Gastrointestinal Stromal Tumors With KIT Exon 11 Deletions Are Associated With Poor Prognosis
2006; Elsevier BV; Volume: 130; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2006.01.043
ISSN1528-0012
AutoresJohanna C. Andersson‐Assarsson, Per Bümming, Jeanne M. Meis‐Kindblom, Harri Sihto, Nina N. Nupponen, Heikki Joensuu, Anders Odén, Bengt Gustavsson, Lars‐Gunnar Kindblom, Bengt Nilsson,
Tópico(s)Neurofibromatosis and Schwannoma Cases
ResumoBackground & Aims: Gain-of-function mutations in the KIT receptor tyrosine kinase gene and rare mutations in the platelet-derived growth factor receptor α (PDGFRA) gene are important events in gastrointestinal stromal tumor (GIST) development. Different mutations are reportedly associated with distinctive phenotypes and possibly clinical behavior. We investigated the correlation among mutation type, phenotype, and clinical course in a preimatinib, population-based series of GIST with long-term follow-up. Methods: Genomic DNA from 177 GIST patients was analyzed for KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 mutations using denaturating high-performance liquid chromatography and bidirectional sequencing. Results:KIT exon 11 mutations were detected in 101 of 177 GIST (61 deletions, 23 missense mutations, and 17 duplications); wild-type (WT) KIT and PDGFRA were detected in 63; KIT exon 9 and exon 17 mutations in 6 and 1, respectively; and PDGFRA exons 12 and 18 mutations in 3 each. GIST >5 cm vs GIST ≤1 cm had mutations in 73% and 33%, respectively. KIT exon 11 deletions were significantly associated with a higher proportion of high risk or overtly malignant groups compared with WT GIST. KIT exon 11 deletions adversely affected outcome. KIT exon 11 duplications and exon 9 mutations were found exclusively in gastric and small intestinal GIST, respectively. Conclusions: KIT exon 11 deletion is an independent adverse prognostic factor in patients with GIST. Background & Aims: Gain-of-function mutations in the KIT receptor tyrosine kinase gene and rare mutations in the platelet-derived growth factor receptor α (PDGFRA) gene are important events in gastrointestinal stromal tumor (GIST) development. Different mutations are reportedly associated with distinctive phenotypes and possibly clinical behavior. We investigated the correlation among mutation type, phenotype, and clinical course in a preimatinib, population-based series of GIST with long-term follow-up. Methods: Genomic DNA from 177 GIST patients was analyzed for KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 mutations using denaturating high-performance liquid chromatography and bidirectional sequencing. Results:KIT exon 11 mutations were detected in 101 of 177 GIST (61 deletions, 23 missense mutations, and 17 duplications); wild-type (WT) KIT and PDGFRA were detected in 63; KIT exon 9 and exon 17 mutations in 6 and 1, respectively; and PDGFRA exons 12 and 18 mutations in 3 each. GIST >5 cm vs GIST ≤1 cm had mutations in 73% and 33%, respectively. KIT exon 11 deletions were significantly associated with a higher proportion of high risk or overtly malignant groups compared with WT GIST. KIT exon 11 deletions adversely affected outcome. KIT exon 11 duplications and exon 9 mutations were found exclusively in gastric and small intestinal GIST, respectively. Conclusions: KIT exon 11 deletion is an independent adverse prognostic factor in patients with GIST. Gastrointestinal stromal tumor (GIST), the most common nonepithelial neoplasm of the gastrointestinal tract, has historically been problematic both conceptually and clinically. Until recently, its origin and pathogenesis have been unclear. Predictive factors have been difficult to define, and survivals of patients with malignant GIST treated solely with surgery have been disappointing. Recent studies have shown that GIST shares many phenotypic features with the interstitial cells of Cajal and that they almost uniformly express the type III tyrosine kinase receptor KIT1Kindblom L.G. Remotti H.E. Aldenborg F. Meis-Kindblom J.M. Gastrointestinal pacemaker cell tumor (GIPACT) gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal.Am J Pathol. 