High expression of cystine-glutamate antiporter xCT (SLC7A11) is an independent biomarker for epileptic seizures at diagnosis in glioma

摘要

Epileptic seizures are an important cause of morbidity in glioma patients. Substantial lines of evidence support the concept of the excitatory neurotransmitter glutamate being a crucial mediator of glioma-associated seizures. In gliomas, non-vesicular secretion of glutamate via the cystine-glutamate exchanger (SLC7A11, xCT) constitutes the main mechanism contributing to high extracellular glutamate concentrations. However, a convincing "proof-of-relevance" of this mechanism in patient material is lacking. A cohort of 229 consecutive patients with newly diagnosed glioma was analyzed with respect to presence, time course, and severity of epileptic seizures. 14 patients were excluded due to previous epileptic seizures, insufficient clinical data or insufficient tumor material. The maximal immunohistochemical expression of xCT was determined in 1-3 independent samples from central tumor areas of each tumor using tissue microarrays. In addition to histological grading of the tumors, isocitrate dehydrogenase 1 (IDH1) R132H mutational status was determined by immunohistochemistry. 215 consecutive glioma patients were included in the study (7.4% grade II, 7.0% grade III, 85.6% grade IV). High xCT expression was significantly associated with seizures at onset (p = 0.05) but not with development of seizures or with refractory seizures. Low-grade gliomas (WHO II/III) had lower xCT expression than glioblastoma (p = 0.001), and tumors without IDH1 R132H mutation tended to have higher xCT levels (p = 0.07). In a multivariate analysis, high xCT expression and WHO tumor grade but not IDH1 R132H mutation, were significantly associated with epileptic seizures at diagnosis (odds ratio 2.2, p = 0.02). Further, xCT expression did not correlate with survival (p = 0.27, log-rank test). Thus, high xCT expression is an independent marker for glioma-associated seizures at diagnosis especially in high-grade glioma, but is not associated with worse survival in our cohort.