Skip to main content
PMC home page
Cancer Science logoLink to Cancer Science
. 2005 Aug 19;94(6):486–491. doi: 10.1111/j.1349-7006.2003.tb01470.x

Alterations of the c‐kit gene in testicular germ cell tumors

Yuji Sakuma 1, Shinji Sakurai 1,✉, Sachiko Oguni 1, Mitsugu Hironaka 1, Ken Salto 1
PMCID: PMC11160296  PMID: 12824871

Abstract

Expression and gain‐of‐function mutation of the c‐kit gene, that encodes a receptor tyrosine kinase (KIT), have been reported in mast cell tumors and gastrointestinal stromal tumors (GISTs). Among human testicular germ cell tumors (GCTs), seminomas and seminoma components of mixed GCTs have also been shown to express KIT, but only one study has found the c‐kit gene mutation at exon 17 in seminoma. To elucidate the frequency and location of the c‐kit gene mutation of testicular GCTs, we analyzed the whole coding region of the c‐kit complementary DNA along with 4 mutational hot spots (exons 9, 11, 13 and 17) of the c‐kit genomic DNA by polymerase chain reaction and direct sequencing. Somatic mutations were found in 4 pure seminomas of 34 testicular GCTs (11.8%). One mutation was found in exon 11 (W557R) and the others were observed in exon 17 (D816H and D816V). These types of mutations were reported in GISTs (W557R), seminoma (D816H) and mastocytosis (D816V) and were considered to be gain‐of‐function mutations, although there were no differences of any clinicopathological factors or outcome between patients with and without mutations. Additionally, we also demonstrated coexpression of Gly‐Asn‐Asn‐Lys510–513 (GNNK)+ and GNNK‐ isoforms of the c‐kit gene with dominance of the GNNK‐ transcript in all testicular GCTs. The mutations and/or preferential expression of GNNK‐ isoform of the c‐kit gene might play an important role in the development of testicular GCTs, and these tumors may also be targets for STI571, which is a promising drug for advanced and metastatic GISTs.

