Oncogenes hijack a constitutively activeTP53promoter in osteosarcoma

Abstract

AbstractThe 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 normalTP53gene 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 aTP53promoter relocated in this manner, we performed in-depth genetic analyses of osteosarcoma biopsies (n=148) and cell models. We show thatTP53structural variations not only facilitate further chromosomal alterations, but also allow the constitutively activeTP53promoter to upregulate putative oncogenes erroneously placed under its control. Paradoxically, many of the induced genes are part of theTP53-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.