7.P.55 BONE DEVELOPMENT GENE DEREGULATION IS INVOLVED IN HIGH GRADE PEDIATRIC OSTEOSARCOMA ONCOGENESIS AND IN THEIR PROGNOSTIC OUTCOME

Abstract

Dysregulation of differentiation genes involved in developmental signaling pathways seems to be a decisive event taking part in the multistep oncogenesis. As high grade osteosarcomas are histologically defined by the presence of malignant osteoblasts producing an osteoid component, we focused in a pediatric cohort, homogeneously treated with the French OS94 protocol, on the genomic status at diagnosis on tumor biopsies of several genes involved in flat and long bone formation.

Material and methods: In 91 pediatric osteosarcomas, allelotyping analysis of FGFRs, TWIST, DERMO1, APC, MET, HGF, and SDC2 was done. After DNA extraction of paired blood and tumor samples, each locus was analysed by microsatellites bordering closely on each side the targeted genes. Complementary real-time quantitative PCR of TWIST, FGFRs and MET genes and sequencing of APC and TWIST were performed to determine gene status.

Results: The allelotyping results support the frequent role of each gene: 53.1% of allelic imbalances (AI) were found in 7p21.2 (TWIST), 35.3% in 2q37.3 (DERMO1), 38% in 5q21 (APC), 42.5% in 7q31 (MET), 45.5% in 7q21.1 (HGF) and 49% for 8q22 (SDC2). TWIST and MET were mainly deleted and no additional APC and TWIST mutations were identified. Surprisingly, FGFR1 to 4 are only abnormal in small subgroups. Significant associations were found combining the presence of MET AI to HGF abnormalities and the presence of MET, TWIST and APC losses. A worse outcome was significantly linked to the presence of MET, TWIST and APC losses (p=0.05, 0.04 and 0.02, respectively) but the subgroup combining MET and HGF abnormalities seems to have a better survival. No correlations was done with other clinical data.

Conclusion: Several genes involved in normal bone development seem to have a role in osteosarcoma development but also to modulate the prognostic outcome of these pediatric patients.