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Abstract
Objective We aimed to identify pathways for potential therapeutic targets by conducting molecular profiling of endometrial carcinomas in patients with poor prognosis.
Methods The classification of endometrial carcinomas has undergone a paradigm shift with the advent of next generation sequencing based molecular profiling. Although this emerging classification reflects poor prognosis in patients with endometrial carcinoma, knowledge of affected biological pathways is still lacking. In this study, 85 patients with endometrial carcinomas at the Shizuoka Cancer Center were evaluated from January 2014 to March 2019 and classified based on The Cancer Genome Atlas subgroups. The accumulation of germline and somatic mutations was determined using next generation sequencing. Gene expression profiling was used to determine the effect of TP53 inactivation on the recurrence of endometrial carcinoma. Additionally, the biological pathways associated with TP53 inactivation were estimated by pathway analysis based on gene expression.
Results Based on The Cancer Genome Atlas classification, the ratio of polymerase-epsilon to copy number-high subgroups and the frequency of PTEN and TP53 mutations differed in patients, and mutations of ARHGAP35 observed in normal endometrium were accumulated in the polymerase-epsilon and microsatellite instability subgroups. We revealed that copy number-high reflects TP53 inactivation in endometrial carcinomas, and that TP53-inactive tumors with or without TP53 mutations have poor prognosis. Furthermore, overexpression of aurora kinase A and activation of oxidative phosphorylation were found in TP53-inactivated endometrial carcinomas, suggesting that the PI3K/mTOR and autophagy pathways are potential drug targets.
Discussion Our analysis revealed a relationship between pathways involved in oxidative phosphorylation and poor prognosis and provides insight into potential drug targets.
- uterine cancer
Data availability statement
Data are available upon reasonable request. Data are available in a public, open access repository. The authors declare that all data supporting the findings of this study are available within the article, its supplementary information files, and from the corresponding author upon reasonable request. In accordance with the journal’s guidelines, the data were submitted to the National Bioscience Database Center Human Database as “Controlled-Access Data” (Research ID, hum0127, https://humandbs.biosciencedbc.jp/en/).
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Data availability statement
Data are available upon reasonable request. Data are available in a public, open access repository. The authors declare that all data supporting the findings of this study are available within the article, its supplementary information files, and from the corresponding author upon reasonable request. In accordance with the journal’s guidelines, the data were submitted to the National Bioscience Database Center Human Database as “Controlled-Access Data” (Research ID, hum0127, https://humandbs.biosciencedbc.jp/en/).
Footnotes
NT and KH contributed equally.
Contributors NT is responsible for the overall content as the guarantor. NT and KH contributed equally to this work and designed the study. KH, TN, KO, KU performed the experiments. KH and NT analyzed the data. TN and KH performed statistical analyses. KH and NT wrote the paper, with contributions from KY and YH. All authors have read and approved the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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