1998; 152: 1259-1269PubMed Google Scholar, 2Sarlomo-Rikala M. Kovatich A.J. Barusevicius A. Miettinen M. CD117 a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34.Mod Pathol. 1998; 11: 728-734PubMed Google Scholar that is encoded by the proto-oncogene KIT located on chromosome 4q11-12.3Yarden Y. Kuang W.J. Yang-Feng T. Coussens L. Munemitsu S. 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Inhibition of KIT tyrosine kinase activity a novel molecular approach to the treatment of KIT-positive malignancies.J Clin Oncol. 2002; 20: 1692-1703Crossref PubMed Scopus (583) Google Scholar Response to imatinib mesylate has been found to correlate with KIT mutational status; GIST with exon 11 mutations respond more frequently to imatinib mesylate than tumors with other KIT mutations and wild-type KIT.11Heinrich M.C. Corless C.L. Demetri G.D. Blanke C.D. von Mehren M. Joensuu H. McGreevey L.S. Chen C.J. Van den Abbeele A.D. Druker B.J. Kiese B. Eisenberg B. Roberts P.J. Singer S. Fletcher C.D. Silberman S. Dimitrijevic S. Fletcher J.A. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor.J Clin Oncol. 2003; 21: 4342-4349Crossref PubMed Scopus (2010) Google Scholar Clinical studies regarding the correlation of exon 11 mutations with disease outcome have been contradictory. Studies by Ernst et al,12Ernst S.I. Hubbs A.E. Przygodzki R.M. 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Kim B.S. Lee J.S. Prognostic significance of c-kit mutation in localized gastrointestinal stromal tumors.Clin Cancer Res. 2004; 10: 3076-3081Crossref PubMed Scopus (148) Google Scholar have indicated that GIST with exon 11 KIT mutations have a more aggressive course than those with wild-type KIT, whereas studies by Andersson et al,17Andersson J. Sjogren H. Meis-Kindblom J.M. Stenman G. Aman P. Kindblom L.G. The complexity of KIT Gene mutations and chromosome rearrangements and their clinical correlation in gastrointestinal stromal (pacemaker cell) tumors.Am J Pathol. 2002; 160: 15-22Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar Sakurai et al,18Sakurai S. Fukasawa T. Chong J.M. Tanaka A. Fukayama M. C-kit gene abnormalities in gastrointestinal stromal tumors (tumors of interstitial cells of Cajal.Jpn J Cancer Res. 1999; 90: 1321-1328Crossref PubMed Scopus (128) Google Scholar and Wardelmann et al19Wardelmann E. Neidt I. Bierhoff E. Speidel N. Manegold C. Fischer H.P. Pfeifer U. Pietsch T. C-kit mutations in gastrointestinal stromal tumors occur preferentially in the spindle rather than in the epithelioid cell variant.Mod Pathol. 2002; 15: 125-136Crossref PubMed Scopus (108) Google Scholar have not. Additionally, Corless et al7Corless C.L. McGreevey L. Haley A. Town A. Heinrich M.C. KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size.Am J Pathol. 2002; 160: 1567-1572Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar have reported a high frequency of KIT mutations in very small, incidentally detected GIST; these findings suggest that KIT mutations are an early event in the development of GIST.7Corless C.L. McGreevey L. Haley A. Town A. Heinrich M.C. KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size.Am J Pathol. 