Osteosarcoma is an extremely genetically unstable tumor with multiple numerical and structural chromosomal alterations. Chromothripsis and alternative lengthening of telomeres are potential sources of the instability. Genomic profiling of tumor DNA using comparative genomic hybridization (CGH), single-nucleotide polymorphism (SNP) arrays, and whole-genome sequencing (WGS) has revealed some recurrent chromosomal alterations. The roles of TP53 and RB pathway genes are well established as are the contributions of a variety of other oncogenes and tumor suppressor genes. Three of the RECQ helicases (RECQL4, WRN (RECQL2), and BLM (RECQL3)) are associated with autosomal recessive syndromes with an increased risk of osteosarcoma. Recent data suggest that miRNAs are differentially expressed in osteosarcoma, suggesting a novel posttranslational mechanism for fine-tuning the pathways relevant to osteosarcoma. Furthermore, the frontier is now moving toward a better understanding of tumor progression, metastasis, and a therapeutic response to this tumor. We expect that our knowledge of basic molecular events involved in osteosarcoma will further advance our understanding of this disease and highlight treatment modalities directed at these basic molecular pathways.
