p53 Is Functionally Inhibited in Clear Cell Renal Cell Carcinoma (ccRCC): A Mechanistic and Correlative Investigation into Genetic and Molecular Characteristics - Beyond the Abstract

The gold standard therapy for localized clear cell renal cell carcinoma (ccRCC) is surgery while metastatic ccRCCs are treated with systemic therapies. Immune checkpoint and tyrosine kinase inhibition are the main therapeutic strategies for metastatic ccRCCs. They have substantially improved the prognosis of patients with metastatic ccRCC. However, a substantial number of patients never respond or develop resistance mechanisms against standard of care therapies after an initial response to these treatments. Thus, examinations of alternative therapy targets are still an issue of utmost importance although much progress has been made in ccRCC therapy during the past few years.


When mentioning p53 as an experimental target people often react with disinterest: there is probably no other tumor suppressor protein that has been more often examined in cancer research during the past decades. Although we may know almost everything about this protein, analyses of the natural history of p53 are still able to deliver astonishing results.

In ccRCC, the overexpression p53 has been described as a poor prognosis factor. High levels of p53 have been explained with mutations that lead to a constant accumulation of p53 in ccRCC tumor cells. However, smaller studies had already suggested that most of the tumors demonstrating p53 overexpression in immunohistochemistry do not harbor p53 mutations. This interesting finding was the peg for more in-depth characterizing assessments of the role of p53 in ccRCC.

We were able to demonstrate that the frequency of p53 mutations is overall low (2%) although TP53 has been described among the most heavily mutated genes in the ccRCC data of The Cancer Genome Atlas (TCGA) project. Although mRNA levels of p53 were correlated with poor prognosis and clinicopathological features, there was no monotonous association of p53 mRNA levels with survival outcome.

Furthermore, higher p53 protein levels could be confirmed as poor prognostic features as described in several studies previously.

In vitro, irradiation of ccRCC cell lines with none-mutated and mutated p53 markedly induced protein levels of p53 and of activated (phosphorylated) p53. However, irradiated ccRCC cells demonstrated similar proliferation, migration, and p53 transcriptional activity like non-irradiated controls indicating a functional inhibition of p53. p53 isoforms could not be associated with the clinical outcome of ccRCC patients.

The current study underscores that p53 has a unique role in ccRCC: although it is overexpressed and in almost all cases not mutated, the function of wild-type p53 is suppressed by a mechanism that has not been characterized yet. The authors of the current study were unable to provide plausible explanations for their observations. The authors speculated that p53 isoforms may explain the pro-apoptotic loss of p53 in ccRCC. However, there was no correlative relationship of clinicopathological features or survival outcome with p53 isoforms in ccRCC.

The findings of the current study leave room for speculation why p53 demonstrates a pro-apoptotic loss in ccRCC. Further examinations into mechanisms that could explain the pro-apoptotic loss of p53 could provide new treatment options of ccRCC particularly in those tumors that are resistant to the current standard of care therapies. Even though, investigations into the widely characterized tumor suppressor protein p53 might be boring in some tumor entities. In ccRCC, the unique role of p53 makes it an attractive objective to examine and may help to expand the amendatory of therapeutic options in the treatment of metastatic ccRCC.

Written by: Nils Kroeger, MD, University Medicine, Department of Urology, Ferdinand-Sauerbruch-Stra├če, Greifswald, Germany

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