High expression of cystine-glutamate antiporter xCT (SLC7A11) is an independent biomarker for epileptic seizures at diagnosis in glioma
High expression of cystine-glutamate antiporter xCT (SLC7A11) is an independent biomarker for epileptic seizures at diagnosis in glioma
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DOI：
10.1007/s11060-018-2785-9
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发表时间：
2018-05-01
影响因子：
3.9
通讯作者：
Beier, Christoph Patrick
中科院分区：
文献类型：
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作者：
Sorensen, Mai Froberg;Heimisdottir, Solborg Berglind;Beier, Christoph Patrick
癫痫发作是脑胶质瘤患者发病的重要原因。大量证据支持兴奋性神经递质谷氨酸是胶质瘤相关癫痫发作的关键介质的概念。在胶质瘤中，通过半胱氨酸-谷氨酸交换系统(SLC7A11，XCT)的非囊泡性谷氨酸分泌是导致细胞外谷氨酸浓度升高的主要机制。然而，在患者材料中缺乏令人信服的这一机制的“相关性证据”。对229例新诊断的脑胶质瘤患者的癫痫发作的发生率、发作时间和严重程度进行了分析。排除14例因癫痫发作史、临床资料不足或肿瘤材料不足。采用组织芯片技术，对1~3个独立的肿瘤中心区标本进行XCT最大免疫组织化学检测。除肿瘤组织学分级外，用免疫组织化学方法检测异柠檬酸脱氢酶1(IDH1)R132H突变状态。215例连续的胶质瘤患者纳入研究，其中II级占7.4%，III级占7.0%，IV级占85.6%。XCT的高表达与癫痫发作显著相关(p=0.05)，但与癫痫的发展或难治性癫痫无关。低级别胶质瘤(WHO II/III)的XCT表达低于胶质母细胞瘤(p=0.001)，无IDH1R132H突变的肿瘤XCT表达水平高于胶质母细胞瘤(p=0.07)。在多因素分析中，XCT的高表达和WHO肿瘤分级，而与IDH1 R132H突变无关，与确诊时癫痫发作显著相关(优势比2.2，p=0.02)。此外，XCT表达与生存期无关(p=0.27，log-ranch检验)。因此，XCT的高表达在诊断时是胶质瘤相关癫痫的独立标志物，特别是在高级别胶质瘤中，但在我们的队列中与较差的存活率无关。
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.