Frequent genomic abnormalities at TWIST in human pediatric osteosarcomas.

The identification of genes as markers for chromosome aberrations in specific tumors might facilitate oncogenesis mechanism comprehension, cancer detection, prediction of clinical outcomes, and response to therapy. Previous physiologic and oncologic data identified the TWIST gene as a marker for mesodermal derivative and bone tissue differentiation, but its contribution to bone malignancies has not been investigated. In the present study, search for genomic alterations in high-grade pediatric osteosarcomas was focused on the 7p21 region, and more specifically on the TWIST gene. In a cohort of 74 patients, we observed by allelotyping that 31 of 68 informative tumors were rearranged at the TWIST locus. Among them, analysis by quantitative PCR (QPCR) revealed that, surprisingly, mostly deletions (22/68), but also amplifications (9/68), of the TWIST gene were detected. Furthermore, deletions at TWIST were statistically correlated to other molecular abnormalities, like alterations at the APC or c-kit loci, as well as to clinical features such as a poor outcome. This work shows that the TWIST gene seemed to be involved in high-grade pediatric osteosarcomas and is a new marker with a possible initial predictive value.

Prognostic significance of allelic imbalance at the c-kit gene locus and c-kit overexpression by immunohistochemistry in pediatric osteosarcomas.

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.

[Update on rhabdomyosarcomas in children]. / Actualités sur le rhabdomyosarcome chez l'enfant.

Rhabdomyosarcoma is a rare tumour corresponding to 60-70% of soft tissue sarcomas in children. Significant advances in treatment have been made possible, and will be further obtained, by multicentric treatment protocols conducted in paediatric oncology centres. Overall survival and disease-free survival have been significantly improved over the past 30 years. In the meantime, diagnosis improvements have made the classification of rhabdomyosarcomas more complex. A review of European and American studies has evidenced a number of criteria that should be taken into account for selecting treatment strategy: histological examination (refined with the use of molecular biology) had proved very informative, suggesting a worse prognosis for alveolar rhabdomyosarcomas. Other criteria of interest are the tumour site (favourable or unfavourable), patient age (under or above 10), tumour size ( 5 cm), and disease stage. The number of sub-groups of patients requiring different, more adapted treatment strategies increases with the number of prognostic parameters to be considered. For convenient clinical management, patients will therefore be classified into 4 risk groups for systemic therapy (low, standard, high and very high risk), whereas local treatment strategies will take into account the whole set of prognostic criteria defined above.