Expression and mutation of c-Kit in intracranial germ cell tumors: A single-centre retrospective study of 30 cases in China

Gao,Yu‑Ping; Jiang,Ji‑Yao; Liu,Qiang

doi:10.3892/ol.2016.4373

May-2016 Volume 11 Issue 5

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May-2016 Volume 11 Issue 5

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Article Open Access

Expression and mutation of c-Kit in intracranial germ cell tumors: A single-centre retrospective study of 30 cases in China

Authors:
- Yu‑Ping Gao
- Ji‑Yao Jiang
- Qiang Liu
View Affiliations / Copyright

Affiliations: Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China, Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China, Department of Pathology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China

Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Pages: 2971-2976
|
Published online on: March 23, 2016

https://doi.org/10.3892/ol.2016.4373
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Abstract

Although primary central nervous system (CNS) germ cell tumors (GCTs) are one of the most treatable types of malignant brain tumor, a subset of patients remain resistant to standard chemotherapy. Gain-of-function mutations of the c-Kit gene, and KIT protein expression, have been observed in a number of GCTs, including testicular seminoma, ovarian dysgerminoma and mediastinal seminoma in various ethnic groups. Although a small number of studies have reported the role of c-Kit in CNS GCTs, few have focused on Chinese patients exhibiting CNS GCTs. In the present study, the frequency and location of c-Kit mutations and KIT protein expression levels in CNS GCTs were investigated in 30 patients, between January 1994 and October 2014. Immunohistochemical assays suggested that KIT protein expression was present in 59.1% patients (66.7% in males and 42.9% in females); however, no statistically significant correlation was identified between KIT protein expression and patient clinicopathological features. By performing PCR amplification and direct sequencing, 4 mutational hot spots of the c‑Kit gene (exons 9, 11, 13 and 17) were examined, and c‑Kit gene mutation was identified in 1/17 (5.9%) CNS germinoma cases. This mutation was located in exon 11 at codon 557-558 WK (Tryptophan-Lysine). No c-Kit gene mutations were detected in non-germinomatous GCTs. Imatinib, a tyrosine kinase inhibitor, may be an effective treatment against standard chemotherapy‑resistant CNS germinoma patients exhibiting c-Kit mutations.

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1	Thakkar JP, Chew L and Villano JL: Primary CNS germ cell tumors: Current epidemiology and update on treatment. Med Oncol. 30:4962013. View Article : Google Scholar : PubMed/NCBI
2	Dufour C, Guerrini-Rousseau L and Grill J: Central nervous system germ cell tumors: An update. Curr Opin Oncol. 26:622–626. 2014. View Article : Google Scholar : PubMed/NCBI
3	Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW and Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114:97–109. 2007. View Article : Google Scholar : PubMed/NCBI
4	Subbiah V, Meric-Bernstam F, Mills GB, Shaw KR, Bailey AM, Rao P, Ward JF and Pagliaro LC: Next generation sequencing analysis of platinum refractory advanced germ cell tumor sensitive to Sunitinib (Sutent^®) a VEGFR2/PDGFRβ/c-kit/FLT3/RET/CSF1R inhibitor in a phase II trial. J Hematol Oncol. 7:522014. View Article : Google Scholar : PubMed/NCBI
5	Sakuma Y, Sakurai S, Oguni S, Hironaka M and Saito K: Alterations of the c-kit gene in testicular germ cell tumors. Cancer Sci. 94:486–491. 2003. View Article : Google Scholar : PubMed/NCBI
6	Cruse G, Metcalfe DD and Olivera A: Functional deregulation of KIT: Link to mast cell proliferative diseases and other neoplasms. Immunol Allergy Clin North Am. 34:219–237. 2014. View Article : Google Scholar : PubMed/NCBI
7	Rossi P: Transcriptional control of KIT gene expression during germ cell development. Int J Dev Biol. 57:179–184. 2013. View Article : Google Scholar : PubMed/NCBI
8	Yamada T, Hasegawa S, Inoue Y, Date Y, Yamamoto N, Mizutani H, Nakata S, Matsunaga K and Akamatsu H: Wnt/β-catenin and kit signaling sequentially regulate melanocyte stem cell differentiation in UVB-induced epidermal pigmentation. J Invest Dermatol. 133:2753–2762. 2013. View Article : Google Scholar : PubMed/NCBI
9	Reber LL, Marichal T and Galli SJ: New models for analyzing mast cell functions in vivo. Trends Immunol. 33:613–625. 2012. View Article : Google Scholar : PubMed/NCBI
10	Huizinga JD, Thuneberg L, Klüppel M, Malysz J, Mikkelsen HB and Bernstein A: W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature. 373:347–349. 1995. View Article : Google Scholar : PubMed/NCBI
11	Broudy VC: Stem cell factor and hematopoiesis. Blood. 90:1345–1364. 1997.PubMed/NCBI
12	Rammohan A, Sathyanesan J, Rajendran K, Pitchaimuthu A, Perumal SK, Srinivasan U, Ramasamy R, Palaniappan R and Govindan M: A gist of gastrointestinal stromal tumors: A review. World J Gastrointest Oncol. 5:102–112. 2013. View Article : Google Scholar : PubMed/NCBI
13	Coffey J, Linger R, Pugh J, Dudakia D, Sokal M, Easton DF, Bishop Timothy D, Stratton M, Huddart R and Rapley EA: Somatic KIT mutations occur predominantly in seminoma germ cell tumors and are not predictive of bilateral disease: Report of 220 tumors and review of literature. Genes Chromosomes Cancer. 47:34–42. 2008. View Article : Google Scholar : PubMed/NCBI
14	Hoei-Hansen CE, Kraggerud SM, Abeler VM, Kaern J, Rajpert-De Meyts E and Lothe RA: Ovarian dysgerminomas are characterised by frequent KIT mutations and abundant expression of pluripotency markers. Mol Cancer. 6:122007. View Article : Google Scholar : PubMed/NCBI
15	Terada T: Mediastinal seminoma with multiple KIT gene mutations. Pathology. 41:695–697. 2009. View Article : Google Scholar : PubMed/NCBI
16	Yuan F, Shi M, Ji J, Shi H, Zhou C, Yu Y, Liu B, Zhu Z and Zhang J: KRAS and DAXX/ATRX gene mutations are correlated with the clinicopathological features, advanced diseases, and poor prognosis in Chinese patients with pancreatic neuroendocrine tumors. Int J Biol Sci. 10:957–965. 2014. View Article : Google Scholar : PubMed/NCBI
17	Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M and Saito K: c-kit gene mutations in intracranial germinomas. Cancer Sci. 95:716–720. 2004. View Article : Google Scholar : PubMed/NCBI
18	Kamakura Y, Hasegawa M, Minamoto T, Yamashita J and Fujisawa H: C-kit gene mutation: Common and widely distributed in intracranial germinomas. J Neurosurg. 104(Suppl): 173–180. 2006.PubMed/NCBI
19	Miettinen M and Lasota J: KIT (CD117): A review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. Appl Immunohistochem Mol Morphol. 13:205–220. 2005. View Article : Google Scholar : PubMed/NCBI
20	McIntyre A, Summersgill B, Grygalewicz B, Gillis AJ, Stoop J, van Gurp RJ, Dennis N, Fisher C, Huddart R, Cooper C, et al: Amplification and overexpression of the KIT gene is associated with progression in the seminoma subtype of testicular germ cell tumors of adolescents and adults. Cancer Res. 65:8085–8089. 2005. View Article : Google Scholar : PubMed/NCBI
21	Willmore-Payne C, Holden JA, Chadwick BE and Layfield LJ: Detection of c-kit exons 11- and 17-activating mutations in testicular seminomas by high-resolution melting amplicon analysis. Mod Pathol. 19:1164–1169. 2006. View Article : Google Scholar : PubMed/NCBI
22	Cheng L, Roth LM, Zhang S, Wang M, Morton MJ, Zheng W, Karim Abdul FW, Montironi R and Lopez-Beltran A: KIT gene mutation and amplification in dysgerminoma of the ovary. Cancer. 117:2096–2103. 2011. View Article : Google Scholar : PubMed/NCBI
23	Lennartsson J and Rönnstrand L: Stem cell factor receptor/c-Kit: From basic science to clinical implications. Physiol Rev. 92:1619–1649. 2012. View Article : Google Scholar : PubMed/NCBI
24	Bodemer C, Hermine O, Palmérini F, Yang Y, Grandpeix-Guyodo C, Leventhal PS, Hadj-Rabia S, Nasca L, Georgin-Lavialle S, Cohen-Akenine A, et al: Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations. J Invest Dermatol. 130:804–815. 2010. View Article : Google Scholar : PubMed/NCBI
25	Corbin AS, O'Hare T, Gu Z, Kraft IL, Eiring AM, Khorashad JS, Pomicter AD, Zhang TY, Eide CA, Manley PW, et al: KIT signaling governs differential sensitivity of mature and primitive CML progenitors to tyrosine kinase inhibitors. Cancer Res. 73:5775–5786. 2013. View Article : Google Scholar : PubMed/NCBI
26	Calibasi G, Baskin Y, Alyuruk H, Cavas L, Oztop I, Sagol O, Atila K, Ellidokuz H and Yilmaz U: Molecular analysis of the KIT gene in gastrointestinal stromal tumors with novel mutations. Appl Immunohistochem Mol Morphol. 22:37–45. 2014. View Article : Google Scholar : PubMed/NCBI
27	Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, et al: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 21:4342–4349. 2003. View Article : Google Scholar : PubMed/NCBI
28	Corless CL, Ballman KV, Antonescu CR, Kolesnikova V, Maki RG, Pisters PW, Blackstein ME, Blanke CD, Demetri GD, Heinrich MC, et al: Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial. J Clin Oncol. 32:1563–1570. 2014. View Article : Google Scholar : PubMed/NCBI
29	Hou YY, Tan YS, Sun MH, Wei YK, Xu JF, Lu SH, A-Ke-Su SJ, Zhou YN, Gao F, Zheng AH, et al: C-kit gene mutation in human gastrointestinal stromal tumors. World J Gastroenterol. 10:1310–1314. 2004.PubMed/NCBI
30	Tetzlaff ED and Davey MP: Optimizing adherence to adjuvant imatinib in gastrointestinal stromal tumor. J Adv Pract Oncol. 4:238–250. 2013.PubMed/NCBI