Osteosarcoma: An Evolving Understanding of a Complex Disease

John H. Alexander, MD; Odion T. Binitie, MD; G. Douglas Letson, MD; David M. Joyce, MD


J Am Acad Orthop Surg. 2021;29(20):e993-e1004. 

In This Article

Molecular Genetics

Osteosarcoma is genetically complex without a single requisite mutation or translocation. Mutations commonly involve tumor suppressor genes which contribute to the observed genetic instability. Certain hereditary syndromes are associated with an increased risk of osteosarcoma, most commonly Li-Fraumeni syndrome (TP53), hereditary retinoblastoma (RB1), Rothmund-Thomson syndrome, Bloom syndrome, RAPADILINO syndrome, Diamond-Blackfan anemia, and Werner syndrome. Most osteosarcoma cases are thought to be sporadic; however, using genome sequencing techniques, high rates (28%) of likely pathogenic germline variants in cancer susceptibility genes have been identified in patients with osteosarcoma. Furthermore, germline TP53 variants are associated with younger age at presentation, axial location, and poorer overall survival (OS).[2] However, a direct relationship between these variants and the development of osteosarcoma has not been clearly defined.