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Association of a novel endometrial cancer biomarker panel with prognostic risk, platinum insensitivity, and targetable therapeutic options
Journal article   Open access   Peer reviewed

Association of a novel endometrial cancer biomarker panel with prognostic risk, platinum insensitivity, and targetable therapeutic options

Jesus Gonzalez Bosquet, Qing Zhang, William A. Cliby, Jamie N. Bakkum-Gamez, Ling Cen, Sean C. Dowdy, Mark E. Sherman, S. John Weroha, Amy C. Clayton, Benjamin R. Kipp, …
PloS one, Vol.16(1), pp.e0245664-e0245664
01/27/2021
DOI: 10.1371/journal.pone.0245664
PMCID: PMC7840025
PMID: 33503056
url
https://doi.org/10.1371/journal.pone.0245664View
Published (Version of record) Open Access

Abstract

During the past decade, the age-adjusted mortality rate for endometrial cancer (EC) increased 1.9% annually with TP53 mutant (TP53-mu) EC disproportionally represented in advanced disease and deaths. Therefore, we aimed to assess pivotal molecular parameters that differentiate clinical outcomes in high- and low-risk EC. Using the Cancer Genome Atlas, we analyzed EC specimens with available DNA sequences and quantitative gene-specific RNA expression data. After polymerase epsilon (POLE)-mutant specimens were excluded, differential gene-specific mutations and mRNA expressions were annotated and integrated. Consequent to TP53-mu failure to induce p21, derepression of multiple oncogenes harboring promoter p21 repressive sites was observed, including CCNA2 and FOXM1 (P < .001 compared with TP53 wild type [TP53-wt]). TP53-wt EC with high CCNA2 expression (CCNA2-H) had a targeted transcriptomic profile similar to that of TP53-mu EC, suggesting CCNA2 is a seminal determinant for both TP53-wt and TP53-mu EC. CCNA2 enhances E2F1 function, upregulating FOXM1 and CIP2A, as observed in TP53-mu and CCNA2-H TP53-wt EC (P < .001). CIP2A inhibits protein phosphatase 2A, leading to AKT inactivation of GSK3 beta and restricted oncoprotein degradation; PPP2R1A and FBXW7 mutations yield similar results. Upregulation of FOXM1 and failed degradation of FOXM1 is evidenced by marked upregulation of multiple homologous recombination genes (P < .001). Integrating these molecular aberrations generated a molecular biomarker panel with significant prognostic discrimination (P = 5.8x10(-7)); adjusting for age, histology, grade, myometrial invasion, TP53 status, and stage, only CCNA2-H/E2F1-H (P = .0003), FBXW7-mu/PPP2R1A-mu (P = .0002), and stage (P = .017) were significant. The generated prognostic molecular classification system identifies dissimilar signaling aberrations potentially amenable to targetable therapeutic options.
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