Some aspects of mutant p53 in ovarian cancer biology

Epithelial ovarian cancer (EOC) is known as the most lethal gynaecologic malignancy. The poor prognosis of EOC has been attributed to e.g., late diagnosis of the disease and to chemoresistance. Further, we are still missing biomarkers that may reliably predict prognosis or chemosensitivity of an individual patient.

Mutations of TP53, which encodes the tumour suppressor protein p53, seem to be present in the large majority of serous ovarian cancer cases and are supposed to majorly influence pleiotropic tumour-biologic characteristics of EOC (1). For instance, since p53 plays a critical role in apoptosis and proliferation, loss of active p53 is closely associated with multidrug resistance (2). Intriguingly, unlike other ‘classical’ tumour suppressor genes mutations in TP53 comprise some special features contributing to a complex tumour-biologic phenotype. First, while ‘classical’ tumour suppressor genes (TSGs) commonly undergo mutations that cause either deletion or truncation of the gene product, most of the aberrations detected in TP53 are single base substitutions that cause hyper-stabilization of p53 (3). Second, though wild-type p53 is known as a tumour suppressor, some mutations in TP53 may actively drive oncogenesis by activating tumour promoting processes. Those aberrations that are able to promote tumorigenesis may—due to historical reasons—be termed ‘gain-of-function’ mutations, since oncogenic activities are ‘gained’ while tumour suppressive features are ‘lost’ (3). Third, some mutations in TP53 may exert dominant negative effects on the wild type allele (4,5).

Numerous studies investigated a potential prognostic or predictive use of mutant TP53. However, the results reported in these trials are conflicting. This may at least partly be due to the different methods employed thus to detect TP53 mutations and to the fact that there is no consent on how to group TP53 mutations that may exert distinct biological effects. A comprehensive review by Brachova et al. defined four types of TP53 mutations: wild type, loss of wild type function, partial loss of wild type function, and gain of function (so called ‘oncomorphic’) (3). Whether sub-grouping of mutations as suggested by Brachova et al. may help to elucidate clinical use of TP53 aberrations remains to be determined.

A recent work by Ren et al. published in Cancer Research dissected tumour-biological effects of such an—most likely—‘oncomorphic’ mutation in TP53 (5). The authors were able to demonstrate that Trp53R172H holds oncogene-like activity and—even more interesting—exerts different biological effects depending on whether the wild type allele was expressed or not. Mice carrying both the wild type and the mutant (Trp53R172H) allele at the same time presented with marked peritoneal carcinomatosis. Furthermore, their tumours showed strong stromal invasion and high expression of ESR1 encoding estrogen receptor alpha. Importantly, heterozygous tumours retained responsiveness to p53 activating nutilin-3a. Most interestingly, those mice heterozygous for Trp53R172H developed a type of EOC closely resembling the mucinous subtype in humans. Having excluded mucinous ovarian neoplasms of low malignant potential and cases diagnosed with metastasis originally deriving from gastro-intestinal malignancies, mucinous ovarian carcinomas account for less than five percent of EOC (6-8). Mucinous EOC cases display some distinct clinical and biological characteristics. Though patients diagnosed with mucinous EOC staged as FIGO I have rather good prognosis, both OS and PFS of those women diagnosed with mucinous EOC classified as FIGO III are even shorter than in staged matched patients with serous EOC (8,9). This may be attributed to the high frequency of platinum resistance found in mucinous EOC (10). Accordingly, TP53R172H among other gain of function mutations has been demonstrated to be associated with platinum resistance (11). Whether re-activation of remaining p53 function by nutilin-3a may add to overcome platinum resistance in a model of mucinous ovarian cancer needs to be determined. Those tumours homozygously expressing Trp53R172H displayed a distinct molecular profile that was markedly different from those of heterozygous counterparts. Moreover, complete loss of the wildtype allele was associated with highly metastatic potential, low histologic differentiation, and with poor transactivation activity.

Altogether, Ren et al. revealed several novel aspects on biological activity of a TP53 gain of function mutation that may turn out to be of clinical relevance in the future. Further studies on TP53R172H (human homolog of mice Trp53R172H) in human ovarian cancer cases need to be performed thus to further elucidate its clinical utility.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Da Li (Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China).

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2016.09.21). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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