Open AccessAssociation of a novel endometrial cancer biomarker panel with prognostic risk, platinum insensitivity, and targetable therapeutic options
Author(s) -
Jesús González 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,
Kevin C. Halling,
Fergus J. Couch,
Karl C. Podratz
Publication year - 2021
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0245664
Subject(s) - cancer research , biology , endometrial cancer , e2f1 , foxm1 , downregulation and upregulation , cancer , transcriptome , microbiology and biotechnology , cell cycle , gene , gene expression , genetics
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.