Abstract
Osteosarcoma is a common malignant bone tumor in children and adolescents. The overall survival of osteosarcoma patients is remarkably poor. Herein, we sought to establish a reliable risk prognostic model to predict the prognosis of osteosarcoma patients. Patients ' RNA expression and corresponding clinical data were downloaded from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus databases. A consensus clustering was conducted to uncover novel molecular subgroups based on 200 hypoxia-linked genes. A hypoxia-risk models were established by Cox regression analysis coupled with LASSO regression. Functional enrichment analysis, including Gene Ontology annotation and KEGG pathway analysis, were conducted to determine the associated mechanisms. Moreover, we explored relationships between the risk scores and age, gender, tumor microenvironment, and drug sensitivity by correlation analysis. We identified two molecular subgroups with significantly different survival rates and developed a risk model based on 12 genes. Survival analysis indicated that the high-risk osteosarcoma patients likely have a poor prognosis. The area under the curve (AUC) value showed the validity of our risk scoring model, and the nomogram indicates the model's reliability. High-risk patients had lower Tfh cell infiltration and a lower stromal score. We determined the abnormal expression of three prognostic genes in osteosarcoma cells. Sunitinib can promote osteosarcoma cell apoptosis with down-regulation of KCNJ3 expression. In summary, the constructed hypoxia-related risk score model can assist clinicians during clinical practice for osteosarcoma prognosis management. Immune and drug sensitivity analysis can provide essential insights into subsequent mechanisms. KCNJ3 may be a valuable prognostic marker for osteosarcoma development.