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Decreased expression of the mitochondrial bcat protein correlates with improved patient survival in idh-wt gliomas

Williams, Maggie; Hull, Jonathon; Ellis, Hayley P.; Hull, Jonathan; Conway, Myra E.; El Hindy, Maya; Taylor, Scott C.; El Amraoui, Farah; Williams, H; Paton-Thomas, Caroline; Haynes, H; White, Paul; Bertoni, Anna; Radlwimmer, Bernhard; Hutson, Susan M.; Kurian, Kathreena M.

Authors

Maggie Williams

Jonathon Hull

Hayley P. Ellis

Jonathon Hull Jonathon2.Hull@uwe.ac.uk
Senior Lecturer in Biomedical Sci (Biochemistry)

Myra Conway Myra.Conway@uwe.ac.uk
Occasional Associate Lecturer - HAS DAS

Maya El Hindy

Scott C. Taylor

Farah El Amraoui

H Williams

Caroline Paton-Thomas

H Haynes

Paul White

Anna Bertoni

Bernhard Radlwimmer

Susan M. Hutson

Kathreena M. Kurian



Abstract

Background and research question: Gliomas represent 43% of all solid intracranial tumours, of which glioblastomas have the poorest prognosis. Recently, the human cytosolic branched-chain aminotransferase protein (hBCATc), which metabolises the branched-chain amino acids (BCAA), was identified as a biomarker and therapeutic target for glioblastomas carrying wild-type isocitrate dehydrogenase (IDH-WT) genes. However, the clinical utility of the mitochondrial isoform, hBCATm, which also metabolises BCAAs, was not determined nor its potential role in predicting patient survival.

Methods: Glioblastomas, of grades II-IV, from 53 patients were graded by a neuropathologist, where the IDH and MGMT status were assessed. Tumours positive for hBCATm, hBCATc and BCKDC were characterised using immunohistochemistry and Western blot analysis using antibodies specific to these proteins.

Results: Here, we report that in IDH-WT tumours, the expression of hBCATm is significantly increased (p=0.034) relative to IDH mutation gliomas, and significantly correlates with patient survival, on Kaplan-Meier analysis, where low hBCATm expression is a positive prognostic factor (p=0.003). Moreover, increased hBCATm expression in these glioblastomas correlated with tumour grade indicating their role as a predictive biomarker of glioma progression. Multiple banding was observed for the branched-chain α-keto acid dehydrogenase complex, which catalyses the committed step in BCAA metabolism, but a significant change in expression was absent (p=0.690).

Conclusion: Until now, IDH-WT glioblastomas have a uniformly poor prognosis, however we demonstrate for the first time that relatively low hBCATm may select for a better performing subset within this group and may represent a therapeutic target in these hard to treat patients.

Citation

Conway, M. E., Hull, J., El Hindy, M., Taylor, S., El Amraoui, F., Paton-Thomas, C., …Kurian, K. (2016). Decreased expression of the mitochondrial bcat protein correlates with improved patient survival in idh-wt gliomas. Brain Pathology, 26(6), 789-791. https://doi.org/10.1111/bpa.12385

Journal Article Type Article
Acceptance Date Apr 6, 2016
Online Publication Date Apr 12, 2016
Publication Date Nov 1, 2016
Journal Brain Pathology
Print ISSN 1015-6305
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 26
Issue 6
Pages 789-791
DOI https://doi.org/10.1111/bpa.12385
Keywords BCAT, glioma, predictive markers
Public URL https://uwe-repository.worktribe.com/output/906641
Publisher URL http://dx.doi.org/10.1111/bpa.12385
Additional Information Additional Information : This is the peer reviewed version of the following article: Conway, M. E., Hull, J., El Hindy, M., Taylor, S., El Amraoui, F., Paton-Thomas, C., White, P., Williams, H., Haynes, H., Bertoni, A., Radlwimmer, B., Hutson, S. and Kurian, K. (2016) Decreased expression of the mitochondrial bcat protein correlates with improved patient survival in idh-wt gliomas. Brain Pathology, which has been published in final form at http://dx.doi.org/10.1111/bpa.12385. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

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