Decreased expression of the mitochondrial BCAT protein correlates with improved patient survival in IDH-WT gliomas

Hull, Jonathon; Williams, Maggie; 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.

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.

• Journal Article Type: Letter
• Acceptance Date: Apr 6, 2016
• Online Publication Date: Apr 12, 2016
• Publication Date: Nov 1, 2016
• Deposit Date: May 18, 2016
• Publicly Available Date: Apr 12, 2017
• Journal: Brain Pathology
• Print ISSN: 1015-6305
• Electronic ISSN: 1750-3639
• 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.
• Contract Date: May 18, 2016