2002; 160: 1567-1572Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar Correlation between other KIT mutations and clinical course has been reported in subgroups of GIST. Exon 9 mutations have been associated predominantly with small intestinal GIST that have an aggressive clinical course.20Antonescu C.R. Sommer G. Sarran L. Tschernyavsky S.J. Riedel E. Woodruff J.M. Robson M. Maki R. Brennan M.F. Ladanyi M. DeMatteo R.P. Besmer P. Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors.Clin Cancer Res. 2003; 9: 3329-3337PubMed Google Scholar, 21Lasota J. Kopczynski J. Sarlomo-Rikala M. Schneider-Stock R. Stachura T. Kordek R. Michal M. Boltze C. Roessner A. Stachura J. Miettinen M. KIT 1530ins6 mutation defines a subset of predominantly malignant gastrointestinal stromal tumors of intestinal origin.Hum Pathol. 2003; 34: 1306-1312Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Internal tandem duplications in the 3′-end of exon 11 have been observed primarily in gastric GIST with an indolent clinical course.20Antonescu C.R. Sommer G. Sarran L. Tschernyavsky S.J. Riedel E. Woodruff J.M. Robson M. Maki R. Brennan M.F. Ladanyi M. DeMatteo R.P. Besmer P. Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors.Clin Cancer Res. 2003; 9: 3329-3337PubMed Google Scholar, 22Lasota J. Dansonka-Mieszkowska A. Stachura T. Schneider-Stock R. Kallajoki M. Steigen S.E. Sarlomo-Rikala M. Boltze C. Kordek R. Roessner A. Stachura J. Miettinen M. Gastrointestinal stromal tumors with internal tandem duplications in 3′ end of KIT juxtamembrane domain occur predominantly in stomach and generally seem to have a favorable course.Mod Pathol. 2003; 16: 1257-1264Crossref PubMed Scopus (95) Google Scholar GIST with platelet-derived growth factor receptor α (PDGFRA) mutations have been reported to occur predominantly in gastric GIST with an epithelioid morphology and with little or no malignant potential; they also frequently lack KIT immunoreactivity.23Heinrich M.C. Corless C.L. Duensing A. McGreevey L. Chen C.J. Joseph N. Singer S. Griffith D.J. Haley A. Town A. Demetri G.D. Fletcher C.D. Fletcher J.A. PDGFRA activating mutations in gastrointestinal stromal tumors.Science. 2003; 299: 708-710Crossref PubMed Scopus (2063) Google Scholar, 24Lasota J. Dansonka-Mieszkowska A. Sobin L.H. Miettinen M. A great majority of GISTs with PDGFRA mutations represent gastric tumors of low or no malignant potential.Lab Invest. 2004; 84: 874-883Crossref PubMed Scopus (268) Google Scholar, 25Medeiros F. Corless C.L. Duensing A. Hornick J.L. Oliveira A.M. Heinrich M.C. Fletcher J.A. Fletcher C.D. KIT-negative gastrointestinal stromal tumors proof of concept and therapeutic implications.Am J Surg Pathol. 2004; 28: 889-894Crossref PubMed Scopus (428) Google Scholar, 26Sakurai S. Hasegawa T. Sakuma Y. Takazawa Y. Motegi A. Nakajima T. Saito K. Fukayama M. Shimoda T. Myxoid epithelioid gastrointestinal stromal tumor (GIST) with mast cell infiltrations a subtype of GIST with mutations of platelet-derived growth factor receptor α gene.Hum Pathol. 2004; 35: 1223-1230Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar Different types of KIT exon 11 mutations have also been reported to be prognostically significant. Singer et al reported 89% ± 11% 5-year recurrence-free survival in 9 patients with GIST having missense exon 11 mutations compared with 40% ± 8% in 39 patients having other types of KIT mutations, most of which were exon 11 deletions.27Singer S. Rubin B.P. Lux M.L. Chen C.J. Demetri G.D. Fletcher C.D. Fletcher J.A. Prognostic value of KIT mutation type, mitotic activity, and histologic subtype in gastrointestinal stromal tumors.J Clin Oncol. 2002; 20: 3898-3905Crossref PubMed Scopus (405) Google Scholar The deletion site of the mutation in exon 11 may also be prognostically significant. Wardelmann et al reported a significantly poorer disease-free survival among 21 patients with GIST having KIT exon 11 deletions involving Trp557 and/or Lys558 compared with 34 patients having tumors with other types of exon 11 mutations or wild-type (WT) KIT.28Wardelmann E. Losen I. Hans V. Neidt I. Speidel N. Bierhoff E. Heinicke T. Pietsch T. Buttner R. Merkelbach-Bruse S. Deletion of Trp-557 and Lys-558 in the juxtamembrane domain of the c-kit protooncogene is associated with metastatic behavior of gastrointestinal stromal tumors.Int J Cancer. 2003; 106: 887-895Crossref PubMed Scopus (212) Google Scholar Our study aimed to analyze further the correlation among different types of KIT and PDGFRA mutations and tumor phenotype, risk group assessment, and clinical course in a large population-based series of patients with GIST from the preimatinib era. All potential cases of GIST diagnosed and treated from 1983 through 2000 within Västra Götaland, a province in western Sweden with a population of 1.3–1.6 million, were retrieved and analyzed.29Nilsson B. Bumming P. Meis-Kindblom J.M. Oden A. Dortok A. Gustavsson B. Sablinska K. Kindblom L.G. Gastrointestinal stromal tumors the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden.Cancer. 2005; 103: 821-829Crossref PubMed Scopus (1066) Google Scholar Criteria for the diagnosis of GIST included tumor site (in or adjacent to the gastrointestinal tract, mesentery, omentum, or retroperitoneum), spindled and/or epithelioid morphology, and immunoreactivity for CD117. A total of 259 patients with clinically detected primary GIST were identified. Of these, 11 were excluded because of insufficient tumor material and 15 because of poor DNA quality. Thus, a total of 233 patients with GIST were analyzed for KIT exon 11 mutations. Tumors lacking KIT exon 11 mutations were further analyzed for KIT exon 9 and PDGFRA exons 12 and 18 as well as KIT exon 13 and 17 mutations. In the Results section and the Statistical Analysis section, only tumors from 1990-2000 (n = 177) were included because of the low mutation detection frequency in the older samples from 1983-1989 (see below). This study was approved by the ethics committee of Göteborg University. Molecular analyses were performed on 246 tumors from 233 patients with GIST. Genomic DNA was prepared from 4 to 8, 5-μm-thick sections of paraffin-embedded tumor material using the QIAamp DNA Mini Kit (Qiagen, Hilden, Germany). Paraffin blocks were trimmed to minimize the amount of nonneoplastic tissue prior to sectioning. One hundred nanograms of genomic DNA was amplified in 50 μL PCR reactions using BD Advantage 2 or BD Sprint (Clonetech; BD Biosciences, Erembodegem, Belgium) according to the manufacturer’s instructions. Primer sequences and annealing temperatures were as previously described.30Andersson J. Sihto H. Meis-Kindblom J. Joensuu H. Nupponen N. Kindblom L.G. NF1 associated gastrointestinal stromal tumors have unique clinical, phenotypic and genotypic characteristics.Am J Surg Pathol. 2005; 29: 1170-1176Crossref PubMed Scopus (234) Google Scholar Heteroduplex formation was created by denaturating the polymerase chain reaction (PCR) products for 5 minutes at 95°C and then allowing the samples to reanneal by decreasing the temperature 1°C per minute to 45°C. Three to 8 μL of the PCR product were injected on a Helix DNA HPLC Column 50 × 3.0 mm (part No. CP28353; Varian Inc, Walnut Creek, CA) and eluted at a flow rate of 0.45 mL/min within a linear acetonitrile gradient created by mixing buffer A (100 mmol/L triethylammonium acetate and 0.1 mmol/L EDTA; Varian Inc.) and buffer B (100 mmol/L triethylammonium acetate, 0.1 mmol/L EDTA, and 25% acetonitrile; Varian Inc). Elution temperatures were as previously described.30Andersson J. Sihto H. Meis-Kindblom J. Joensuu H. Nupponen N. Kindblom L.G. NF1 associated gastrointestinal stromal tumors have unique clinical, phenotypic and genotypic characteristics.Am J Surg Pathol. 