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Osteosarcoma is the most common malignant primary bone tumor among children and adolescents. Patterns of presentation and clinical progression have been well-characterized, and cytogenetic and molecular analyses have demonstrated genomic complexity with a substantial degree of structural variation. Nevertheless, extensive research has facilitated only limited understanding of the molecular events that govern oncogenic transformation of a mesenchymal progenitor or that drive clinical phenotypes such as metastasis and chemoresponsiveness. Initial clinical management of patients is well-standardized, and the majority of patients whose tumors are localized at the time of presentation, are amenable to effective surgical resection, and exhibit extensive tumoricidal response to chemotherapy can enjoy long term survival. Outcomes for the significant proportion of patients differing with respect to any one of these clinical characteristics are much less favorable, however, and therapeutic strategies to address clinically advanced disease and chemoresistance to date have been disappointing. This review will discuss the current understanding of OS oncogenesis, clinical presentation, and the status of OS clinical management. The discussion will focus on genetic and epigenetic events associated with chemoresistance in OS and the insights such a mechanistic understanding may offer toward circumventing this major clinical barrier.