Gastroenterology
Volume 130, Issue 6 , Pages 1573-1581 , May 2006

Gastrointestinal Stromal Tumors With KIT Exon 11 Deletions Are Associated With Poor Prognosis

  • Johanna Andersson

      Affiliations

    • Department of Pathology at the Sahlgrenska Academy, Lundberg Laboratory for Cancer Research, Göteborg University, Göteborg, Sweden
    • J.A. and P.B. contributed equally to this paper.
  • ,
  • Per Bümming

      Affiliations

    • Department of Surgery at the Sahlgrenska Academy, Lundberg Laboratory for Cancer Research, Göteborg University, Göteborg, Sweden
    • J.A. and P.B. contributed equally to this paper.
  • ,
  • Jeanne M. Meis–Kindblom

      Affiliations

    • Department of Pathology at the Sahlgrenska Academy, Lundberg Laboratory for Cancer Research, Göteborg University, Göteborg, Sweden
  • ,
  • Harri Sihto

      Affiliations

    • Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland
  • ,
  • Nina Nupponen

      Affiliations

    • Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland
  • ,
  • Heikki Joensuu

      Affiliations

    • Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland
  • ,
  • Anders Odén

      Affiliations

    • Department of Mathematical Statistics, Chalmers Institute of Technology, Göteborg, Sweden
  • ,
  • Bengt Gustavsson

      Affiliations

    • Novartis Oncology, Stockholm, Sweden
  • ,
  • Lars–Gunnar Kindblom

      Affiliations

    • Department of Pathology at the Sahlgrenska Academy, Lundberg Laboratory for Cancer Research, Göteborg University, Göteborg, Sweden
    • Corresponding Author InformationAddress requests for reprints to: Lars–Gunnar Kindblom, MD, PhD, Department of Musculoskeletal Pathology, Royal Orthopaedic Hospital NHS Trust, Robert Aitken Institute of Clinical Research, The Medical School, University of Birmingham, Birmingham B15 2TT, United Kingdom. fax: (44) 121-414-7640
  • ,
  • Bengt Nilsson

      Affiliations

    • Department of Surgery at the Sahlgrenska Academy, Lundberg Laboratory for Cancer Research, Göteborg University, Göteborg, Sweden

Received 20 December 2005 ,Accepted 11 January 2006.

