Advertisement

Virchows Archiv

, Volume 443, Issue 6, pp 741–744 | Cite as

Sequence analysis and high-throughput immunhistochemical profiling of KIT (CD 117) expression in uveal melanoma using tissue microarrays

  • Mona Pache
  • Katharina Glatz
  • Doris Bösch
  • Stephan Dirnhofer
  • Martina Mirlacher
  • Ronald Simon
  • Peter Schraml
  • Alex Rufle
  • Josef Flammer
  • Guido Sauter
  • Peter MeyerEmail author
Original Article

Abstract

We aimed to immunohistochemically examine the expression of KIT (CD 117) in human posterior uveal melanoma and to analyze KIT-positive tumors for gene mutations. Brought into a tissue microarray (TMA) format were 101 formalin-fixed, paraffin-embedded posterior uveal melanomas. Immunhistochemistry was performed using the polyclonal anti-CD117 antibody from Dako (A4502). In ten selected KIT-positive tumors, exons 2, 8, 9, 11, 13 and 17 were sequenced. Of the 101 cases, 89 (88%) could be evaluated on the TMAs. Immunohistochemistry for CD 117 was weakly positive in 5 cases (6%), moderately positive in 10 cases (12%) and strongly positive in 57 cases (69%). No KIT mutations were detected in the analyzed exons. In conclusion, human posterior uveal melanoma frequently expresses CD117 at high levels. Although KIT mutations could not be found, it appears justified to investigate the utility of imatinib mesylate in the treatment of these patients.

Keywords

Uveal melanoma CD 117 cKIT Tissue microarray Sequence analysis 

Notes

Acknowledgement

The authors thank Miriam Vonlanten and Andreas Meyer for their technical assistance.

