Oncogenes hijack a constitutively active TP53 promoter in osteosarcoma

The malignant bone tumor osteosarcoma harbors an extreme number of chromosome rearrangements. How such massive DNA errors confer a competitive advantage to a cancer cell has remained an enigma. Osteosarcoma typically presents mutations disrupting normal TP53 gene function, frequently in the form of structural rearrangements that separate the promoter region from the coding parts of the gene. To unravel the consequences of a TP53 promoter relocated in this manner, we performed in-depth genetic analyses of osteosarcoma biopsies (n=148) and cell models. We show that TP53 structural variations not only facilitate further chromosomal alterations, but also allow the constitutively active TP53 promoter to upregulate putative oncogenes erroneously placed under its control. Paradoxically, many of the induced genes are part of the TP53-associated transcriptome, suggesting a need to counterbalance the initial loss of function. Our findings demonstrate how the promoter region of a tumor suppressor gene can functionally turn into an oncogenic driver.