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Expression of activating transcription factor 5 (ATF5) is increased in astrocytomas of different WHO grades and correlates with survival of glioblastoma patients

Authors Feldheim J, Kessler AF, Schmitt D, Wilczek L, Linsenmann T, Dahlmann M, Monoranu CM, Ernestus RI, Hagemann C, Löhr M

Received 8 June 2018

Accepted for publication 18 October 2018

Published 4 December 2018 Volume 2018:11 Pages 8673—8684


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Arseniy Yuzhalin

Video abstract presented by Jonas Feldheim

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Jonas Feldheim,1 Almuth F Kessler,1 Dominik Schmitt,1 Lara Wilczek,1 Thomas Linsenmann,1 Mathias Dahlmann,2,3 Camelia M Monoranu,4 Ralf-Ingo Ernestus,1 Carsten Hagemann,1,* Mario Löhr1,*

1Department of Neurosurgery, Tumorbiology Labo­ratory, University of Würzburg, Würzburg, Germany; 2Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; 3German Cancer Consortium (DKTK), Heidelberg, Germany; 4Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany

*These authors contributed equally to this work

Background: ATF5 suppresses differentiation of neuroprogenitor cells and is overexpressed in glioblastoma (GBM). A reduction of its expression leads to apoptotic GBM cell death. Data on ATF5 expression in astrocytoma WHO grade II (low-grade astrocytoma [LGA]) are scarce and lacking on recurrent GBM.
Patients and methods: ATF5 mRNA was extracted from frozen samples of patients’ GBM (n=79), LGA (n=40), and normal brain (NB, n=10), quantified by duplex qPCR and correlated with retrospectively collected clinical data. ATF5 protein expression was evaluated by measuring staining intensity on immunohistochemistry.
Results: ATF5 mRNA was overexpressed in LGA (sevenfold, P<0.001) and GBM (tenfold, P<0.001) compared to NB, which was confirmed on protein level. Although ATF5 mRNA expression in GBM showed a considerable fluctuation range, groups of varying biological behavior, that is, local/multifocal growth or primary tumor/relapse and the tumor localization at diagnosis, were not significantly different. ATF5 mRNA correlated with the patients’ age (r=0.339, P=0.028) and inversely with Ki67-staining (r=-0.421, P=0.007). GBM patients were allocated to a low and a high ATF5 expression group by the median ATF5 overexpression compared to NB. Kaplan–Meier analysis and Cox regression indicated that ATF5 mRNA expression significantly correlated with short-term survival (t<12 months, median survival 18 vs 13 months, P=0.022, HR 2.827) and progression-free survival (PFS) (12 vs 6 months, P=0.024). This advantage vanished after 24 months (P=0.084).
Conclusion: ATF5 mRNA expression could be identified as an additional, though not independent factor correlating with overall survival and PFS. Since its inhibition might lead to the selective death of glioma cells, it might serve as a potential ubiquitous therapeutic target in astrocytic tumors.

Keywords: glioblastoma multiforme, recurrence, growth pattern, protein and mRNA expression

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