References

  1. 1.
    Arber DA, Tamayo R, Weiss LM (1998) Paraffin section detection of the c-kit gene product (CD117) in human tissues: value in the diagnosis of mast cell disorders. Hum Pathol 29:498–504PubMedGoogle Scholar
  2. 2.
    Bubendorf L, Kolmer M, Kononen J, Koivisto P, Mousses S, Chen Y, Mahlamaki E, Schraml P, Moch H, Willi N, Elkahloun AG, Pretlow TG, Gasser TC, Mihatsch MJ, Sauter G, Kallioniemi OP (1999) Hormone therapy failure in human prostate cancer: analysis by complementary DNA and tissue microarrays. J Natl Cancer Inst 91:1758–1764PubMedGoogle Scholar
  3. 3.
    Bubendorf L, Kononen J, Koivisto P, Schraml P, Moch H, Gasser TC, Willi N, Mihatsch MJ, Sauter G, Kallioniemi OP (1999) Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays. Cancer Res 59:803–806PubMedGoogle Scholar
  4. 4.
    Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480Google Scholar
  5. 5.
    Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042PubMedGoogle Scholar
  6. 6.
    Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ (2000) Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96:925–932PubMedGoogle Scholar
  7. 7.
    Hornick JL, Fletcher CD (2002) Immunohistochemical staining for KIT (CD117) in soft tissue sarcomas is very limited in distribution. Am J Clin Pathol 117:188–193CrossRefPubMedGoogle Scholar
  8. 8.
    Joensuu H, Fletcher C, Dimitrijevic S, Silberman S, Roberts P, Demetri G (2002) Management of malignant gastrointestinal stromal tumours. Lancet Oncol 3:655–664PubMedGoogle Scholar
  9. 9.
    Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847PubMedGoogle Scholar
  10. 10.
    Lasota J, Jasinski M, Sarlomo-Rikala M, Miettinen M (1999) 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 154:53–60PubMedGoogle Scholar
  11. 11.
    Ma Y, Zeng S, Metcalfe DD, Akin C, Dimitrijevic S, Butterfield JH, McMahon G, Longley BJ (2002) The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. Blood 99:1741–1744CrossRefPubMedGoogle Scholar
  12. 12.
    Matsuda R, Takahashi T, Nakamura S, Sekido Y, Nishida K, Seto M, Seito T, Sugiura T, Ariyoshi Y, et al (1993) Expression of the c-kit protein in human solid tumors and in corresponding fetal and adult normal tissues. Am J Pathol 142:339–346PubMedGoogle Scholar
  13. 13.
    Montone KT, van Belle P, Elenitsas R, Elder DE (1997) Proto-oncogene c-kit expression in malignant melanoma: protein loss with tumor progression. Mod Pathol 10:939–944PubMedGoogle Scholar
  14. 14.
    Natali PG, Nicotra MR, Sures I, Santoro E, Bigotti A, Ullrich A (1992) Expression of c-kit receptor in normal and transformed human nonlymphoid tissues. Cancer Res 52:6139–6143PubMedGoogle Scholar
  15. 15.
    Nocito A, Bubendorf L, Maria Tinner E, Suess K, Wagner U, Forster T, Kononen J, Fijan A, Bruderer J, Schmid U, Ackermann D, Maurer R, Alund G, Knonagel H, Rist M, Anabitarte M, Hering F, Hardmeier T, Schoenenberger AJ, Flury R, Jager P, Luc Fehr J, Schraml P, Moch H, Mihatsch MJ, Gasser T, Sauter G (2001) Microarrays of bladder cancer tissue are highly representative of proliferation index and histological grade. J Pathol 194:349–357PubMedGoogle Scholar
  16. 16.
    Radford IR (2002) Imatinib. Novartis. Curr Opin Investig Drugs 3:492–499PubMedGoogle Scholar
  17. 17.
    Richter J, Wagner U, Kononen J, Fijan A, Bruderer J, Schmid U, Ackermann D, Maurer R, Alund G, Knonagel H, Rist M, Wilber K, Anabitarte M, Hering F, Hardmeier T, Schonenberger A, Flury R, Jager P, Fehr JL, Schraml P, Moch H, Mihatsch MJ, Gasser T, Kallioniemi OP, Sauter G (2000) High-throughput tissue microarray analysis of cyclin E gene amplification and overexpression in urinary bladder cancer. Am J Pathol 157:787–794PubMedGoogle Scholar
  18. 18.
    Schraml P, Kononen J, Bubendorf L, Moch H, Bissig H, Nocito A, Mihatsch MJ, Kallioniemi OP, Sauter G (1999) Tissue microarrays for gene amplification surveys in many different tumor types. Clin Cancer Res 5:1966–1975PubMedGoogle Scholar
  19. 19.
    Shields JA, Shields CL, Donoso LA (1991) Management of posterior uveal melanoma. Surv Ophthalmol 36:161–195PubMedGoogle Scholar
  20. 20.
    Simon R, Nocito A, Hubscher T, Bucher C, Torhorst J, Schraml P, Bubendorf L, Mihatsch MM, Moch H, Wilber K, Schotzau A, Kononen J, Sauter G (2001) Patterns of her-2/neu amplification and overexpression in primary and metastatic breast cancer. J Natl Cancer Inst 93:1141–1146PubMedGoogle Scholar
  21. 21.
    Simon R, Richter J, Wagner U, Fijan A, Bruderer J, Schmid U, Ackermann D, Maurer R, Alund G, Knonagel H, Rist M, Wilber K, Anabitarte M, Hering F, Hardmeier T, Schonenberger A, Flury R, Jager P, Fehr JL, Schraml P, Moch H, Mihatsch MJ, Gasser T, Sauter G (2001) High-throughput tissue microarray analysis of 3p25 (RAF1) and 8p12 (FGFR1) copy number alterations in urinary bladder cancer. Cancer Res 61:4514–4519PubMedGoogle Scholar
  22. 22.
    Torhorst J, Bucher C, Kononen J, Haas P, Zuber M, Kochli OR, Mross F, Dieterich H, Moch H, Mihatsch M, Kallioniemi OP, Sauter G (2001) Tissue microarrays for rapid linking of molecular changes to clinical endpoints. Am J Pathol 159:2249–2256Google Scholar
  23. 23.
    Tsuura Y, Hiraki H, Watanabe K, Igarashi S, Shimamura K, Fukuda T, Suzuki T, Seito T (1994) Preferential localization of c-kit product in tissue mast cells, basal cells of skin, epithelial cells of breast, small cell lung carcinoma and seminoma/dysgerminoma in human: immunohistochemical study on formalin-fixed, paraffin-embedded tissues. Virchows Arch 424:135–141PubMedGoogle Scholar
  24. 24.
    van Oosterom AT, Judson I, Verweij J, Stroobants S, Donato di Paola E, Dimitrijevic S, Martens M, Webb A, Sciot R, Van Glabbeke M, Silberman S, Nielsen OS (2001) Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 358:1421–1423CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Mona Pache
    • 1
  • Katharina Glatz
    • 2
  • Doris Bösch
    • 1
    • 2
  • Stephan Dirnhofer
    • 2
  • Martina Mirlacher
    • 2
  • Ronald Simon
    • 2
  • Peter Schraml
    • 2
  • Alex Rufle
    • 2
  • Josef Flammer
    • 1
  • Guido Sauter
    • 2
  • Peter Meyer
    • 1
    • 2
    • 3
    Email author
  1. 1.University Eye Clinic of BaselBaselSwitzerland
  2. 2.Institute of PathologyUniversity of BaselBaselSwitzerland
  3. 3.University Eye Clinic BaselBaselSwitzerland

Personalised recommendations