D cells. Using these Wt- and mutant KIT expressing 32D cells, we examined the anti-leukemia activity of KI-328 in comparison with another potent KIT inhibitors. ResultsIn Wt- and M541L-KIT expressing cells, KITs were phosphorylated by the SCF stimulation. In contrast, mutant KITs were constitutively phosphorylated in D816V-, V540L-, T417F-, and N822K-KIT expressing cells. However, the autonomous proliferation was observed only in D816V-KIT expressing cells, and the other mutant KIT expressing cells required SCF for their proliferations like Wt-KIT expressing cells. These results were confirmed by the colony formation ability in the semi-liquid media, where only D816V-KIT expressing cells could form the colony without any growth factors. The growth inhibitory effect of KI-328 was, therefore, examined in the existence of 50 ng/ml of SCF. KI-328 inhibited the growth of Wt-, M541L-, V540L-, T417F- and N822K-KIT expressing cells with the GI50 value 127 nM, 229 nM, 575 nM, 445 nM and 997 nM, respectively. The cell cycle analysis showed the KI-328 increased sub-G1 populations in these cells at each GI50 value. In consistent with the growth inhibitory effects, KI-328 potently inhibited the phosphorylations of Wt- and mutant KITs except D816V as well as their downstream molecules STAT3, AKT, MAPK at the concentration of over the GI50 value, indicating the proof of concept that KI-328 inhibits the growth of these cells by the KIT kinase inhibition. However, the significant growth inhibition was not observed in D816V-KIT expressing cells up to the 5 μM, and more than 2 μM of KI-328 were required for the de-phosphorylation of D816V-KIT. We further examined whether another potent KIT inhibitors showed the different sensitivities between D816V-KIT and Wt-KIT. Multi-kinase inhibitors such as dasatinib and sunitinib showed the same growth inhibitory effects on D816V- and Wt-KIT expressing cells: each GI50 value against D816V- and Wt-KIT was 43 nM and 72 nM, and 116 nM and 206 nM, respectively. In contrast, imatinib, which is relatively selective against KIT kinase, did not inhibit the growth of the D816V-KIT expressing cells like KI-328. ConclusionsWe demonstrated that KI-328 is a potent and selective KIT inhibitor. Although KI-328 did not show the significant growth inhibitory effect on the D816V-KIT expressing 32D cells up to the 5 μM, G-CSF mediating neutrophil maturation was observed when those were treated with less than 1 μM of KI-328, indicating that KI-328 has a weak potency against the D816V-KIT kinase. Therefore, the combination therapy with another potent KIT inhibitors, such as HSP90 inhibitor, might conquer the resistance against the D816V-KIT kinase. Since the kinase inhibitory profile seemed to be associated with the resistance against the D816V-KIT kinase, the structural analysis of the D816V-KIT is required for developing more potent inhibitors against all mutant KIT kinases. Disclosures:Shiotsu:Kyowa Hakko Kirin Co., Ltd.: Employment. Kiyoi:Kyowa Hakko Kirin Co. Ltd.: Consultancy; Novartis Pharma Co. Ltd.: Research Funding. Ishida:Kyowa Hakko Kirin Co., Ltd.: Employment. Naoe:Kyowa Hakko Kirin Co., Ltd. : Research Funding; Chugai Pharmaceutical Co.,Ltd.: Research Funding; Wyeth K.K.: Research Funding.

Multiple Gastrointestinal Stromal Tumors: Clinicopathologic and Genetic Analysis of 12 Patients

Multiple gastrointestinal stromal tumors (GISTs) are extremely rare and usually associated with type 1 neurofibromatosis and familial GIST. The aim of this study was to investigate the clinical, phenotypic, and genetic characteristics of multiple GISTs to gain insights into their underlying pathogenesis and clinical behavior. Forty-seven paraffin blocks of multiple GISTs from 12 patients were analyzed. Genomic DNA was extracted from the tumor and normal mucosa and mutations for 4 exons of KIT gene and 3 exons of PDGFRA gene were determined. Among 12 patients with multiple GISTs, 5 were sporadic, 2 were familial with germline mutations of KIT gene, and 5 were associated with type 1 neurofibromatosis. All but 1 sporadic and familial multiple GISTs showed mutations of KIT gene shared by the same mutation on each GIST mass within a patient. But in 1 sporadic case, different types of KIT mutations were observed. Two familial multiple GIST cases showed diffuse involvement of the gastrointestinal tract with diffuse hyperplasia of interstitial cell of Cajal. Multiple GISTs associated with type 1 neurofibromatosis were located in the jejunum and harbored no mutations of KIT or PDGFRA. Different types of KIT gene mutation found in our case raise a possibility that recurrence of GISTs within a gastrointestinal tract may have a chance to be a rare occurrence of multiple primary GISTs instead of true recurrence. Multiple GISTs show unique clinical, phenotypic, and genotypic characteristics that are dependent on the particular underlying mechanisms, but the overall prognosis is favorable regardless of the numbers or phenotype of GISTs.

Differential protein expression profile in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) arise from the interstitial cells of Cajal through gain of function mutations of the oncogene KIT. Imatinib offers the first effective treatment for patients with GISTs, but the therapeutic outcome strongly depends on the type of KIT mutation. We used ProteinChip technology to investigate whether GISTs with different KIT mutations express different proteins. In total, 154 proteins were significantly differentially expressed in GISTs with exon 9 KIT mutation compared to GISTs with exon 11 KIT mutation.

Gastrointestinal stromal tumors show site-dependent differ-ences in the patterns of chromosomal imbalances and in the type of KIT mutation

Gastrointestinal stromal tumors show site-dependent differ-ences in the patterns of chromosomal imbalances and in the type of KIT mutation