Oncogenes hijack a constitutively active TP53 promoter in osteosarcoma

Abstract

How massive genome rearrangements confer a competitive advantage to a cancer cell has remained an enigma. The malignant bone tumour osteosarcoma harbours an extreme number of structural variations and thereby holds the key to understand complex cancer genomes. Genome integrity in osteosarcoma is generally lost together with disruption of normal TP53 gene function, the latter commonly through either missense mutations or structural alterations 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 are early events that not only facilitate further chromosomal alterations, but also allow the TP53 promoter to upregulate genes erroneously placed under its control. Paradoxically, many of the induced genes are part of the TP53-associated transcriptome, suggesting a need to counterbalance loss of TP53 function through separation-of-function mutations via promoter swapping. Our findings demonstrate how massive genome errors can functionally turn the promoter region of a tumour suppressor gene into a constitutively active oncogenic driver.