2005; 29: 1170-1176Crossref PubMed Scopus (234) Google Scholar Samples showing an aberrant elution profile were reextracted, reamplified, and purified by ExoSAP-IT (2.5 μL sample and 1 μL ExoSAP-IT per sequencing reaction; Amersham Biosciences, Uppsala, Sweden) and bidirectionally sequenced using Big Dye Terminators (version 1.1, Applied Biosystems, Foster City, CA). Sequence reactions were purified with ethanol and EDTA precipitation and analyzed on a 310 or a 3100 ABI Prism Genetic Analyzer (Applied Biosystems). All mutations were confirmed using an independent DNA isolate. In addition, to verify the validity of the denaturating high-performance liquid chromatography technique, all cases with a normal elution profile for KIT exon 11 were sequenced. Four additional mutations were detected among these cases, 1 of which only revealed the mutant sequence. For statistical analysis, Fisher exact test or Mann–Whitney test were performed to compare the distribution of WT KIT and PDGFRA and different mutations with regard to phenotypic characteristics, risk group assessment, risk score, and surviving patients free of disease. The Kaplan–Meier method31Kaplan E. Meier J. Nonparametric estimation from incomplete observations.J Am Stat Assoc. 1958; 53: 457-481Crossref Scopus (49615) Google Scholar was used to calculate estimates of the proportion of patients alive and without disease. Differences between mutation groups were compared using the log-rank test.32Peto R. Peto J. Asymptomatically efficient rank invariant test procedures.J R Stat. 1972; 135: 185-206Google Scholar In the Kaplan–Meier calculation, the time period from the initial histologic diagnosis until the first event (local recurrence, metastasis, persistent disease, or tumor-related death) was determined. Patients without evidence of local recurrence or metastasis at last follow-up (no evidence of disease [NED]; median follow-up, 74 months; range, 13–151 months) and patients who died because of non-GIST causes (dead of other causes [DOC]; median interval, 32 months; range 1–132 months) were censored. To analyze the independent influence of mutation type vs WT KIT and PDGFRA in a multivariate model (Poisson regression),33Breslow N.E. Day N.E. Statistical methods in cancer research. Volume II. The design and analysis of cohort studies. IARC Sci Publ, Lyon1987: 1-406Google Scholar a hazard function that included the previously documented independent prognostic factors of tumor size and proliferative index (Ki67 max %) was evaluated.29Nilsson B. Bumming P. Meis-Kindblom J.M. Oden A. Dortok A. Gustavsson B. Sablinska K. Kindblom L.G. Gastrointestinal stromal tumors the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden.Cancer. 2005; 103: 821-829Crossref PubMed Scopus (1066) Google Scholar P < .05 was considered statistically significant. Data from 177 patients (1990–2000) regarding mutation status, tumor site and size, mitotic rate (per 50 high-power fields [hpf]), proliferative index (Ki67 max %), risk group according to the consensus report,34Fletcher C.D. Berman J.J. Corless C. Gorstein F. Lasota J. Longley B.J. Miettinen M. O’Leary T.J. Remotti H. Rubin B.P. Shmookler B. Sobin L.H. Weiss S.W. Diagnosis of gastrointestinal stromal tumors a consensus approach.Hum Pathol. 