The consequence of oncomorphic TP53 mutations in ovarian cancer

Abstract

Ovarian cancer is the most lethal gynecological malignancy, with an alarmingly poor prognosis attributed to late detection and chemoresistance. Initially, most tumors respond to chemotherapy but eventually relapse due to the development of drug resistance. Currently, there are no biological markers that can be used to predict patient response to chemotherapy. However, it is clear that mutations in the tumor suppressor gene TP53, which occur in 96% of serous ovarian tumors, alter the core molecular pathways involved in drug response. One subtype of TP53 mutations, widely termed gain-of-function (GOF) mutations, surprisingly converts this protein from a tumor suppressor to an oncogene. We term the resulting change an oncomorphism. In this review, we discuss particular TP53 mutations, including known oncomorphic properties of the resulting mutant p53 proteins. For example, several different oncomorphic mutations have been reported, but each mutation acts in a distinct manner and has a different effect on tumor progression and chemoresistance. An understanding of the pathological pathways altered by each mutation is necessary in order to design appropriate drug interventions for patients suffering from this deadly disease.

Figure 1

The spectrum of protection against cancer provided by WT p53. As copies of WT p53 (TP53^+/+) are lost, cancer protection decreases. When oncomorphic mutations are acquired, cancer susceptibility is increased.

Figure 2

Hotspots for TP53 mutations. Mutations that occur at a frequency greater than 3% are highlighted. Certain p53 mutants have oncomorphic activity (denoted by ^*), functioning through novel protein interactions as well as novel transcriptional targets to promote cell survival and potentially chemoresistance. Codons in the “other” category include those that produce non-functional p53 or have not been characterized to date.

Figure 3

Proposed strategies for uncovering oncomorphic p53 functions: (a) Example of an experimental outline used to understand the function of specific TP53 mutants. Two cellular models are employed: (1) In cells containing WT p53, an shRNA can be stably expressed to knock down endogenous p53, while simultaneously overexpressing an shRNA-resistant oncomorphic p53 mutant; (2) Cells with LOF TP53 mutations that do not produce a p53 protein can be used to overexpress oncomorphic p53 variants. Both of these models can then be used to examine the effect of each p53 mutant compared to control cells; (b) Example of identifying endogenous p53 function in various ovarian cancer cell lines. Top panel, baseline p53 expression in SKOV3 cells (LOF TP53, nonsense mutation), TOV112D (oncomorphic p53, R175H), and UCI-107 cells (WT p53). Middle panel, expression of p21, a marker of WT p53 activation, was assessed 10 h after 8 Gy radiation-induced DNA damage. Bottom panel, stabilization of p53 expression was demonstrated 10 h after irradiation.