Prognostic role of mitochondrial pyruvate carrier in isocitrate dehydrogenase-mutant glioma
Prognostic role of mitochondrial pyruvate carrier in isocitrate dehydrogenase-mutant glioma
复制标题
DOI：
10.3171/2017.9.jns172036
复制
发表时间：
2019-01-01
影响因子：
4.1
通讯作者：
Huang, L. Eric
中科院分区：
文献类型：
--
作者：
Karsy, Michael;Guan, Jian;Huang, L. Eric
目的 胶质瘤是最常见的原发性脑肿瘤类型之一。最近的研究支持了关键遗传改变（包括异柠檬酸脱氢酶 (IDH) 突变和 1p19q 联缺失）在神经胶质瘤预后中的重要性。突变 IDH 从 α-酮戊二酸产生 2-羟基戊二酸，α-酮戊二酸是克雷布斯循环的关键代谢物。线粒体丙酮酸载体 (MPC) 由 MPC1 和 MPC2 亚基组成，在功能上对于克雷布斯循环至关重要。作者试图探讨 MPC1 和 MPC2 表达对患者预后的影响。 方法 使用 Kaplan-Meier 分析和危害模型评估来自癌症基因组图谱 (TCGA) 的低级别胶质瘤（WHO II 级和 III 级）患者的基因组和临床数据。使用包括胶质母细胞瘤在内的其他数据集进行验证。 结果 总共 286 例低级别胶质瘤患者（平均年龄 42.7 +/- 13.5 岁，55.6% 男性）包括 54 例 IDH 野生型 (18.9%)；54 例 IDH 野生型 (18.9%)；54 例 IDH 野生型 (18.9%)。 IDH突变140例，1p19q完整（49.0%）； 85 例 IDH 突变、1p19q 共缺失 (29.7%) 肿瘤。 Kaplan-Meier 分析表明，MPC1 z 分数 > 0 可以区分更好的生存，特别是在 IDH 突变型肿瘤中 (p < 0.01)，但在 IDH 野生型肿瘤中则不然。相反，MPC2 z 得分 > 0 表明生存率恶化，特别是在 IDH 突变型肿瘤中 (p < 0.01)，但在 IDH 野生型肿瘤中则不然。一致的是，在包含 5% IDH 突变病例的胶质母细胞瘤数据集中，MPC1 和 MPC2 都无法预测。在 IDH 分层的低级别胶质瘤数据集中，MPC1 状态表明 1p19q 编码缺失肿瘤的生存率提高（p < 0.05），而 MPC2 表达则表明 1p19q 完整肿瘤的生存率恶化（p < 0.01）。风险模型将 IDH 和 1p19q 状态、年龄（p = 0.01，HR = 1.03）、卡诺夫斯基表现量表（KPS）评分（p = 0.03，HR = 0.97）和 MPC1（p = 0.003，HR = 0.52）而非 MPC2（p = 0.38）确定为影响总体生存的关键变量。进一步验证证实 MPC1 是低级别胶质瘤的独立预测因子。使用 IDH 和 1p19q 状态、年龄、KPS 评分以及 MPC1 和 MPC2 z 评分的临床风险评分定义了低级别胶质瘤的 4 个风险类别；该评分使用二级神经胶质瘤数据集进行了验证。结论这些结果支持 MPC（尤其是 MPC1）在改善 IDH 突变肿瘤预后方面的重要性。风险评分系统的产生直接将这一发现转化为临床应用；然而，需要进一步研究以提高对 MPC 在神经胶质瘤代谢基因组调控中的作用的分子理解。
OBJECTIVE Gliomas are one of the most common types of primary brain tumors. Recent studies have supported the importance of key genetic alterations, including isocitrate dehydrogenase (IDH) mutations and 1p19q codeletion, in glioma prognosis. Mutant IDH produces 2-hydroxyglutarate from alpha-ketoglutarate, a key metabolite of the Krebs cycle. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 subunits and is functionally essential for the Krebs cycle. The authors sought to explore the impact of MPC1 and MPC2 expression on patient prognosis.METHODS Genomic and clinical data in patients with lower-grade glioma (WHO grades II and III) from The Cancer Genome Atlas (TCGA) were evaluated using Kaplan-Meier analysis and hazards modeling. Validation was conducted with additional data sets, including glioblastoma.RESULTS A total of 286 patients with lower-grade glioma (mean age 42.7 +/- 13.5 years, 55.6% males) included 54 cases of IDH-wild type (18.9%); 140 cases of IDH-mutant, 1p19q-intact (49.0%); and 85 cases of IDH-mutant, 1p19q-co-deleted (29.7%) tumors. Kaplan-Meier analysis showed that an MPC1 z-score > 0 distinguished better survival, particularly in IDH-mutant (p < 0.01) but not IDH-wild type tumors. Conversely, an MPC2 z-score > 0 identified worsened survival, particularly in IDH-mutant (p < 0.01) but not IDH-wild type tumors. Consistently, neither MPC1 nor MPC2 was predictive in a glioblastoma data set containing 5% IDH-mutant cases. Within the IDH-stratified lower-grade glioma data set, MPC1 status distinguished improved survival in 1p19q-codeleted tumors (p < 0.05), whereas MPC2 expression delineated worsened survival in 1p19q-intact tumors (p < 0.01). A hazards model identified IDH and 1p19q status, age (p = 0.01, HR = 1.03), Karnofsky Performance Scale (KPS) score (p = 0.03, HR = 0.97), and MPC1 (p = 0.003, HR = 0.52) but not MPC2 (p = 0.38) as key variables affecting overall survival. Further validation confirmed MPC1 as an independent predictor of lower-grade glioma. A clinical risk score using IDH and 1p19q status, age, KPS score, and MPC1 and MPC2 z-scores defined 4 risk categories for lower-grade glioma; this score was validated using a secondary glioma data set.CONCLUSIONS These results support the importance of MPC, especially MPC1, in improving prognostication of IDHmutant tumors. The generation of a risk score system directly translates this finding to clinical application; however, further research to improve the molecular understanding of the role of MPC in the metabologenomic regulation of gliomas is warranted.