2002; 33: 459-465Abstract Full Text Full Text PDF PubMed Scopus (2903) Google Scholar GIST risk score (tumor size in cm) + proliferative index as Ki67 max %,29Nilsson B. Bumming P. Meis-Kindblom J.M. Oden A. Dortok A. Gustavsson B. Sablinska K. Kindblom L.G. Gastrointestinal stromal tumors the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden.Cancer. 2005; 103: 821-829Crossref PubMed Scopus (1066) Google Scholar recurrent tumor disease (local recurrence and/or metastasis), and survival are summarized in Table 1.Table 1Summary of Clinicopathologic Data and Mutation Status in 177 Patients With GISTMutationSite (%)Size, median, cmMitotic rate, median MRProlif. index, median Ki67 max %RG (%)GRS (%)Recur (n)SurvivalDOD (n)AWD (n)DOC (n)NED (n)WTS: 524 (1–30) 7: 48KIT ex 11S: 547 (1–33)2–51 (0.5–50)VL, L, I: 51≤7: 34152161024Del n = 61SI: 41H, OM: 49>7: 66MissS: 435 (1–30) 7: 52DuplS: 1005 (1.5–20)2–52.5 (0.5–25)VL, L, I: 71≤7: 31230311n = 17SI: 0H, OM: 29>7: 69KIT ex 9S: 06 (2–15) 7: 50KIT ex 17S: 1002.5 7: 0PDGFRA ex 12S: 664 (2.5–4) 7: 66PDGFRA ex 18S: 663 (1–6) 7: 33AWD, alive with disease; cm, centimeter; Del, deletion; DOC, dead of other causes; DOD, dead of disease; Dupl, duplication; GRS, GIST risk score (maximum tumor size + Ki67 max %); H, high risk; I, intermediate risk; L, low risk; Miss, missense mutation; MR, mitotic rate (mitoses/50 hpf); Mutation, type of KIT or PDGFRA mutation; NED, no evidence of disease; OM, overtly malignant; Site, primary tumor site; Recur, recurrent disease; RG, risk group; SI, small intestine; S, stomach; VL, very low risk; WT, wild type KIT and PDGFRA. Open table in a new tab AWD, alive with disease; cm, centimeter; Del, deletion; DOC, dead of other causes; DOD, dead of disease; Dupl, duplication; GRS, GIST risk score (maximum tumor size + Ki67 max %); H, high risk; I, intermediate risk; L, low risk; Miss, missense mutation; MR, mitotic rate (mitoses/50 hpf); Mutation, type of KIT or PDGFRA mutation; NED, no evidence of disease; OM, overtly malignant; Site, primary tumor site; Recur, recurrent disease; RG, risk group; SI, small intestine; S, stomach; VL, very low risk; WT, wild type KIT and PDGFRA. In the older material (1983–1989), a low frequency of mutations was detected, overall mutation rate 37.5% (WT, 35/56; ex 11 deletion, 10/56; ex 11 missense, 6/56; ex 11 duplication, 4/56; ex 9 mutation, 1/56). In the more recent material (1990–2000), the overall mutation rate was 64%. In this part of the material that constituted the basis for this study, KIT exon 11 mutations were detected in tumors from 101 of 177 (57%) patients; deletions were detected in 61 (34%) patients (4 of these also had a missense mutation); missense mutations were detected in 23 (13%), and duplications in 17 (10%). Detailed mapping of these mutations is shown in Table 2, Table 3, Table 4, Table 5. KIT exon 9 mutations were detected in 6 patients (6/177, 3.3%), PDGFRA exon 12 and 18 mutations in 3 patients each (6/177, 3.3%), and KIT exon 17 mutation in 1 patient (1/177, 0.6%). No mutations were detected in KIT exon 13.Table 2Summary of 60 KIT Exon 11 DeletionsKIT550555560565570575580No. of