Clinical and molecular evidence for c-kit receptor as a therapeutic target in neuroblastic tumors.
OBJECTIVE
Clinicobiological characteristics of neuroblastic tumor (NT) expressing c-kit tyrosine kinase receptor and/or its ligand, stem cell factor (SCF), are debated. This study aimed at investigating the clinicobiological features of primary NTs expressing c-kit and/or SCF in order to define the clinical relevance of selective therapeutic targeting.


METHODS
c-Kit and SCF expression was studied in 168 NTs using immunohistochemistry and in 106 of 168 using Northern blot. Quantitative determination of c-kit expression in 54 additional NTs was also done using real-time reverse transcription-PCR. Correlations between c-kit and SCF expression and clinicobiological features were analyzed using chi2 test, univariate, and multivariate regression analyses.


RESULTS
c-Kit protein was detected in 21 of 168 NTs (13%) and its mRNA in 23 of 106 NTs (22%). SCF protein was shown in 30 of 106 NTs (28%) and its mRNA in 33 of 106 NTs (31%). No mutations in exon 11 of c-kit gene were identified. By univariate analysis, c-kit and SCF expression correlated with advanced stage, MYCN amplification, and 1p36 allelic loss. Cox simple regression analysis showed that overall survival probability was 17% in the c-kit-positive subset versus 68% in the negative (P < 0.001), 43% in the SCF-positive subset versus 78% in the negative (P < 0.001). When using real-time reverse transcription-PCR, significant levels of c-kit mRNA were found in 35 of 54 NTs (65%), but the correlations with clinicobiological features were no longer documented.


CONCLUSIONS
c-Kit expression can be detected in the majority of primary NTs. High levels of expression are preferentially found in tumors with unfavorable clinicobiological variables. c-Kit may represent a useful therapeutic target in a subset of otherwise untreatable NTs.
Uccini
Stefania
S
Department of Experimental Medicine/Pathology, La Sapienza University, Rome, Italy. stefania.uccini@uniroma1.it
Mannarino
Olga
O
McDowell
Heather P
HP
Pauser
Ursula
U
Vitali
Roberta
R
Natali
Pier Giorgio
PG
Altavista
Pierluigi
P
Andreano
Tiziana
T
Coco
Simona
S
Boldrini
Renata
R
Bosco
Sandro
S
Clerico
Anna
A
Cozzi
Denis
D
Donfrancesco
Alberto
A
Inserra
Alessandro
A
Kokai
George
G
Losty
Paul D
PD
Nicotra
Maria R
MR
Raschellà
Giuseppe
G
Tonini
Gian Paolo
GP
Dominici
Carlo
C
D000293:Adolescent; D000367:Age Factors; D000483:Alleles; D015152:Blotting, Northern; D015139:Blotting, Southern; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D015999:Multivariate Analysis; D009154:Mutation; D009447:Neuroblastoma / Q000628:therapy*; D010766:Phosphorylation; D016016:Proportional Hazards Models; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019089:Stem Cell Factor / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
D012333:RNA, Messenger; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit