Journal
GYNECOLOGIC ONCOLOGY
Volume 162, Issue 1, Pages 182-189Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ygyno.2021.04.008
Keywords
CIP2A; FBXW7; PIK3CA; PP2A; PTEN
Categories
Ask authors/readers for more resources
The study investigates the role of PI3K-AKT pathway in endometrial cancer and found that deficiencies in PP2A and E3UL are seminal biological drivers in EC, independent of PIK3CA mutations, PTEN mutations, and PIK3R1 mutations, as well as PIK3CA copy number variation. These deficiencies are associated with compromised progression-free survival and were prognostically discriminatory for certain tumor characteristics.
Objective. PI3K-AKT pathway mutations initiate a kinase cascade that characterizes endometrial cancer (EC). As kinases seldom cause oncogenic transformation without dysregulation of antagonistic phosphatases, pivotal interactions governing this pathway were explored and correlated with clinical outcomes. Methods. After exclusion of patients with POLE mutations from The Cancer Genome Atlas EC cohort with endometrioid or serous EC, the study population was 209 patients with DNA sequencing, quantitative gene specific RNA expression, copy number variation (CNV), and surveillance data available. Extracted data were annotated and integrated. Results. A PIK3CA, PTEN, or PIK3R1 mutant (-mu) was present in 83% of patients; 57% harbored more than 1 mutation without adversely impacting progression-free survival (PFS) (P = .10). PIK3CA CNV of at least 1.1 (CNV high [-H]) was detected in 26% and linked to TP53-mu and CIP2A expression (P < .001) but was not associated with PFS (P = .24). PIK3CA expression was significantly different between those with CIP2A-H and CIP2A low (-L) expression (the endogenous inhibitor of protein phosphatase 2A [PP2A]), when stratified by PIK3CA mutational status or by PIK3CA CNV-H and CNV-L (all P < .01). CIP2A-H or PPP2R1A-mu mitigates PP2A kinase dephosphorylation, and FBXW7-mu nullifies E3 ubiquitin ligase (E3UL) oncoprotein degradation. CIP2A-H and PPP2R1A-mu (PP2A impairment) and FBXW7-mu (E3UL impairment) were associated with compromised PFS (P < .001) and were prognostically discriminatory for PIK3CA-mu and PIK3CA CNV-H tumors (P < .001). Among documented recurrences, 84% were associated with impaired PP2A (75%) and/or E3UL (20%). Conclusion. PP2A and E3UL deficiencies are seminal biological drivers in EC independent of PIK3CA-mu, PTEN- mu, and PIK3R1-mu and PIK3CA CNV. (c) 2021 Elsevier Inc. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available