A recent genetic and transcriptomic study on 148 osteosarcoma patients published by Saba, Difilippo et al. [7] provides a novel paradigm in which TP53 rearrangements can simultaneously result in inactivation of p53 tumour suppressor functions and activation of oncogenic pathways by fusing the TP53 promoter region to new target genes (promoter swapping). In ~40% of analysed cases, evidence for TP53 promoter translocation was found, and in ~20% of cases, a putative fusion partner was readily identified. The authors further demonstrated that the resulting fusions were in-frame, and transcription of the TP53 fusion partner was increased. At the same time, expression of TP53 was lost, suggesting that promoter translocations of one TP53 allele co-occur with inactivating genetic aberrations of the other allele in osteosarcoma, and a selective advantage can be inferred. Functionally, the authors elegantly showed that DNA damage induced by cisplatin (a front-line drug to treat osteosarcoma) readily induced expression of the fusion partner in several different cell lines with different fusion partners.

Hence, these translocations do not only bring potential oncogenes under the control of the TP53 promoter, but they also disrupt the expression of a functional p53 protein. In essence, this results in both disruption of safeguarding TP53 responses upon, e.g., replication stress, reactive oxygen species and DNA damage and rewiring of the upstream stress response machinery to effector functions of a potentially oncogenic fusion partner (Fig. 1). In fact, a subset of the identified fusion partners had already been implicated in the pathobiology of osteosarcoma and other malignancies.

Upper panel: Cellular stress results in transactivation of the TP53 promoter, leading to transcription and eventually translation of TP53 protein whose transcriptional activity is responsible for physiological stress responses like cell cycle arrest, DNA repair and apoptosis. Lower panel: Translocation of the TP53 promoter brings an oncogene under the control of cellular stress, which can cause oncogenesis, treatment resistance and tumour survival.

Of note, this separation-of-function paradigm (a term originally developed for specific TP53 missense mutations [6]) combines a canonical loss-of-function of the TP53 gene body with the overexpression of an oncogene through TP53 promoter hijacking as described in other tumours like lipoblastoma [8].