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.

Citation

Ellis, H. P., Williams, M., Hull, J., Conway, M. E., Hull, J., El Hindy, M., …Kurian, K. M. (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: 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.