Abstract
Osteosarcoma is the most common malignancy of bone, and occurs most frequently in children and adolescents. Currently, the most reliable technique for determining a patients’ prognosis is measurement of histopathologic tumor necrosis following pre-operative neo-adjuvant chemotherapy. Unfavourable prognosis is indicated by less than 90% estimated necrosis of the tumor. Neither genetic testing nor molecular biomarkers for diagnosis and prognosis have been described for osteosarcomas. We used the novel nanoString mRNA digital expression analysis system to analyse gene expression in 32 patients with sporadic paediatric osteosarcoma. This system used specific molecular barcodes to quantify expression of a set of 17 genes associated with osteosarcoma tumorigenesis. Five genes, from this panel, which encoded the bone differentiation regulator RUNX2, the cell cycle regulator CDC5L, the TP53 transcriptional inactivator MDM2, the DNA helicase RECQL4, and the cyclin-dependent kinase gene CDK4, were differentially expressed in tumors that responded poorly to neo-adjuvant chemotherapy. Analysis of the signalling relationships of these genes, as well as other expression markers of osteosarcoma, indicated that gene networks linked to RB1, TP53, PI3K, PTEN/Akt, myc and RECQL4 are associated with osteosarcoma. The discovery of these networks provides a basis for further experimental studies of role of the five genes (RUNX2, CDC5L, MDM2, RECQL4, and CDK4) in differential response to chemotherapy.
Highlights
Osteosarcoma is the most common primary malignant bone tumor arising from bone in children and adolescents
Chemotherapy followed by surgical resection is the standard treatment for high-grade osteosarcoma, and the current drug regimen is a combination of high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide
An unsupervised clustering was performed using Cluster 3.0 and Java tree view to determine the aggregation of the 40 RNA samples from the cohort in comparison to normal human osteoblasts and three osteosarcoma cell lines (Figure S1)
Summary
Osteosarcoma is the most common primary malignant bone tumor arising from bone in children and adolescents. Chemotherapy followed by surgical resection is the standard treatment for high-grade osteosarcoma, and the current drug regimen is a combination of high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide. Histopathologic examination to estimate tumor necrosis following neo-adjuvant pre-operative chemotherapy is currently one of the most reliable tools for response evaluation and prognostication. Unfavorable response, corresponding to a bad prognosis, is indicated by less than 90% estimated necrosis of the tumor following neo-adjuvant chemotherapy [1]. A large number of gene products have potential for driving oncogenesis or disease progression in osteosarcoma [4]. This complex biology of osteosarcoma has limited the identification of reliable molecular biomarkers for tumor classification or therapeutic targeting
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