Top

World Journal of Surgical Oncology

Published in:

Open Access 01-12-2014 | Research

Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumors: a meta-analysis

Authors: Liang Zong, Ping Chen

Published in: World Journal of Surgical Oncology | Issue 1/2014

Abstract

Background

The postulated relationship between KIT/PDGFRA mutations and their prognostic value in gastrointestinal stromal tumors (GISTs) has generated intense attention during the past decade, despite the fact that a great deal of studies have been conducted on this subject. To provide a strong quantitative estimate of this postulated relationship, we carried out a meta-analysis which combined, compared, and summarized the results of existing relevant studies.

Methods

Studies were identified by searching databases and reviewing citations in relevant articles. Of 48 potentially relevant studies, we combined individual patient data from 18 studies which involved 1,487 patients with GISTs, by which we made a comparison between the positive KIT mutation subgroup and the negative KIT mutation subgroup (PDGFRA mutation and wild type). We tabulated and analyzed the patient characteristics from each study, including general information such as age and gender, histopathological parameters, and clinical follow-up outcomes.

Results

KIT mutations, compared with PDGFRA mutations and wild type, showed a marked increased risk not only for tumor size (>5 cm) but also for higher mitotic activity (>5), suggesting that KIT mutations significantly correlated with the National Comprehensive Cancer Network (NCCN) high risk or National Institutes of Health (NIH) high risk (1.74 (95% CI, 1.20 to 2.53) and 2.00 (95% CI, 1.08 to 3.68), respectively). Moreover, higher recurrence and metastasis was observed in GISTs with KIT mutations, revealing its closer correlation with clinical malignant risk (P <0.001 for each, with odds ratio (OR) of 2.06 (95%, 1.37 to 3.11) and 2.77 (95%, 1.64 to 4.67), respectively). High risk or malignant GISTs with KIT mutations had a significantly poorer prognosis, as measured by 3-year overall survival, compared to those with PDGFRA mutations and wild type (0.47 (95% CI, 0.25 to 0.90)).

Conclusions

KIT mutations, compared with PDGFRA mutations and wild type, represent a poorer prognostic marker in high risk or malignant GISTs.

Available only for authorised users

George S, Desai J: Management of gastrointestinal stromal tumors in the era of tyrosine kinase inhibitors. Curr Treat Options Oncol. 2002, 3 (6): 489-496. 10.1007/s11864-002-0068-2.CrossRefPubMed

Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y: Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998, 279 (5350): 577-580. 10.1126/science.279.5350.577.CrossRefPubMed

Daniels M, Lurkin I, Pauli R, Erbstösser E, Hildebrandt U, Hellwig K, Zschille U, Lüders P, Krüger G, Knolle J, Stengel B, Prall F, Hertel K, Lobeck H, Popp B, Theissig F, Wünsch P, Zwarthoff E, Agaimy A, Schneider-Stock R: Spectrum of KIT/PDGFRA/BRAF mutations and Phosphatidylinositol-3-Kinase pathway gene alterations in gastrointestinal stromal tumors (GIST). Cancer Lett. 2011, 312 (1): 43-54. 10.1016/j.canlet.2011.07.029.CrossRefPubMed

Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA: PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003, 299 (5607): 708-710. 10.1126/science.1079666.CrossRefPubMed

Hirota S, Ohashi A, Nishida T, Isozaki K, Kinoshita K, Shinomura Y, Kitamura Y: Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology. 2003, 125 (3): 660-667. 10.1016/S0016-5085(03)01046-1.CrossRefPubMed

Miettinen M, Lasota J: Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006, 23 (2): 70-83. 10.1053/j.semdp.2006.09.001.CrossRefPubMed

Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O’Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW: Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002, 33 (5): 459-465. 10.1053/hupa.2002.123545.CrossRefPubMed

Miettinen M, Lasota J: Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006, 130 (10): 1466-1478.PubMed

National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma V.2.2009. 2009, Fort Washington, PA: NCCN

10.

Lasota J, Vel Dobosz AJ, Wasag B, Wozniak A, Kraszewska E, Michej W, Ptaszynski K, Rutkowski P, Sarlomo-Rikala M, Steigen SE, Schneider-Stock R, Stachura J, Chosia M, Ogun G, Ruka W, Siedlecki JA, Miettinen M: Presence of homozygous KIT exon 11 mutations is strongly associated with malignant clinical behavior in gastrointestinal stromal tumors. Lab Invest. 2007, 87 (10): 1029-1041. 10.1038/labinvest.3700628.CrossRefPubMed

11.

Lasota J, Dansonka-Mieszkowska A, Sobin LH, Miettinen M: A great majority of GISTs with PDGFRA mutations represent gastric tumors of low or no malignant potential. Lab Invest. 2004, 84 (7): 874-883. 10.1038/labinvest.3700122.CrossRefPubMed

12.

Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, Shiraga S, Bainbridge T, Morich J, Heinrich MC: PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005, 23 (23): 5357-5364. 10.1200/JCO.2005.14.068.CrossRefPubMed

13.

Chen P, Zong L, Zhao W, Shi L: Efficacy evaluation of imatinib treatment in patients with gastrointestinal stromal tumors: a meta-analysis. World J Gastroenterol. 2010, 16 (33): 4227-4232. 10.3748/wjg.v16.i33.4227.PubMedCentralCrossRefPubMed

14.

Taniguchi M, Nishida T, Hirota S, Isozaki K, Ito T, Nomura T, Matsuda H, Kitamura Y: Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. Cancer Res. 1999, 59 (17): 4297-4300.PubMed

15.

Sakurai S, Fukasawa T, Chong JM, Tanaka A, Fukayama M: C-kit gene abnormalities in gastrointestinal stromal tumors (tumors of interstitial cells of Cajal). Jpn J Cancer Res. 1999, 90 (12): 1321-1328. 10.1111/j.1349-7006.1999.tb00715.x.CrossRefPubMed

16.

Yamamoto H, Oda Y, Kawaguchi K, Nakamura N, Takahira T, Tamiya S, Saito T, Oshiro Y, Ohta M, Yao T, Tsuneyoshi M: c-kit and PDGFRA mutations in extragastrointestinal stromal tumor (gastrointestinal stromal tumor of the soft tissue). Am J Surg Pathol. 2004, 28 (4): 479-488. 10.1097/00000478-200404000-00007.CrossRefPubMed

17.

Lin SC, Liu CL, Wang TI, Chang WS, Tzen CY, Huang MJ: Clinical implications of C-kit gene mutation in patients with large gastrointestinal stromal tumors. J Gastroenterol Hepatol. 2006, 21 (10): 1604-1608. 10.1111/j.1440-1746.2006.04322.x.CrossRefPubMed

18.

Kim TW, Lee H, Kang YK, Choe MS, Ryu MH, Chang HM, Kim JS, Yook JH, Kim BS, Lee JS: Prognostic significance of c-kit mutation in localized gastrointestinal stromal tumors. Clin Cancer Res. 2004, 10 (9): 3076-3081. 10.1158/1078-0432.CCR-03-0581.CrossRefPubMed

19.

Liu XH, Bai CG, Xie Q, Feng F, Xu ZY, Ma DL: Prognostic value of KIT mutation in gastrointestinal stromal tumors. World J Gastroenterol. 2005, 11 (25): 3948-3952.PubMedCentralPubMed

20.

Tzen CY, Wang MN, Mau BL: Spectrum and prognostication of KIT and PDGFRA mutation in gastrointestinal stromal tumors. Eur J Surg Oncol. 2008, 34 (5): 563-568. 10.1016/j.ejso.2007.04.005.CrossRefPubMed

21.

Cho S, Kitadai Y, Yoshida S, Tanaka S, Yoshihara M, Yoshida K, Chayama K: Deletion of the KIT gene is associated with liver metastasis and poor prognosis in patients with gastrointestinal stromal tumor in the stomach. Int J Oncol. 2006, 28 (6): 1361-1367.PubMed

22.

Keun Park C, Lee EJ, Kim M, Lim HY, Choi DI, Noh JH, Sohn TS, Kim S, Kim MJ, Lee HK, Kim KM: Prognostic stratification of high-risk gastrointestinal stromal tumors in the era of targeted therapy. Ann Surg. 2008, 247 (6): 1011-1018. 10.1097/SLA.0b013e3181724f9d.CrossRefPubMed

23.

Andersson J, Bümming P, Meis-Kindblom JM, Sihto H, Nupponen N, Joensuu H, Odén A, Gustavsson B, Kindblom LG, Nilsson B: Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. Gastroenterology. 2006, 130 (6): 1573-1581. 10.1053/j.gastro.2006.01.043.CrossRefPubMed

24.