casesKPMYEVQWKVVEEINGNNYVYIDPTQLPYDH10KPMYEVQ--VVEEINGNNYVYIDPTQLPYDH5KPMYEVQWKVVEEINGNNYVYIDPTQLPY-H4KPMYEVQC--VEEINGNNYVYIDPTQLPYDH3K-LYEVQWKVVEEINGNNYVYIDPTQLPYDH3KPMYEVQWK-VEEINGNNYVYIDPTQLPYDH2K----VQWKVVEEINGNNYVYIDPTQLPYDH2KPMY----KVVEEINGNNYVYIDPTQLPYDH2KPMYEVQ-------------------LPYDH1-----IQWKVVEEINGNNYVYIDPTQLPYDH1I----VQWKVVEEINGNNYVYIDPTQLPYDH1Q------RKVVEEINGNNYVYIDPTQLPYDH1K------WKVVEEINGNNYVYIDPTQLPYDH1K------------------LYIDPTQLPYDH1K-----QWKVVEEINGNNYVYIDPTQLPYDH1KP--EVQWKVVEEINGNNYVYIDPTQLPYDH1KPMY--QWKVVEEINGNNYVYIDPTQLPYDH1KPMY-----VVEEINGNNYVYIDPTQLPYDH1KPMYE----GVEEINGNNYVYIDPTQLPYDH1KPMYE-----VEEINGNNYVYIDPTQLPYDH1KPMYEV----VEEINGNNYVYIDPTQLPYDH1KPMYEV-----EEINGNNYVYIDPTQLPYDH1KPMYEVH----EEINGNNYVYIDPTQLPYDH1KPMYEVH--------------------PYDH1KPMYEVQ--FVEEINGNNYVYIDPTQLPYDH1KPMYEVQ---VEEINGNNYVYIDPTQLPYDH1KPMYEVQ-----EINGNNYVYIDPTQLPYDH1KPMYEVQW--VEEINGNNYVYIDPTQLPYDH1KPMYEVQW--IEEINGNNYVYIDPTQLPYDH1KPMYEVQW---EEINGNNYVYIDPTQLPYDH1KPMYEVQW-------RNNYVYIDPTQLPYDH1KPMYEVQWR--EEINGNNYVYIDPTQLPYDH1KPMYEVQWK---EINGNNYVYIDPTQLPYDH1KPMYEVQWKVVEE-----------TQLPYDH1KPMYEVQWKVVEEI-------------PYDH1KPMYEVQWKVVEEING--------TQLPYDH1KPMYEVQWKVVEEINGNNYVGS--TQLPYDH1KPMYEVQWKVVEEINGNNYVY------PYDH-, Deletion; boldface, missense mutation because of deletion; italics, missense mutation occurring together with deletion. Open table in a new tab Table 3One Tumor With a Deletion Involving KIT Intron 10-exon 11 BorderKIT75655Intron 10Exon 11756657567575685(nt)cccacagAAACCCATGTATGAAGTACAGTGGAAGCasec-------------------------------agNOTE. An identical deletion has been previously described by Corless et al37Corless C.L. McGreevey L. Town A. Schroeder A. Bainbridge T. Harrell P. Fletcher J.A. Heinrich M.C. KIT gene deletions at the intron 10-exon 11 boundary in GI stromal tumors.J Mol Diagn. 2004; 6: 366-370Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar and Chen et al.38Chen L.L. Sabripour M. Wu E.F. Prieto V.G. Fuller G.N. Frazier M.L. A mutation-created novel intra-exonic pre-mRNA splice site causes constitutive activation of KIT in human gastrointestinal stromal tumors.Oncogene. 2005; 24: 4271-4280Crossref PubMed Scopus (35) Google Scholar-, Deletion; nt, nucleotide. Open table in a new tab Table 4Summary of 23 Missense Mutations in KIT Exon 11550555560565570575580KITKPMYEVQWKVVEEINGNNYVYIDPTQLPYDHNo. of cases6KPMYEVQWKAVEEINGNNYVYIDPTQLPYDH3KPMYEVQWKDVEEINGNNYVYIDPTQLPYDH2KPMYEVQRKVVEEINGNNYVYIDPTQLPYDH2KPMYEVQGKVVEEINGNNYVYIDPTQLPYDH2KPMYEVQWKGVEEINGNNYVYIDPTQLPYDH1KPMYEVLWKVVEEINGNNYVYIDPTQLPYDH1KPMYEVQWKVDEEINGNNYVYIDPTQLPYDH1KPMYEVQWTGVEEINGNNYVYIDPTQLPYDH1KPVYEVQWKVVEEINGNNYVYIDPTQLPYDH1KPMYEVQWKVVEEINRNNDVYIDPTQLPYDH1KPMYEVQWKVVEEINGNNYVYIDPTQLSYDH1KPMYEVQWKVVEEINGNNYVYIDPTQPPYDH1KPMYEVQCEVVEEINGNNYVYIDPTQLPYDHBoldface, missense mutation. Open table in a new tab Table 5Summary of 17 Duplications in KIT Exon 11570575580585590KITVYIDPTQLPYDHKWEFPRNRLSFNo. of cases2VYIDPTQLPYDDPTQLPYDHKWEFPRNRLSF2VYIDPTQLPYDHKWEFPRTQLPYDHKWEFPRNRLSF1VYIDPYIDPTQLPYDHKWEFPRNRLSF1VYIDPTQLPYDQDPTQLPYDHKWEFPRNRLSF1VYIDPTQLPYDIDPTQLPYDHKWEFPRNRLSF1VYIDPTQLPYPTQLPYDHKWEFPRNRLSF1VYIDPTQLPYDHKWEFPRPTQLPYDHKWEFPRNRLSF1VYIDPTQLPQLPYDHKWEFPRNRLSF1VYIDPTQLPYDHKWEFPQLPYDHKWEFPRNRLSF1VYIDPTQLPYDHKWEFPRNRLQLPYDHKWEFPRNRLSF1VYIDPTQLPYDHKWEFPRNRLSFQLPYDHKWEFPRNRLSF1VYIDPTQLPYDHKWEFPRNRLPYDHKWEFPRNRLSF1VYIDPTQLPYDHKWEFPRNRLSFPYDHKWEFPRNRLSF1VYIDPTQLPYDHKYDHKWEFPRNRLSF1VYIDPTQLPYDHKWEFPRNRLSFDHKWEFPRNRLSFNormal sequence, italic; duplicated sequence, boldface; missense mutation due to duplication, italic and boldface. Open table in a new tab -, Deletion; boldface, missense mutation because of deletion; italics, missense mutation occurring together with deletion. NOTE. An identical deletion has been previously described by Corless et al37Corless C.L. McGreevey L. Town A. Schroeder A. Bainbridge T. Harrell P. Fletcher J.A. Heinrich M.C. KIT gene deletions at the intron 10-exon 11 boundary in GI stromal tumors.J Mol Diagn. 2004; 6: 366-370Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar and Chen et al.38Chen L.L. Sabripour M. Wu E.F. Prieto V.G. Fuller
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