A229: Decreased expression of the mitochondrial BCAT protein correlates with improved patient survival in IDH wild-type gliomas
1School of Life Sciences, University of the West of England, Bristol, UK,2Department of Human Nutition, Foods and Excercise, Virginia Polytechnic Institute and State Universit, Virginia, USA,3Brain Tumour Research Group, University of Bristol, Bristol, UK
Gliomas represent 43% of all solid intracranial tumours and are associated with a poor prognosis. Recent studies indicated that the human cytosolic branched chain aminotransferase protein (hBCATc), which metabolises the branched chain amino acids (BCAA), was significantly upregulated in IDH1/2 wild type (WT) glioblastomas, correlated with methylation patterns in the BCAT1 promoter and is associated with a worse prognosis compared with IDH mutant gliomas. The diagnostic and prognostic significance of markers of BCAA metabolism is currently under investigation.
64 glioma tumour samples were compared for hBCATc, hBCATm and BCKDC expression using western blotting and immunohistochemistry. DNA was extracted from fresh frozen tissue. Sanger sequencing of the p.Arg132 region of IDH1 and p.Arg172 region of IDH2 was undertaken using a 3730 DNA analyser (Applied Bio-Systems).
In IDH WT tumours, like hBCATc (p=0.007), the expression of the mitochondrial isoform (hBCATm) is significantly (p=0.036) expressed relative to IDH mutant gliomas. hBCATm additionally shows a more significant correlation with patient survival than hBCATc on Kaplan-Meier analysis. In IDH WT tumours, low hBCATm expression is a positive prognostic factor (p = 0.003). hBCATm expression additionally correlated with WHO grade. Although previous reports indicate that increased hBCATc occurs exclusively in IDH-WT tumours, our studies demonstrate that 30% of IDH mutant tumours express comparable levels of hBCATc. Although hBCATc alone has been suggested as a putative therapeutic target, it is important to evaluate the expression of hBCATm in glioblastomas as its expression may impact the efficacy of new treatments targeting hBCATc.
IDH WT high grade gliomas traditionally have a poor prognosis. However we demonstrate for the first time that relatively low hBCATm may select for a better performing clinical cohort and may be a possible candidate target for drug therapy.