References 

  1. Kindblom LG , Remotti HE , Aldenborg F , Meis-Kindblom JM . Gastrointestinal pacemaker cell tumor (GIPACT) (gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal) . Am J Pathol . 1998;152:1259–1269
  2. Sarlomo-Rikala M , Kovatich AJ , Barusevicius A , Miettinen M . CD117 (a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34) . Mod Pathol . 1998;11:728–734
  3. Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, et al. Human proto-oncogene c-kit (a new cell surface receptor tyrosine kinase for an unidentified ligand) . EMBO J . 1987;6:3341–3351
  4. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors . Science . 1998;279:577–580
  5. Lux ML, Rubin BP, Biase TL, Chen CJ, Maclure T, Demetri G, et al. KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors . Am J Pathol . 2000;156:791–795
  6. Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors . Cancer Res . 2001;61:8118–8121
  7. Corless CL , McGreevey L , Haley A , Town A , Heinrich MC . KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size . Am J Pathol . 2002;160:1567–1572
  8. Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor . N Engl J Med . 2001;344:1052–1056
  9. van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato di Paola E, Dimitrijevic S, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours (a phase I study) . Lancet . 2001;358:1421–1423
  10. Heinrich MC , Blanke CD , Druker BJ , Corless CL . Inhibition of KIT tyrosine kinase activity (a novel molecular approach to the treatment of KIT-positive malignancies) . J Clin Oncol . 2002;20:1692–1703
  11. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor . J Clin Oncol . 2003;21:4342–4349
  12. Ernst SI , Hubbs AE , Przygodzki RM , Emory TS , Sobin LH , O’Leary TJ . KIT mutation portends poor prognosis in gastrointestinal stromal/smooth muscle tumors . Lab Invest . 1998;78:1633–1636
  13. 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;154:53–60
  14. Taniguchi M, Nishida T, Hirota S, Isozaki K, Ito T, Nomura T, et al. Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors . Cancer Res . 1999;59:4297–4300
  15. Nishida T , Hirota S . Biological and clinical review of stromal tumors in the gastrointestinal tract . Histol Histopathol . 2000;15:1293–1301
  16. Kim TW, Lee H, Kang YK, Choe MS, Ryu MH, Chang HM, et al. Prognostic significance of c-kit mutation in localized gastrointestinal stromal tumors . Clin Cancer Res . 2004;10:3076–3081
  17. Andersson J , Sjogren H , Meis-Kindblom JM , Stenman G , Aman P , Kindblom LG . The complexity of KIT Gene mutations and chromosome rearrangements and their clinical correlation in gastrointestinal stromal (pacemaker cell) tumors . Am J Pathol . 2002;160:15–22
  18. 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;90:1321–1328
  19. Wardelmann E, Neidt I, Bierhoff E, Speidel N, Manegold C, Fischer HP, et al. C-kit mutations in gastrointestinal stromal tumors occur preferentially in the spindle rather than in the epithelioid cell variant . Mod Pathol . 2002;15:125–136
  20. Antonescu CR, Sommer G, Sarran L, Tschernyavsky SJ, Riedel E, Woodruff JM, et al. 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;9:3329–3337
  21. Lasota J, Kopczynski J, Sarlomo-Rikala M, Schneider-Stock R, Stachura T, Kordek R, et al. KIT 1530ins6 mutation defines a subset of predominantly malignant gastrointestinal stromal tumors of intestinal origin . Hum Pathol . 2003;34:1306–1312
  22. Lasota J, Dansonka-Mieszkowska A, Stachura T, Schneider-Stock R, Kallajoki M, Steigen SE, et al. 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;16:1257–1264
  23. Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, et al. PDGFRA activating mutations in gastrointestinal stromal tumors . Science . 2003;299:708–710
  24. 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;84:874–883
  25. Medeiros F, Corless CL, Duensing A, Hornick JL, Oliveira AM, Heinrich MC, et al. KIT-negative gastrointestinal stromal tumors (proof of concept and therapeutic implications) . Am J Surg Pathol . 2004;28:889–894
  26. Sakurai S, Hasegawa T, Sakuma Y, Takazawa Y, Motegi A, Nakajima T, et al. 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;35:1223–1230
  27. Singer S, Rubin BP, Lux ML, Chen CJ, Demetri GD, Fletcher CD, et al. Prognostic value of KIT mutation type, mitotic activity, and histologic subtype in gastrointestinal stromal tumors . J Clin Oncol . 2002;20:3898–3905
  28. Wardelmann E, Losen I, Hans V, Neidt I, Speidel N, Bierhoff E, et al. 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;106:887–895
  29. Nilsson B, Bumming P, Meis-Kindblom JM, Oden A, Dortok A, Gustavsson B, et al. Gastrointestinal stromal tumors (the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden) . Cancer . 2005;103:821–829
  30. Andersson J , Sihto H , Meis-Kindblom J , Joensuu H , Nupponen N , Kindblom LG . NF1 associated gastrointestinal stromal tumors have unique clinical, phenotypic and genotypic characteristics . Am J Surg Pathol . 2005;29:1170–1176
  31. Kaplan E , Meier J . Nonparametric estimation from incomplete observations . J Am Stat Assoc . 1958;53:457–481
  32. Peto R , Peto J . Asymptomatically efficient rank invariant test procedures . J R Stat . 1972;135:185–206
  33. Breslow NE , Day NE . In: Statistical methods in cancer research. Volume II. The design and analysis of cohort studies . Lyon: IARC Sci Publ; 1987;p. 1–406
  34. Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, et al. Diagnosis of gastrointestinal stromal tumors (a consensus approach) . Hum Pathol . 2002;33:459–465
  35. Corless CL , Fletcher JA , Heinrich MC . Biology of gastrointestinal stromal tumors . J Clin Oncol . 2004;22:3813–3825
  36. Miettinen M , Sobin LH , Lasota J . Gastrointestinal stromal tumors of the stomach (a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up) . Am J Surg Pathol . 2005;29:52–68
  37. Corless CL, McGreevey L, Town A, Schroeder A, Bainbridge T, Harrell P, et al. KIT gene deletions at the intron 10-exon 11 boundary in GI stromal tumors . J Mol Diagn . 2004;6:366–370
  38. Chen LL , Sabripour M , Wu EF , Prieto VG , Fuller GN , Frazier ML . A mutation-created novel intra-exonic pre-mRNA splice site causes constitutive activation of KIT in human gastrointestinal stromal tumors . Oncogene . 2005;24:4271–4280

 Supported by the Swedish Cancer Society, Sahlgrenska Academy (the government ALF agreement), Inga-Britt and Arne Lundberg Research Foundation, Swedish Medical Research Foundation, Johan Jansson Foundation for Cancer Research, Assar Gabrielsson Research Foundation, Göteborg Medical Society, Capio Research Foundation, Björnsson Research Foundation, King Gustav V Jubilee Clinical Cancer Research Foundation, and Sahlgrenska University Hospital Research Foundation.

PII: S0016-5085(06)00071-0

doi: 10.1053/j.gastro.2006.01.043

Gastroenterology
Volume 130, Issue 6 , Pages 1573-1581 , May 2006