TP53 separation-of-function mutations through promoter swapping in osteosarcoma

Abstract

TP53 is a tumour suppressor gene but typically shows recurrent missense mutations or retained structural alterations in cancer, indicative of a concurrent loss- and gain-of-function mechanism. Structural variants in TP53 often result in loss of the coding parts of the gene while simultaneously preserving the promoter region. This phenomenon is particularly common in osteosarcoma, the most common primary bone malignancy. To unravel the consequences of a TP53 promoter relocated in this manner, we performed in-depth genetic analyses of osteosarcoma biopsies and cell models. We show that TP53 structural variants are early events that denote a subgroup of young osteosarcoma patients, frequently associated with positive selection for the TP53 promoter and a high breakpoint burden. Furthermore, the active TP53 promoter region paradoxically upregulates genes significantly associated with the TP53 signalling pathway itself. This suggests that while tumor supressor actitivites of the TP53 pathway are lost, survival and proliferative features are retained. Our findings demonstrate a need to counterbalance loss of TP53 function through separation-of-function mutations via promoter swapping.