title: Clinical and molecular evidence for c-kit receptor as a therapeutic target in neuroblastic tumors.
abstract: 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.
authors.affiliation: Department of Experimental Medicine/Pathology, La Sapienza University, Rome, Italy. stefania.uccini@uniroma1.it
authors.forename: Stefania
authors.initials: S
authors.lastname: Uccini
authors.forename: Olga
authors.initials: O
authors.lastname: Mannarino
authors.forename: Heather P
authors.initials: HP
authors.lastname: McDowell
authors.forename: Ursula
authors.initials: U
authors.lastname: Pauser
authors.forename: Roberta
authors.initials: R
authors.lastname: Vitali
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Natali
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Altavista
authors.forename: Tiziana
authors.initials: T
authors.lastname: Andreano
authors.forename: Simona
authors.initials: S
authors.lastname: Coco
authors.forename: Renata
authors.initials: R
authors.lastname: Boldrini
authors.forename: Sandro
authors.initials: S
authors.lastname: Bosco
authors.forename: Anna
authors.initials: A
authors.lastname: Clerico
authors.forename: Denis
authors.initials: D
authors.lastname: Cozzi
authors.forename: Alberto
authors.initials: A
authors.lastname: Donfrancesco
authors.forename: Alessandro
authors.initials: A
authors.lastname: Inserra
authors.forename: George
authors.initials: G
authors.lastname: Kokai
authors.forename: Paul D
authors.initials: PD
authors.lastname: Losty
authors.forename: Maria R
authors.initials: MR
authors.lastname: Nicotra
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Raschellà
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.forename: Carlo
authors.initials: C
authors.lastname: Dominici
mesh_terms: 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
chemical_list: D012333:RNA, Messenger; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit