Affiliation of authors: Institute of Pathology, University of Basel, Basel, Switzerland.
Correspondence to: Holger Moch, M.D., Institute of Pathology, University of Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland (e-mail: hmoch{at}uhbs.ch).
Analysis of the tyrosine kinase receptor KIT in malignant tumors is important because it can be therapeutically targeted by the tyrosine kinase inhibitor imatinib mesylate (Gleevec or Glivec, formerly STI-571), as demonstrated in gastrointestinal stromal tumors (GISTs) and in Ewings sarcoma (1,2). The oncogenic activating event in most GISTs is mutation of the KIT gene. GISTs with regulatory-region KIT mutations, best characterized in exon 11 of the KIT gene, are more likely to respond to imatinib mesylate than are GISTs with enzymatic-region mutations (3,4).
Immunohistochemical studies of ovarian carcinoma (OC) have shown KIT protein expression rates of up to 87% (5,6). These findings led us to hypothesize that KIT is commonly activated in OC and might be a promising treatment target for this devastating disease, which has a lack of auspicious treatment options. To test our hypothesis, we decided to comprehensively investigate KIT gene and protein expression in all histologic types, stages, and differentiation grades of OC. We first immunohistochemically analyzed KIT protein with a KIT-specific antibody (1 : 300 dilution, 4502; DAKO, Denmark) on a tissue microarray containing tissue samples from 325 OCs. Weak positive KIT protein immunoreactivity was detected in only 14 OC samples. As a specificity control, a preabsorption assay was performed with a peptide with the same sequence used by DAKO to generate the polyclonal KIT antibody (NeoMarkers, product PP1518; Lab Vision, Fremont, CA). Four of the 14 initially KIT-positive neoplasms maintained their immunoreactivity in the preabsorption control assay and were, therefore, excluded. KIT protein was not detected in normal ovarian surface epithelium and stromal cells. In GISTs used as control, 95% of the samples showed a true positive staining. To investigate KIT mutations, purified DNA from microdissected tissue isolated from the 10 tumors with immunohistochemically detected KIT protein and 40 immunonegative OC specimens of all histologic types, stages, and differentiation grades were amplified with a semi-nested polymerase chain reaction (PCR) for exons 2, 8, 9, 11, 13, and 17, and the PCR products were directly sequenced. All 50 tumors had wild-type KIT genes. Unequivocal KIT mutations were detected in GISTs used as control (data not shown).
In contrast to previous reports (5,6), KIT alterations appear to be rare in OC. Because current clinical treatment decisions are based on the immunohistochemical detection of KIT protein (1), we urge that reevaluation of KIT data, including a KIT mutational analysis in particular for imatinib mesylate-susceptible regulatory type mutations, be considered in many other malignancies. In view of the fact that many tyrosine kinases exist with homology to KIT (http://www.ncbi.nih.gov/mapview/map_search.cgi?chr=hum_chr.inf&query=tyrosine+kinase=), other therapeutic targets for imatinib mesylate or other tyrosine kinase inhibitors in OC may be found.
NOTES
Supported by the Swiss Cancer League grant KFS 1090-09-2000 (to H. Moch).
REFERENCES
1 Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:47280.
2 Merchant MS, Woo CW, Mackall CL, Thiele CJ. Potential use of imatinib in Ewings sarcoma: evidence for in vitro and in vivo activity. J Natl Cancer Inst 2002;94:16739.
3 Longley BJ, Reguera MJ, Ma Y. Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy. Leuk Res 2001;25:5716.[CrossRef][ISI][Medline]
4 Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol 2002;33:48495.[CrossRef][ISI][Medline]
5 Arber DA, Tamayo R, Weiss LM. Paraffin section detection of the c-kit gene product (CD117) in human tissues: value in the diagnosis of mast cell disorders. Hum Pathol 1998;29:498504.[ISI][Medline]
6 Tonary AM, Macdonald EA, Faught W, Senterman MK, Vanderhyden BC. Lack of expression of c-KIT in ovarian cancers is associated with poor prognosis. Int J Cancer 2000;89:24250.[CrossRef][ISI][Medline]
This article has been cited by other articles in HighWire Press-hosted journals:
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |