TY - JOUR
T1 - Clinical and molecular evidence for c-kit receptor as a therapeutic target in neuroblastic tumors
AU - Uccini, Stefania
AU - Mannarino, Olga
AU - McDowell, Heather P.
AU - Pauser, Ursula
AU - Vitali, Roberta
AU - Natali, Pier Giorgio
AU - Altavista, Pierluigi
AU - Andreano, Tiziana
AU - Coco, Simona
AU - Boldrini, Renata
AU - Bosco, Sandro
AU - Clerico, Anna
AU - Cozzi, Denis
AU - Donfrancesco, Alberto
AU - Inserra, Alessandro
AU - Kokai, George
AU - Losty, Paul D.
AU - Nicotra, Maria R.
AU - Raschellà, Giuseppe
AU - Tonini, Gian Paolo
AU - Dominici, Carlo
PY - 2005/1/1
Y1 - 2005/1/1
N2 - Purpose: 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. Experimental Design: 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 χ 2 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.
AB - Purpose: 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. Experimental Design: 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 χ 2 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.
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M3 - Article
C2 - 15671569
AN - SCOPUS:19944428974
VL - 11
SP - 380
EP - 389
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 1
ER -