Involvement of C-KIT Mutation in the Development of Gastrointestinal Stromal Tumors Through Proliferation Promotion and Apoptosis Inhibition

Overview

Journal Onco Targets Ther

Publisher Dove Medical Press

Specialty Oncology

Date 2014 May 17

PMID 24833907

Citations 10

Authors

Ying-Yu Ma

Sheng Yu

Xu-Jun He

Yuan Xu

Fang Wu

Ying-Jie Xia

Kun Guo

Hui-Ju Wang

Zai-Yuan Ye

Wei Zhang

Hou-Quan Tao

Affiliations

Soon will be listed here.

Abstract

The aim of this study was to discuss the role of c-KIT mutation in the pathogenesis of gastrointestinal stromal tumors (GISTs) and analyze its correlation with proliferation and apoptosis. c-KIT and PDGFRA genotypes were examined by deoxyribonucleic acid sequencing. Immunohistochemistry was performed to determine the expression levels of Kit, Ki-67 (proliferation marker), and apoptotic protease-activating factor (APAF)-1 (apoptosis marker) and the relationship between their three genes. In the 68 cases examined, 44 cases (64.7%) showed mutations in one of the four exons of c-KIT. The mutations were most frequently found in exon 11 (30 cases [44.1%]), followed by exon 9 (ten cases [14.7%]) and exon 13 (four cases [5.9%]). c-KIT mutation showed no association with prognostic factors using the classification of risk of aggressive behavior in GIST proposed by Fletcher et al. No cases had mutated exon 17 of c-KIT, and neither did exon 12, 14, or 18 of PDGFRA in our present study. There was a positive correlation between the expression level of Kit and Ki-67 (R=0.282, P=0.020). Conversely, a negative correlation was found between the expression levels of Kit and APAF1 (R=-0.243, P=0.046). In conclusion, most GISTs with Kit expression showed c-KIT mutation. Kit expression has a positive correlation with Ki-67 and a negative correlation with APAF1, showing that c-KIT is involved in GIST occurrence and development through proliferation promotion and apoptosis inhibition.

Citing Articles

Bioinformatic analysis of KIT juxtamembrane domain mutations in Syrian GIST patients: jigsaw puzzle completed.

Pharaon N, Habbal W, Monem F J Egypt Natl Canc Inst. 2023; 35(1):25.

PMID: 37574490 DOI: 10.1186/s43046-023-00185-0.

c-kit2 G-quadruplex stabilized via a covalent probe: exploring G-quartet asymmetry.

Peterkova K, Durnik I, Marek R, Plavec J, Podbevsek P Nucleic Acids Res. 2021; 49(15):8947-8960.

PMID: 34365512 PMC: 8421218. DOI: 10.1093/nar/gkab659.

Prognostic Impact of MicroRNA and Its Target Genes in Localized High-Risk Intestinal GIST: A Spanish Group for Research on Sarcoma (GEIS) Study.

Fernandez-Serra A, Moura D, Sanchez-Izquierdo M, Calabuig-Farinas S, Lopez-Alvarez M, Martinez-Martinez A Cancers (Basel). 2020; 12(10).

PMID: 33066614 PMC: 7602387. DOI: 10.3390/cancers12102979.

Therapeutic Potential of PI3K/AKT/mTOR Pathway in Gastrointestinal Stromal Tumors: Rationale and Progress.

Duan Y, Haybaeck J, Yang Z Cancers (Basel). 2020; 12(10).

PMID: 33066449 PMC: 7602170. DOI: 10.3390/cancers12102972.

Gastrointestinal stromal tumors (GIST): Facing cell death between autophagy and apoptosis.

Ravegnini G, Sammarini G, Nannini M, Pantaleo M, Biasco G, Hrelia P Autophagy. 2017; 13(3):452-463.

PMID: 28055310 PMC: 5361605. DOI: 10.1080/15548627.2016.1256522.

References

Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S . Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998; 279(5350):577-80. DOI: 10.1126/science.279.5350.577. View

Heinrich M, Corless C, Demetri G, Blanke C, von Mehren M, Joensuu H . Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003; 21(23):4342-9. DOI: 10.1200/JCO.2003.04.190. View

Bachet J, Hostein I, Le Cesne A, Brahimi S, Beauchet A, Tabone-Eglinger S . Prognosis and predictive value of KIT exon 11 deletion in GISTs. Br J Cancer. 2009; 101(1):7-11. PMC: 2713701. DOI: 10.1038/sj.bjc.6605117. View

Heinrich M, Corless C, Duensing A, McGreevey L, Chen C, Joseph N . PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003; 299(5607):708-10. DOI: 10.1126/science.1079666. View

Antonescu C, Sommer G, Sarran L, Tschernyavsky S, Riedel E, Woodruff J . 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(9):3329-37. View

Fletcher C, Berman J, Corless C, Gorstein F, Lasota J, Longley B . Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol. 2002; 33(5):459-65. DOI: 10.1053/hupa.2002.123545. View

Pawson T . Regulation and targets of receptor tyrosine kinases. Eur J Cancer. 2003; 38 Suppl 5:S3-10. DOI: 10.1016/s0959-8049(02)80597-4. View

Hirota S, Ohashi A, Nishida T, Isozaki K, Kinoshita K, Shinomura Y . Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology. 2003; 125(3):660-7. DOI: 10.1016/s0016-5085(03)01046-1. View

Corless C, Heinrich M . Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol. 2007; 3:557-86. DOI: 10.1146/annurev.pathmechdis.3.121806.151538. View

10.

Besmer P, Murphy J, George P, Qiu F, Bergold P, Lederman L . A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family. Nature. 1986; 320(6061):415-21. DOI: 10.1038/320415a0. View

11.

Emile J, Theou N, Tabone S, Cortez A, Terrier P, Chaumette M . Clinicopathologic, phenotypic, and genotypic characteristics of gastrointestinal mesenchymal tumors. Clin Gastroenterol Hepatol. 2004; 2(7):597-605. DOI: 10.1016/s1542-3565(04)00243-5. View

12.

Sawhney N, Hall P . Ki67--structure, function, and new antibodies. J Pathol. 1992; 168(2):161-2. DOI: 10.1002/path.1711680202. View

13.

Yasuda A, Sawai H, Takahashi H, Ochi N, Matsuo Y, Funahashi H . The stem cell factor/c-kit receptor pathway enhances proliferation and invasion of pancreatic cancer cells. Mol Cancer. 2006; 5:46. PMC: 1634869. DOI: 10.1186/1476-4598-5-46. View

14.

Yarden Y, Kuang W, Coussens L, MUNEMITSU S, Dull T, Chen E . Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J. 1987; 6(11):3341-51. PMC: 553789. DOI: 10.1002/j.1460-2075.1987.tb02655.x. View

15.

Wardelmann E, Losen I, Hans V, Neidt I, Speidel N, Bierhoff E . 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(6):887-95. DOI: 10.1002/ijc.11323. View

16.

Heinrich M, Maki R, Corless C, Antonescu C, Harlow A, Griffith D . Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008; 26(33):5352-9. PMC: 2651076. DOI: 10.1200/JCO.2007.15.7461. View

17.

DeMatteo R, Gold J, Saran L, Gonen M, Liau K, Maki R . Tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Cancer. 2007; 112(3):608-15. DOI: 10.1002/cncr.23199. View

18.

Karin M . Signal transduction from cell surface to nucleus in development and disease. FASEB J. 1992; 6(8):2581-90. DOI: 10.1096/fasebj.6.8.1317309. View

19.

Zsebo K, Williams D, Geissler E, Broudy V, Martin F, Atkins H . Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell. 1990; 63(1):213-24. DOI: 10.1016/0092-8674(90)90302-u. View

20.

Lasota J, Dansonka-Mieszkowska A, Sobin L, Miettinen M . A great majority of GISTs with PDGFRA mutations represent gastric tumors of low or no malignant potential. Lab Invest. 2004; 84(7):874-83. DOI: 10.1038/labinvest.3700122. View