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.

TP53 mutations in high grade serous ovarian cancer and impact on clinical outcomes: a comparison of next generation sequencing and bioinformatics analyses

“…If the mutation was unclassified by this method, then the Brachova et al . 8 classification was assigned to these cases. If the mutation was still unclassified, the Kang et al  .…”

“…Mutations for each cluster were assigned to each of the six classification schemes as defined by coding effect, the IARC classification,20 Brachova et a l ,8 Kang et a l ,11 our hierarchal system, and the lung classification scheme 21. The chi-square test was performed for each scheme to compare differences in the type of mutations between the cluster with the worse survival and the union of the clusters with better survival.…”

Development and translational imaging of a TP53 porcine tumorigenesis model

“…Compared with the essentially undetectable expression of nonmutated p53 from wild-type pig brain tissue, mutant p53-R167H protein was expressed at higher levels in each malignant sample ( Figure 9A), as anticipated. The porcine p53-R167H mutation, like its human (R175H) and mouse (R172H) counterparts, is expected to behave as a gain-of-function mutant that fails to regulate normal p53 transcriptional targets (such as p21; see Figure 2 and Supplemental Figure 1B) and instead transactivates a new set of oncogenic gene targets, including cyclin B1 (17,39). Indeed, tumors and lymph nodes expressing p53-R167H showed marked upregulation of cyclin B1 protein ( Figure 9A).…”

p53 regulates cytoskeleton remodeling to suppress tumor progression

“…1). Mutations in TP53 frequently occur in the later stages of colorectal, pancreatic, breast, and ovarian cancers [43,44]. There are several different types of TP53 gene mutation, which can be described based on their phenotype.…”