title: Prognostic significance of allelic imbalance at the c-kit gene locus and c-kit overexpression by immunohistochemistry in pediatric osteosarcomas.
abstract: OBJECTIVE
  Since the recent development of biologic agents targeting oncogenes, increasing attention has been focused on determining the role of tyrosine kinase receptors in the pathogenesis of tumors. Our study was designed to investigate the status of region 4q12, which contains the candidate gene c-kit, and the expression of c-kit by immunohistochemistry (IHC).
  
  
  METHODS
  Paired blood and biopsy specimens of 68 children treated for high-grade primary osteosarcomas were collected. Microsatellite analysis at two genomic sites containing c-kit gene was performed on paired DNA using a sensible fluorescent polymerase chain reaction technology. To confirm the DNA data, we studied c-kit protein expression by IHC in 56 available paraffin-embedded tumor tissues.
  
  
  RESULTS
  The frequency of allelic imbalance (AI) at locus 4q12 was 39% in the overall population. In agreement with previous studies, we did not detect microsatellite instability, allowing us to hypothesize that this pathway is not implicated. Furthermore, the normal status at locus 4q12 was associated with a significantly better survival in the whole osteosarcoma population (P = .05). IHC overexpression of c-kit was concordant in all cases presenting an AI. However, normal status at locus 4q12 was correlated to an absence of c-kit protein expression in 19 (65.5%) of 29 informative cases.
  
  
  CONCLUSIONS
  Allelotyping of locus 4q12, which contains the c-kit gene, could help pediatric osteosarcoma prognostic screening and showed a strong correlation with overexpression of c-kit protein. These results allowed us to hypothesize that, in some cases, a mutation of c-kit gene could lead to a protein overexpression.
authors.affiliation: Pédiatrie Onco-Hématologie, CHRU Hautepierre, Avenue Molière, 67098 Strasbourg Cedex, France. Natacha.entz-werle@chru-strasbourg.fr
authors.forename: Natacha
authors.initials: N
authors.lastname: Entz-Werlé
authors.forename: Luc
authors.initials: L
authors.lastname: Marcellin
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Gaub
authors.forename: Eric
authors.initials: E
authors.lastname: Guerin
authors.forename: Anne
authors.initials: A
authors.lastname: Schneider
authors.forename: Perrine
authors.initials: P
authors.lastname: Berard-Marec
authors.forename: Chantal
authors.initials: C
authors.lastname: Kalifa
authors.forename: Laurence
authors.initials: L
authors.lastname: Brugiere
authors.forename: Helène
authors.initials: H
authors.lastname: Pacquement
authors.forename: Claudine
authors.initials: C
authors.lastname: Schmitt
authors.forename: Marie-Dominique
authors.initials: MD
authors.lastname: Tabone
authors.forename: Corinne
authors.initials: C
authors.lastname: Jeanne-Pasquier
authors.forename: Philippe
authors.initials: P
authors.lastname: Terrier
authors.forename: Frédérique
authors.initials: F
authors.lastname: Dijoud
authors.forename: Pierre
authors.initials: P
authors.lastname: Oudet
authors.forename: Patrick
authors.initials: P
authors.lastname: Lutz
authors.forename: Annie
authors.initials: A
authors.lastname: Babin-Boilletot
mesh_terms: D000293:Adolescent; D000328:Adult; D022981:Allelic Imbalance; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002894:Chromosomes, Human, Pair 4; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis* / Q000235:genetics*; D016019:Survival Analysis
chemical_list: D004273:DNA, Neoplasm; D019009:Proto-Oncogene Proteins c-kit