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Clinical and Molecular Evidence for c-kit Receptor as a Therapeutic Target in Neuroblastic Tumors

Departments of ¹ Experimental Medicine/Pathology and ² Pediatrics, La Sapienza University; ³ Laboratory of Oncology and Divisions of ⁴ Pathology, ⁵ Oncology, and ⁶ Surgery, Bambino Ges Children's Hospital; ⁷ Laboratory of Immunology, Regina Elena National Cancer Institute; ⁸ Section of Toxicology and Biomedical Sciences, ENEA Research Center Casaccia; ⁹ Institute of Molecular Biology and Pathology, Consiglio Nazionale delle Ricerche, Rome, Italy; ¹⁰ Laboratory of Neuroblastoma, National Institute for Cancer Research, Genoa, Italy; Divisions of ¹¹ Oncology, ¹² Pathology, and ¹³ Surgery, RLC NHS Trust Alder Hey, Liverpool, United Kingdom; and ¹⁴ Department of Pathology, University of Kiel, Kiel, Germany

Requests for reprints: Stefania Uccini, Department of Experimental Medicine and Pathology, La Sapienza University, Viale Regina Elena 324, I-00161 Rome, Italy. Phone: 906-446-9903; Fax: 906-494-0896; E-mail:stefania.uccini{at}uniroma1.it.

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 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.

Key Words: Neuroblastoma • c-kit • Stem Cell Factor • Tyrosine Kinase Receptors • Imatinib mesylate

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