Haller F, Gunawan B, von Heydebreck A, Schwager S, Schulten HJ, Wolf-Salgó J, Langer C, Ramadori G, Sültmann H, Füzesi L: Prognostic role of E2F1 and members of the CDKN2A network in gastrointestinal stromal tumors. Clin Cancer Res. 2005, 11 (18): 6589-6597. 10.1158/1078-0432.CCR-05-0329.CrossRefPubMed

25.

Steigen SE, Eide TJ, Wasag B, Lasota J, Miettinen M: Mutations in gastrointestinal stromal tumors: a population-based study from Northern Norway. APMIS. 2007, 115 (4): 289-298. 10.1111/j.1600-0463.2007.apm_587.x.CrossRefPubMed

26.

Zheng S, Huang KE, Tao DY, Pan YL: Gene mutations and prognostic factors analysis in extragastrointestinal stromal tumor of a Chinese three-center study. J Gastrointest Surg. 2011, 15 (4): 675-681. 10.1007/s11605-010-1292-x.CrossRefPubMed

27.

Wardelmann E, Losen I, Hans V, Neidt I, Speidel N, Bierhoff E, Heinicke T, Pietsch T, Büttner 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 (6): 887-895. 10.1002/ijc.11323.CrossRefPubMed

28.

Martín J, Poveda A, Llombart-Bosch A, Ramos R, López-Guerrero JA, García Del Muro J, Maurel J, Calabuig S, Gutierrez A, de Sande JLG, Martínez J, De Juan A, Laínez N, Losa F, Alija V, Escudero P, Casado A, García P, Blanco R, Buesa JM, Spanish Group for Sarcoma Research: Deletions affecting codons 557–558 of the c-KIT gene indicate a poor prognosis in patients with completely resected gastrointestinal stromal tumors: a study by the Spanish Group for Sarcoma Research (GEIS). J Clin Oncol. 2005, 23 (25): 6190-6198. 10.1200/JCO.2005.19.554.CrossRefPubMed

29.

Penzel R, Aulmann S, Moock M, Schwarzbach M, Rieker RJ, Mechtersheimer G: The location of KIT and PDGFRA gene mutations in gastrointestinal stromal tumours is site and phenotype associated. J Clin Pathol. 2005, 58 (6): 634-639. 10.1136/jcp.2004.021766.PubMedCentralCrossRefPubMed

30.

Agaram NP, Baren A, Arkun K, Dematteo RP, Besmer P, Antonescu CR: Comparative ultrastructural analysis and KIT/PDGFRA genotype in 125 gastrointestinal stromal tumors. Ultrastruct Pathol. 2006, 30 (6): 443-452. 10.1080/01913120600854186.CrossRefPubMed

31.

Lasota J, Jasinski M, Sarlomo-Rikala M, Miettinen M: Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. Am J Pathol. 1999, 154 (1): 53-60. 10.1016/S0002-9440(10)65250-9.PubMedCentralCrossRefPubMed

32.

Lasota 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 (12): 1306-1312. 10.1016/S0046-8177(03)00407-6.CrossRefPubMed

33.

Miettinen M, Makhlouf H, Sobin LH, Lasota J: Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up. Am J Surg Pathol. 2006, 30 (4): 477-489. 10.1097/00000478-200604000-00008.CrossRefPubMed

34.

Antonescu CR, Sommer G, Sarran L, Tschernyavsky SJ, Riedel E, Woodruff JM, Robson M, Maki R, Brennan MF, Ladanyi M, DeMatteo RP, 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 (9): 3329-3337.PubMed

35.

Yamaguchi M, Miyaki M, Iijima T, Matsumoto T, Kuzume M, Matsumiya A, Endo Y, Sanada Y, Kumada K: Specific mutation in exon 11 of c-kit proto-oncogene in a malignant gastrointestinal stromal tumor of the rectum. J Gastroenterol. 2000, 35 (10): 779-783. 10.1007/s005350070038.CrossRefPubMed

36.

Gong L, Li YH, Zhao HD, Zhao JY, Zhang W: The clinicopathologic observation, c-KIT gene mutation and clonal status of gastrointestinal stromal tumor in the sacrum. BMC Gastroenterol. 2009, 9: 43-10.1186/1471-230X-9-43.PubMedCentralCrossRefPubMed

37.

Wardelmann E, Merkelbach-Bruse S, Pauls K, Thomas N, Schildhaus HU, Heinicke T, Speidel N, Pietsch T, Buettner R, Pink D, Reichardt P, Hohenberger P: Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res. 2006, 12 (6): 1743-1749. 10.1158/1078-0432.CCR-05-1211.CrossRefPubMed

38.

Koyama T, Nimura H, Kobayashi K, Marushima H, Odaira H, Kashimura H, Mitsumori N, Yanaga K: Recurrent gastrointestinal stromal tumor (GIST) of the stomach associated with a novel c-kit mutation after imatinib treatment. Gastric Cancer. 2006, 9 (3): 235-239. 10.1007/s10120-006-0368-5.CrossRefPubMed

39.

Kikuchi H, Yamamoto M, Hiramatsu Y, Baba M, Ohta M, Kamiya K, Tanaka T, Suzuki S, Sugimura H, Kitagawa M, Kanai T, Kitayama Y, Kanda T, Nishikura K, Konno H: Effect of loss of heterozygosity of the c-kit gene on prognosis after hepatectomy for metastatic liver gastrointestinal stromal tumors. Cancer Sci. 2007, 98 (11): 1734-1739. 10.1111/j.1349-7006.2007.00592.x.CrossRefPubMed

40.

Zheng S, Chen LR, Wang HJ, Chen SZ: Analysis of mutation and expression of c-kit and PDGFR-alpha gene in gastrointestinal stromal tumor. Hepatogastroenterology. 2007, 54 (80): 2285-2290.PubMed

41.

Zheng S, Pan YL, Tao DY, Wang JL, Huang KE: Secondary C-kit mutation is a cause of acquired resistance to imatinib in gastrointestinal stromal tumor. Scand J Gastroenterol. 2009, 44 (6): 760-763. 10.1080/00365520802647459.CrossRefPubMed

42.

Isaac JC, Willmore C, Holden JA, Layfield LJ: A c-kit-negative gastrointestinal stromal tumor with a platelet-derived growth factor receptor alpha mutation. Appl Immunohistochem Mol Morphol. 2006, 14 (1): 52-56. 10.1097/01.pai.0000156866.84350.ec.CrossRefPubMed

43.

Fukasawa T, Chong JM, Sakurai S, Koshiishi N, Ikeno R, Tanaka A, Matsumoto Y, Hayashi Y, Koike M, Fukayama M: Allelic loss of 14q and 22q, NF2 mutation, and genetic instability occur independently of c-kit mutation in gastrointestinal stromal tumor. Jpn J Cancer Res. 2000, 91 (12): 1241-1249. 10.1111/j.1349-7006.2000.tb00910.x.CrossRefPubMed

44.

Shibusawa Y, Tamura A, Mochiki E, Kamisaka K, Kimura H, Ishikawa O: c-kit Mutation in generalized lentigines associated with gastrointestinal stromal tumor. Dermatology. 2004, 208 (3): 217-220. 10.1159/000077302.CrossRefPubMed

45.

Chen LL, Holden JA, Choi H, Zhu J, Wu EF, Jones KA, Ward JH, Andtbacka RH, Randall RL, Scaife CL, Hunt KK, Prieto VG, Raymond AK, Zhang W, Trent JC, Benjamin RS, Frazier ML: Evolution from heterozygous to homozygous KIT mutation in gastrointestinal stromal tumor correlates with the mechanism of mitotic nondisjunction and significant tumor progression. Mod Pathol. 2008, 21 (7): 826-836. 10.1038/modpathol.2008.46.CrossRefPubMed

46.

Kuroda N, Tanida N, Hirota S, Daum O, Hes O, Michal M, Lee GH: Familial gastrointestinal stromal tumor with germ line mutation of the juxtamembrane domain of the KIT gene observed in relatively young women. Ann Diagn Pathol. 2011, 15 (5): 358-361. 10.1016/j.anndiagpath.2010.05.003.CrossRefPubMed

47.

Maeyama H, Hidaka E, Ota H, Minami S, Kajiyama M, Kuraishi A, Mori H, Matsuda Y, Wada S, Sodeyama H, Nakata S, Kawamura N, Hata S, Watanabe M, Iijima Y, Katsuyama T: Familial gastrointestinal stromal tumor with hyperpigmentation: association with a germline mutation of the c-kit gene. Gastroenterology. 2001, 120 (1): 210-215. 10.1053/gast.2001.20880.CrossRefPubMed

48.

