ZEB1 Is a Transcription Factor That Is Prognostic and Predictive in Diffuse Gliomas.

Lincoln A Edwards,Miriam Nuno,Keith L Black,Sungjin Kim,Xuemo Fan,Tom Thomas,John S Yu,Dror Berel,Bong-Sup Lee,Mecca Madany,Aiguo Li,Wei Zhang,Minzhi Liu

doi:10.3389/fneur.2018.01199

Lincoln A Edwards, Miriam Nuno + Show 11 more

Open Access

https://doi.org/10.3389/fneur.2018.01199

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Abstract

Objective: To address the unmet medical need to better prognosticate patients with diffuse gliomas and to predict responses to chemotherapy regimens.Methods: ZEB1 alterations were retrospectively identified from a cohort of 1,160 diffuse glioma patients. Epigenome-wide association scans (EWAS) were performed on available data. We determined the utility of ZEB1 as a prognostic indicator of patient survival in diffuse gliomas and assessed the value of ZEB1 to predict the efficacy of treating diffuse glioma patients with procarbazine, CCNU, and vincristine along with radiation at diagnosis. Decision curve analysis (DCA) was used to determine if ZEB1 added benefit to clinical decision-making over and above conventional methods.Results: Fifteen percent of diffuse glioma patients had a ZEB1 deletion. ZEB1 deletion was associated with poor overall survival (OS) with and without adjustment for age and tumor grade (adjusted HR: 4.25; 95% CI: 2.35 to 7.66; P < 0.001). Decision curve analysis confirmed that ZEB1 status with or without IDH1 was more beneficial to clinical decision making than conventional information such as age and tumor grade. We showed that ZEB1 regulates TERT expression, and patients with ZEB1 deletions likely subsume patients with mutant TERT expression in diffuse gliomas. ZEB1 influenced clinical decision making to initiate procarbazine, CCNU, and vincristine treatment.Conclusion: We demonstrate the prognostic value of ZEB1 in diffuse glioma patients. We further determine ZEB1 to be a vital and influential molecular marker in clinical decisions that exceed conventional methods regarding whether to treat or not treat patients with diffuse glioma.

Highlights

Diffuse gliomas, comprised of WHO grade II and grade III astrocytomas, oligodendrogliomas, and diffuse gliomas with ambiguous histology are infiltrative malignant tumors of the central nervous system [1]
Adding to the complexity of ZEB1 we previously demonstrated that the loss of ZEB1 imparts “stemness” to cancer stem cells derived from glioblastoma to prevent differentiation and induce self-renewal
An initial 334 diffuse glioma patients were assessed for ZEB1 copy number along with age, histological type and tumor grade

Summary

Introduction

Diffuse gliomas, comprised of WHO grade II and grade III astrocytomas, oligodendrogliomas, and diffuse gliomas with ambiguous histology (formerly known as oligo-astrocytomas) are infiltrative malignant tumors of the central nervous system [1]. Adding to the complexity of ZEB1 we previously demonstrated that the loss of ZEB1 imparts “stemness” to cancer stem cells derived from glioblastoma to prevent differentiation and induce self-renewal. This property was executed by Leukemia Inhibitory Factor [23] whose expression is inhibited by ZEB1. We further analyzed diffuse glioma patient samples for DNA methylation and epigenome-wide association scans (EWAS) to determine epigenetic variation, which may account for changes in ZEB1 expression that could contribute to poor patient outcomes. We describe the use of the molecular marker ZEB1 in prognostication and clinical decision making for patients with diffuse gliomas

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Conclusion