References

  • 1. Kitamura Y, Hirota S, Nishida T. A loss‐of‐function mutation of c‐kit results in depletion of mast cells and interstitial cells of Cajal, while its gain‐of‐function mutation results in their oncogenesis. Mutat Res 2001; 477: 165–71. [DOI] [PubMed] [Google Scholar]
  • 2. Ashman LK. The biology of stem cell factor and its receptor C‐kit . Int J Bio-chem CellBiol 1999; 31: 1037–51. [DOI] [PubMed] [Google Scholar]
  • 3. Rossi P, Sette C, Dolci S, Geremia R. Role of c‐kit in mammalian spermato‐genesis. J Endocrinol Invest 2000; 23: 609–15. [DOI] [PubMed] [Google Scholar]
  • 4. Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H, Koshimizu U, Sugahara H, Butterfield JH, Ashman LK, Kanayama Y, Matsuzawa Y, Kitamura Y, Kanakura Y. Identification of mutations in the coding sequence of the proto‐oncogene c‐kit in a human mast cell leukemia cell line causing ligand‐independent activation of c‐kit product. J Clin Invest 1993; 92: 1736–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Longley BJ Jr, Metcalfe DD, Tharp M, Wang X, Tyrrell L, Lu SZ, Heitjan D, Ma Y. Activating and dominant inactivating c‐KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci USA 1999; 96: 1609–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Tunio GM, Matsuzawa Y, Kanakura Y, Shinomura Y, Kitamura Y. Gain‐of‐function mutations of c‐kit in human gastrointestinal stromal tumors. Science 1998; 279: 577–80. [DOI] [PubMed] [Google Scholar]
  • 7. Lux ML, Rubin BP, Biase TL, Chen CJ, Maclure T, Demetri G, Xiao S, Singer S, Fletcher CD, Fletcher JA. KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am J Pathol 2000; 156: 791–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Isozaki K, Terris B, Belghiti J, Schiffmann S, Hirota S, Vanderwinden JM. Germline‐activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors. Am. J Pathol 2000; 157: 1581–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Hirota S, Nishida T, Isozaki K, Taniguchi M, Nakamura J, Okazaki T, Kitamura Y. Gain‐of‐function mutation at the extracellular domain of KIT in gastrointestinal stromal tumours. J Pathol 2001; 193: 505–10. [DOI] [PubMed] [Google Scholar]
  • 10. Hirota S, Nishida T, Isozaki K, Taniguchi M, Nishikawa K, Ohashi A, Takabayashi A, Obayashi T, Okuno T, Kinoshita K, Chen H, Shinomura Y, Kitamura Y. Familial gastrointestinal stromal tumors associated with dys‐phagia and novel type germline mutation of KIT gene. Gastmenterology 2002; 122: 1493–9. [DOI] [PubMed] [Google Scholar]
  • 11. Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R, Hibbard MK, Chen CJ, Xiao S, Tuveson DA, Dementi GD, Fletcher CD, Fletcher JA. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 2001; 61: 8118–21. [PubMed] [Google Scholar]
  • 12. Tian Q, Frierson HF Jr, Krystal GW, Moskaluk CA. Activating c‐kit gene mutations in human germ cell tumors. Am J Pahtol 1999; 154: 1643–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Sekido Y, Obata Y, Ueda R, Hida T, Suyama M, Shimokata K, Ariyoshi Y, Takahashi T. Preferential expression of c‐kit protooncogene transcripts in small cell lung cancer. Cancer Res 1991; 51: 2416–9. [PubMed] [Google Scholar]
  • 14. Landuzzi L, De Giovanni C, Nicoletti G, Rossi I, Ricci C, Astolfi A, Scopece L, Scotland K, Serra M, Bagnara GP, Nanni P, Lollini PL. The met‐astatic ability of Ewing's sarcoma cells is modulated by stem cell factor and by its receptor c‐kit . Am. J Pathol 2000; 157: 2123–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Sakurai S, Oguni S, Hironaka M, Fukayama M, Morinaga S, Saito K. Mutations in c‐kit gene exons 9 and 13 in gastrointestinal stromal tumors among Japanese. Jpn J Cancer Res 2001; 92: 494–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. 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: 132–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. 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, Silverman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347: 472–80. [DOI] [PubMed] [Google Scholar]
  • 18. Frost MJ, Ferrao FT, Hughes TP, Ashman LK. Juxtamembrane mutant V560GKH is more sensitive to Imatinib (STI571) compared with wild‐type c‐kit whereas the kinase domain mutant D816VKH is resistant. Mol Cancer Ther 2002; 1: 1115–24. [PubMed] [Google Scholar]
  • 19. Ma Y, Zeng S, Metcalfe DD, Akin C, Dimitrijevic S, Butterfield JH, McMahon G, Longley BJ. 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 2002; 99: 1741–4. [DOI] [PubMed] [Google Scholar]
  • 20. Izquierdo MA, Van der Valk P, Van Ark‐Otte J, Rubio G, Germa‐Lluch JR, Ueda R, Scheper RJ, Takahashi T, Gianccone G. Differential expression of the c‐kit proto‐oncogene in germ cell tumours. J Pathol 1995; 177: 253–8. [DOI] [PubMed] [Google Scholar]
  • 21. Bokemeyer C, Kuczyk MA, Dunn T, Serth J, Hartmann K, Jonasson J, Pietsch T, Jonas U, Schmoll HJ. Expression of stem‐cell factor and its receptor c‐kit protein in normal testicular tissue and malignant germ‐cell tumours. J Cancer Res Clin Oncol 1996; 122: 301–6. [DOI] [PubMed] [Google Scholar]
  • 22. Strohmeyer T, Reese D, Press M, Ackermann R, Hartmann M, Slamon D. Expression of the c‐kit proto‐oncogene and its ligand stem cell factor (SCF) in normal and malignant human testicular tissue. J Urol 1995; 153: 511–5. [DOI] [PubMed] [Google Scholar]
  • 23. Przygodzki RM, Hubbs AE, Zhao FQ, O'Leary TJ. Primary mediastinal seminomas: evidence of single and multiple KIT mutations. Lab Invest 2002; 82: 1369–75. [DOI] [PubMed] [Google Scholar]
  • 24. Moriyama Y, Tsujimura T, Hashimoto K, Morimoto M, Kitayama H, Matsuzawa Y, Kitamura Y, Kanakura Y. Role of aspartic acid 814 in the function and expression of c‐kit receptor tyrosine kinase. J Biol Chem 1996; 271: 3347–50. [DOI] [PubMed] [Google Scholar]
  • 25. Hirota S, Okazaki T, Kitamura Y, O'Brien P, Kapusta L, Dardick I. Cause of familial and multiple gastrointestinal autonomic nerve tumors with hyperpla‐sia of interstitial cells of Cajal is germline mutation of the c‐kit gene. Am J Surg Pathol 2000; 24: 326–7. [DOI] [PubMed] [Google Scholar]
  • 26. Kinoshita K, Isozaki K, Hirota S, Nishida T, Chen H, Nakahara M, Nagasawa Y, Ohashi A, Shinomura Y, Kitamura Y, Matsuzawa Y. c‐kit gene mutation at exon 17 or 13 is very rare in sporadic gastrointestinal stromal tumors. J Gastroenterol Hepatol 2003; 18: 147–51. [DOI] [PubMed] [Google Scholar]
  • 27. Reith AD, Ellis C, Lyman SD, Anderson DM, Williams DE, Bernstein A, Pawson T. Signal transduction by normal isoforms and W mutant variants of the Kit receptor tyrosine kinase. EMBO J 1991; 10: 2451–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Caruana G, Cambareri AC, Ashman LK. Isoforms of c‐KIT differ in activation of signalling pathways and transformation of NIH3T3 fibroblasts. Oncogene 1999; 18: 5573–81. [DOI] [PubMed] [Google Scholar]
  • 29. Vuky J, Tickoo SK, Sheinfeld J, Bacik J, Amsterdam A, Mazumdar M, Reuter V, Bajorin DF, Bosl GJ, Motzer RJ. Salvage chemotherapy for patients with advanced pure seminoma. J Clin Oncol 2002; 20: 297–301. [DOI] [PubMed] [Google Scholar]
  • 30. Liao AT, Chien MB, Shenoy N, Mendel DB, McMahon G, Cherrington JM, London CA. Inhibition of constitutively active forms of mutant kit by multi‐targeted indolinone tyrosine kinase inhibitors. Blood 2002; 100: 585–93. [DOI] [PubMed] [Google Scholar]

Articles from Cancer Science are provided here courtesy of Wiley

RESOURCES