Namgung H: Gastrointestinal stromal tumor with KIT mutation in neurofibromatosis type 1. J Korean Surg Soc. 2011, 81 (4): 276-280. 10.4174/jkss.2011.81.4.276.PubMedCentralCrossRefPubMed

49.

Lippai N, Füle T, Németh T, Benedek G, Mályi I, Pádi E, Sápi Z: Keratin-positive gastrointestinal stromal tumor of the stomach mimicking gastric carcinoma: diagnosis confirmed by c-kit mutation analysis. Diagn Mol Pathol. 2008, 17 (4): 241-244. 10.1097/PDM.0b013e31816184c6.CrossRefPubMed

50.

Yasuoka R, Sakakura C, Shimomura K, Fujita Y, Nakanishi M, Aragane H, Hagiwara A, Bamba M, Abe T, Yamagishi H: Mutations in exon 11 of the c-kit gene in a myogenic tumor and a neurogenic tumor as well as in gastrointestinal stromal tumors. Utility of c-kit mutation as a prognostic biomarker for gastrointestinal mesenchymal tumor. Dig Surg. 2003, 20 (3): 183-191. 10.1159/000070384.CrossRefPubMed

51.

Chou CC, Chou MJ, Tzen CY: Prediction of KIT mutation in gastrointestinal stromal tumors by the immunoprofile of the tumor cells. J Formos Med Assoc. 2010, 109 (1): 25-31. 10.1016/S0929-6646(10)60018-6.CrossRefPubMed

52.

Miselli FC, Casieri P, Negri T, Orsenigo M, Lagonigro MS, Gronchi A, Fiore M, Casali PG, Bertulli R, Carbone A, Pierotti MA, Tamborini E, Pilotti S: c-Kit/PDGFRA gene status alterations possibly related to primary imatinib resistance in gastrointestinal stromal tumors. Clin Cancer Res. 2007, 13 (8): 2369-2377. 10.1158/1078-0432.CCR-06-1745.CrossRefPubMed

53.

Hostein I, Debiec-Rychter M, Olschwang S, Bringuier PP, Toffolati L, Gonzalez D, Forget S, Escande F, Morzuch L, Tamborini E, Faur N, Pilotti S, Dei Tos P, Emile JF, Coindre JM: A quality control program for mutation detection in KIT and PDGFRA in gastrointestinal stromal tumours. J Gastroenterol. 2011, 46 (5): 586-594. 10.1007/s00535-011-0375-0.CrossRefPubMed

54.

Haller F, Cortis J, Helfrich J, Cameron S, Schüler P, Schwager S, Gunawan B, Füzesi L, Agaimy A: Epithelioid/mixed phenotype in gastrointestinal stromal tumors with KIT mutation from the stomach is associated with accelerated passage of late phases of the cell cycle and shorter disease-free survival. Mod Pathol. 2011, 24 (2): 248-255. 10.1038/modpathol.2010.188.CrossRefPubMed

55.

Zong L, Chen P, Xu Y: Correlation between P53 expression and malignant risk of gastrointestinal stromal tumors: evidence from 9 studies. Eur J Surg Oncol. 2012, 38 (3): 189-195. 10.1016/j.ejso.2011.12.012.CrossRefPubMed

Title: Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumors: a meta-analysis
Authors: Liang Zong
Ping Chen
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: World Journal of Surgical Oncology / Issue 1/2014
Electronic ISSN: 1477-7819
DOI: https://doi.org/10.1186/1477-7819-12-71

At a glance: The STEP trials

Springer Medicine

Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumors: a meta-analysis

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2014

Dermatofibrosarcoma protuberans of the vulva: margins assessment and reconstructive options – a report of two cases

Prognostic factors affecting survival of patients with cancer-related pericardial effusion managed by surgery

Modular tumor endoprostheses in surgical palliation of long-bone metastases: a reduction in tumor burden and a durable reconstruction

Clinical characteristics of second primary cancer in colorectal cancer patients: the impact of colorectal cancer or other second cancer occurring first

Hepatocellular carcinoma: clinicopathological profile and challenges of management in a resource-limited setting

Giant cell angiofibroma misdiagnosed as a vascular malformation and treated with absolute alcohol for one year: a case report and review of the literature