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01-09-2010

c-kit (CD117) Expression in Human Tumors and its Prognostic Value: An Immunohistochemical Analysis

Authors: Michael Medinger, Manuela Kleinschmidt, Klaus Mross, Barbara Wehmeyer, Clemens Unger, Hans-Eckart Schaefer, Renate Weber, Marc Azemar

Published in: Pathology & Oncology Research | Issue 3/2010

Abstract

c-kit functions as a tyrosine kinase receptor and represents a target for small molecule kinase inhibitors. The expression pattern for c-kit was studied in different human tumor types to their correlation with prognosis. Paraffin-embedded tumor tissues from 282 patients were analyzed immunohistochemically for c-kit expression. Survival and follow-up data were available from 192/282 (68%) patients. c-kit immunopositivity was found in 62/282 (22%) cases. c-kit expression was found in 14/83 (17%) colorectal cancers, in 13/62 (21%) breast cancers, in 7/20 sarcomas (35%), in 5/14 (36%) renal cell carcinomas, in 2/12 ovarian cancers (17%) and in 2/12 (17%) hepatocellular carcinomas. We found no significant correlation between c-kit expression and prognosis although a trend to a worse prognosis in patients with c-kit positive tumors could be observed. Expression of c-kit was found in tumor samples with varying intensities and infrequently.

Besmer P, Murphy JE, George PC, Qiu FH, Bergold PJ, Lederman L, Snyder HW Jr, Brodeur D, Zuckerman EE, Hardy WD (1986) A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family. Nature 320:415–421CrossRefPubMed

Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A (1987) Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J 6:3341–3351PubMed

Ashman LK (1999) The biology of stem cell factor and its receptor C-kit. Int J Biochem Cell Biol 31:1037–1051CrossRefPubMed

Ronnstrand L (2004) Signal transduction via the stem cell factor/c-kit. Cell Mol Life Sci 61:2535–2548CrossRefPubMed

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 29:498–504CrossRefPubMed

Lammie A, Drobnjak M, Gerald W, Saad A, Cote R, Cordon-Cardo C (1994) Expression of c-kit and kit ligand proteins in normal human tissues. J Histochem Cytochem 42:1417–1425PubMed

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 424:135–141CrossRefPubMed

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 52:6139–6143PubMed

Matsuda R, Takahashi T, Nakamura S, Sekido Y, Nishida K, Seto M, Seito T, Sugiura T, Ariyoshi Y, Takahashi T, Ueda R (1993) Expression of the c-kit protein in human solid tumors and in corresponding fetal and adult normal tissues. Am J Pathol 142:339–346PubMed

10.

Hornick JL, Fletcher CD (2002) Immunohistochemical staining for KIT (CD117) in soft tissue sarcomas is very limited in distribution. Am J Clin Pathol 117:188–193CrossRefPubMed

11.

Chui X, Egami H, Yamashita J, Kurizaki T, Ohmachi H, Yamamoto S, Ogawa M (1996) Immunohistochemical expression of the c-kit proto-oncogene product in human malignant and non-malignant breast tissues. Br J Cancer 73:1233–1236PubMed

12.

Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R, Hibbard MK, Chen C-J, Xiao S, Tuveson DA, Demetri GD, Fletcher CDM, Fletcher JA (2001) KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 61:8118–8121PubMed

13.

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 (2002) Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 33:459–465CrossRefPubMed

14.

Blay P, Astudillo A, Buesa JM, Campo E, Abad M, García-García J, Miquel R, Marco V, Sierra M, Losa R, Lacave A, Braña A, Balbín M, Freije JM (2004) Protein kinase C theta is highly expressed in gastrointestinal stromal tumors but not in other mesenchymal neoplasias. Clin Cancer Res 10:4089–4095CrossRefPubMed

15.

Miettinen M, Wang ZF, Lasota J (2009) DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors: a study of 1840 cases. Am J Surg Pathol 33:1401–1408CrossRefPubMed

16.

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

17.

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 (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577–580CrossRefPubMed

18.

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 96:925–932PubMed

19.

Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001) Efficacy and safety of a specific inhibitor of the bcr-abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037CrossRefPubMed

20.

Kantarjian H, Sawyers C, Hochhaus A et al (2002) Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346:645–652CrossRefPubMed

21.

Hochhaus A, Druker B, Sawyers C, Guilhot F, Schiffer CA, Cortes J, Niederwieser DW, Gambacorti-Passerini C, Stone RM, Goldman J, Fischer T, O’Brien SG, Reiffers JJ, Mone M, Krahnke T, Talpaz M, Kantarjian HM (2008) Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood 111:1039–1043CrossRefPubMed

22.

Joensuu H, Roberts PJ, Sarlomo-Rikala M, Andersson LC, Tervahartiala P, Tuveson D, Silberman S, Capdeville R, Dimitrijevic S, Druker B, Demetri GD (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344:1052–1056CrossRefPubMed

23.

Demetri GD, von Mehren M, Blanke CD et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480CrossRefPubMed

24.

Heinrich MC, Corless CL, Demetri GD et al (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumors. J Clin Oncol 21:4342–4349CrossRefPubMed

25.

Sammarco I, Capurso G, Coppola L, Bonifazi AP, Cassetta S, Fave GD, Carrara A, Grassi GB, Rossi P, Sette C, Geremia R (2004) Expression of the proto-oncogene c-Kit in normal and tumor tissues from colorectal carcinoma patients. Int J Colorectal Dis 19:545–553CrossRefPubMed

26.

Preto A, Moutinho C, Velho S, Oliveria C, Rebocho AP, Figueiredo J et al (2007) A subset of colorectal carcinoma expresses c-Kit protein independently of BRAF and/or K-Ras activation. Virchows Arch 450:619–26CrossRefPubMed

27.

Tsuda H, Tani Y, Weisenberger J, Kitada S, Haseqawa T, Murata T et al (2005) Frequent KIT and epidermal growth factor receptor over-expression in undifferentiated type breast carcinomas with “stem cell-like” features. Cancer Sci 96:333–339CrossRefPubMed

28.

Charpin C, Giusiano S, Charfi S, Secq V, Carpentier S, Andrac L, Lavaut MN, Allasia C, Bonnier P, Garcia S (2009) Quantitative immunohistochemical expression of c Kit in breast carcinomas is predictive of patients’ outcome. Br J Cancer 7:48–54CrossRef

29.

Schmandt RE, Broaddus R, Lu KH, Shvartsman H, Thornton A, Malpica A et al (2003) Expression of c-ABL, c-Kit and platelet-derived growth factor receptor-beta in ovarian serous carcinoma and normal ovarian surface epithelium. Cancer 98:758–764CrossRefPubMed

30.

Wei H, Zhao MQ, Dong W, Yang Y, Li JS (2008) Expression of c-kit protein and mutational status of the c-kit gene in osteosarcoma and their clinicopathological significance. J Int Med Res 36:1008–1014PubMed

31.

Simon R, Panussis S, Maurer R, Spichtin H, Glatz K, Tapia C, Mirlacher M, Rufle A, Torhorst J, Sauter G (2004) KIT (CD117)-positive breast cancers are infrequent and lack KIT gene mutations. Clin Cancer Res 10:178–183CrossRefPubMed

32.

Tsutsui S, Yasuda K, Suzuki K, Takeuchi H, Nishizaki T, Higashi H, Era S (2006) A loss of c-kit expression is associated with an advanced stage and poor prognosis in breast cancer. Br J Cancer 94:1874–1878CrossRefPubMed

33.

Friederichs J, von Weyhern CW, Rosenberg R, Doll D, Busch R, Lordick F, Siewert JR, Sarbia M (2009) Immunohistochemical detection of receptor tyrosine kinases c-kit, EGF-R, and PDGF-R in colorectal adenocarcinomas. Langenbecks Arch Surg Mar 12. [Epub ahead of print]

34.

Went PT, Dirnhofer S, Bundi M, Mirlacher M, Schraml P, Mangialaio S, Dimitrijevic S, Kononen J, Lugli A, Simon R, Sauter G (2004) Prevalence of KIT expression in human tumors. J Clin Oncol 22:4514–4522CrossRefPubMed

35.

Becker G, Schmitt-Graeff A, Ertelt V, Blum HE, Allgaier HP (2007) CD117 (c-Kit) expression in human hepatocellular carcinoma. Clin Oncol 19:204–208CrossRef

36.

Lugli A, Went P, Khanlari B, Nikolova Z, Dirnhofer S (2004) Rare KIT (CD117) expression in multiple myeloma abrogates the usefulness of imatinib mesylate treatment. Virchows Arch 444:264–268CrossRefPubMed

37.

Rubin BP, Schuetze SM, Eary JF, Norwood TH, Mirza S, Conrad EU, Bruckner JD (2002) Molecular targeting of platelet-derived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J Clin Oncol 20:3586–3591CrossRefPubMed

38.

Piccaluga PP, Malagola M, Rondoni M, Arpinati M, Paolini S, Candoni A, Fanin R, Messa E, Pirrotta MT, Lauria F, Visani G, Alberti D, Rancati F, Vinaccia V, Russo D, Saglio G, Baccarani M, Martinelli G (2007) Imatinib mesylate in the treatment of newly diagnosed or refractory/resistant c-kit positive acute myeloid leukemia. Results of an Italian multicentre phase II study. Haematologica 92:1721–1722CrossRefPubMed

39.

Coleman RL, Broaddus RR, Bodurka DC, Wolf JK, Burke TW, Kavanagh JJ, Levenback CF, Gershenson DM (2006) Phase II trial of imatinib mesylate in patients with recurrent platinum-and taxane-resistant epithelial ovarian and primary peritoneal cancers. Gynecol Oncol 101:126–131CrossRefPubMed

40.

Dy GK, Miller AA, Mandrekar SJ, Aubry MC, Langdon RM Jr, Morton RF, Schild SE, Jett JR, Adjei AA (2005) A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small cell lung cancer: a CALGB and NCCTG study. Ann Oncol 16:1811–1816CrossRefPubMed

41.

Heinrich MC, Joensuu H, Demetri GD, Corless CL, Apperley J, Fletcher JA, Soulieres D, Dirnhofer S, Harlow A, Town A, McKinley A, Supple SG, Seymour J, Di Scala L, van Oosterom A, Herrmann R, Nikolova Z, McArthur AG (2008) Imatinib Target Exploration Consortium Study B2225. Phase II, open-label study evaluating the activity of imatinib in treating life-threatening malignancies known to be associated with imatinib-sensitive tyrosine kinases. Clin Cancer Res 14:2717–2531CrossRefPubMed

42.

Sihto H, Sarlomo-Rikala M, Tynninen O, Tanner M, Andersson LC, Franssila K, Nupponen NN, Joensuu H (2005) KIT and platelet-derived growth factor receptor alpha tyrosine kinase gene mutations and KIT amplifications in human solid tumors. J Clin Oncol 23:49–57CrossRefPubMed

Title: c-kit (CD117) Expression in Human Tumors and its Prognostic Value: An Immunohistochemical Analysis
Authors: Michael Medinger
Manuela Kleinschmidt
Klaus Mross
Barbara Wehmeyer
Clemens Unger
Hans-Eckart Schaefer
Renate Weber
Marc Azemar
Publication date: 01-09-2010
Publisher: Springer Netherlands
Published in: Pathology & Oncology Research / Issue 3/2010
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI: https://doi.org/10.1007/s12253-010-9247-9

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