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

Jesus Gonzalez Bosquet,William A Cliby,Ling Cen,Fergus J Couch,Karl C Podratz,Amy C Clayton,Mark E Sherman,S John Weroha,Jamie N Bakkum-Gamez,Kevin C Halling,Qing Zhang,Sean C Dowdy,Benjamin R Kipp,Nandini Dey

doi:10.1371/journal.pone.0245664

Jesus Gonzalez Bosquet, William A Cliby + Show 12 more

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https://doi.org/10.1371/journal.pone.0245664

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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 ɛ (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 GSK3β 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 = 5.8×10−7); 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.

Highlights

The American Cancer Society (ACS) predicted 61,880 new cases and 12,160 deaths that would be attributable to endometrial cancer (EC) in 2019 [1]
Molecular characteristics included polymerase ε (POLE)-mu detected in 28 specimens (11.7%), TP53 mutant (TP53-mu) in 70 (29.3%), microsatellite instability-high (MSI-H) in 67 (28%), and estimated copy number variation low (CNV-L)
Synergism occurred in ARK-2 and HEC-1B cell lines exposed to varying concentrations of carboplatin and panobinostat (Fig 5D and 5E). These observations suggested that suppression of FOXM1 and homologous recombination (HR) pathway components might enhance platinum sensitivity in high-risk HR-proficient EC. This is the first report of a classification system for EC that appears to correlate with oncologic outcomes independent of patient age, histology, tumor grade, myometrial invasion, and TP53 mutational status

Summary

Introduction

The American Cancer Society (ACS) predicted 61,880 new cases and 12,160 deaths that would be attributable to endometrial cancer (EC) in 2019 [1]. In 2018, the ACS reported an alarming 1.9% annual increase during the decade in age-adjusted mortality for EC [2]—a trajectory needing reversal. Standard treatment for high-risk EC is definitive surgery followed by systemic platinum-based chemotherapy (PbCT) or radiotherapy, or both. The majority of ECs are HR proficient; tailored molecular-based therapy needs to be developed, which requires identifying molecular profiles that harbor targetable aberrations. The tumor suppressor functions of TP53 include transcription activation and repression; exemplary of the former is the activation of CDKN1A, encoding p21, which targets promoter-repressive elements (cell-cycle–dependent elements [CDE] and cell-cycle genes homology region [CHR] sites), resulting in transcription repression of targeted genes [5]. TP53-mu cancers have derepression of numerous genes containing promoter CDE/CHR sites, including CDK2, CCNA2, AURKA, TPX2, PLK1, FOXM1, MASTL, and ESPL1 [5]

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