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Prognostic Significance of Allelic Imbalance at the c-kit Gene Locus and c-kit Overexpression by Immunohistochemistry in Pediatric Osteosarcomas

From the Laboratoire de Biochimie et Biologie Moléculaire and Service de Pédiatrie Onco-Hématologie, Centre Hospitalier et Universitaire (CHRU) Hautepierre; Service d'Anatomie Pathologique, CHRU Strasbourg; Inserm U381, Strasbourg; Centre Anticancéreux Léon Bérard, Lyon; Institut Gustave Roussy, Villejuif; Service de Pédiatrie Oncologique, Institut Curie; Service de Pédiatrie Onco-Hématologie, Hôpital Trousseau, Paris; Service de Pédiatrie Onco-Hématologie, CHRU Nancy–Hôpital Brabois, Nancy; and Service d'Anatomopathologie, Centre Hospitalier Universitaire Côte de Nacre, Caen, France

Address reprint requests to Natacha Entz-Werlé, MD, Pédiatrie Onco-Hématologie, CHRU Hautepierre, Avenue Molière, 67098 Strasbourg Cedex, France; e-mail: Natacha.entz-werle{at}chru-strasbourg.fr

PURPOSE: 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).

PATIENTS AND 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.

CONCLUSION: 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.

Supported by funds from a national Programme Hospitaliere de Recherche Clinique.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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