Expression of proto-oncogene KIT is up-regulated in subset of human meningiomas.
BACKGROUND
KIT is a proto-oncogene involved in diverse neoplastic processes. Aberrant kinase activity of the KIT receptor has been targeted by tyrosine kinase inhibitor (TKI) therapy in different neoplasias. In all the earlier studies, KIT expression was reported to be absent in meningiomas. However, we observed KIT mRNA expression in some meningioma cases. This prompted us to undertake its detailed analyses in meningioma tissues resected during 2008-2009.


METHODS
Tumor tissues and matched peripheral blood samples collected from meningioma patients were used for detailed molecular analyses. KIT expression was ascertained immunohistochemically and validated by immunoblotting. KIT and KITLG transcript levels were discerned by reverse transcription quantitative real-time PCR (RT-qPCR). Similarly, KIT amplification and allele loss were assessed by quantitative real-time (qPCR) and validated by fluorescence in situ hybridization (FISH) on the neoplastic tissues. Possible alterations of the gene at the nucleotide level were analyzed by sequencing.


RESULTS
Contrary to earlier reports, KIT expression, was detected immunohistochemically in 20.6% meningioma cases (n = 34). Receptor (KIT) and ligand (KITLG) transcripts monitored by RT-qPCR were found to co-express (p = 0.048) in most of the KIT immunopositive tumors. 1/7 KIT positive meningiomas showed allele loss corroborated by reduced FISH signal in the corresponding neoplastic tissue. Sequence analysis of KIT showed M541L substitution in exon 10, in one of the immunopositive cases. However, its biological consequence remains to be uncovered.


CONCLUSIONS
This study clearly demonstrates KIT over-expression in the human meningiomas. The data suggest that up-regulated KIT transcription (p < 0.001), instead of gene amplification (p > 0.05), is a likely mechanism responsible for altered KIT expression. Thus, KIT is a potential candidate for detailed investigation in the context of meningioma pathogenesis.
Molecular Genetics Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
Masum
M
Saini
Ajaya Nand
AN
Jha
Andleeb
A
Abrari
Sher
S
Ali
D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D005091:Exons; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008577:Meningeal Neoplasms / Q000235:genetics* / Q000473:pathology; D008579:Meningioma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D060787:Neoplasm Grading; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit