Association of hyperglycemia and molecular subclass on survival in IDH-wildtype glioblastoma.
Association of hyperglycemia and molecular subclass on survival in IDH-wildtype glioblastoma.
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DOI：
10.1093/noajnl/vdac163
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发表时间：
2022-01
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高血压与胶质母细胞瘤的生存率较差相关。降低血糖的尝试产生了混合反应，这可能是由于分子上不同的GBM亚类。回顾了通过临床下一代测序分析并使用Stupp方案治疗的89例IDH-wt GBM的临床、实验室和分子数据。使用全基因组DNA甲基化将IDH-wt GBM细分为RTK I（原神经）、RTK II（经典）和间充质亚型。平均血糖通过诊断和末次随访之间的时间加权血糖测量值计算。使用平均葡萄糖将患者分为三组：三分之一（<100 mg/dL）、三分之二（100-115 mg/dL）和三分之三（>115 mg/dL）。血糖三分位数之间的比较显示，在体能状态（KPS）、地塞米松剂量、MGMT甲基化或甲基化亚类方面没有差异。总生存期（OS）不受甲基化亚类的影响（P = 0.9），但随血糖升高而降低（P = 0.015）。在RTK I（P = 0.08）和间叶肿瘤（P = 0.05）中，较高的葡萄糖三分位数与较差的OS相关，但与RTK II无关（P = 0.99）。在控制了年龄、KPS、地塞米松和MGMT状态后，葡萄糖仍然与OS显著相关（aHR = 5.2，P = 0.02）。甲基化聚类没有识别出与高或低葡萄糖水平相关的独特特征。23个肿瘤的代谢组学分析显示，代谢物之间的差异极小，分子亚类之间无差异。在RTKI和间充质IDH-wt GBM中，较高的平均葡萄糖值与较差的OS相关，但与RTKII无关。在不同的葡萄糖环境中，肿瘤之间没有可辨别的表观遗传或代谢组学差异，表明在选定的分子亚型中降低全身葡萄糖具有潜在的生存益处。
Hyperglycemia has been associated with worse survival in glioblastoma. Attempts to lower glucose yielded mixed responses which could be due to molecularly distinct GBM subclasses. Clinical, laboratory, and molecular data on 89 IDH-wt GBMs profiled by clinical next-generation sequencing and treated with Stupp protocol were reviewed. IDH-wt GBMs were sub-classified into RTK I (Proneural), RTK II (Classical) and Mesenchymal subtypes using whole-genome DNA methylation. Average glucose was calculated by time-weighting glucose measurements between diagnosis and last follow-up. Patients were stratified into three groups using average glucose: tertile one (<100 mg/dL), tertile two (100–115 mg/dL), and tertile three (>115 mg/dL). Comparison across glucose tertiles revealed no differences in performance status (KPS), dexamethasone dose, MGMT methylation, or methylation subclass. Overall survival (OS) was not affected by methylation subclass (P = .9) but decreased with higher glucose (P = .015). Higher glucose tertiles were associated with poorer OS among RTK I (P = .08) and mesenchymal tumors (P = .05), but not RTK II (P = .99). After controlling for age, KPS, dexamethasone, and MGMT status, glucose remained significantly associated with OS (aHR = 5.2, P = .02). Methylation clustering did not identify unique signatures associated with high or low glucose levels. Metabolomic analysis of 23 tumors showed minimal variation across metabolites without differences between molecular subclasses. Higher average glucose values were associated with poorer OS in RTKI and Mesenchymal IDH-wt GBM, but not RTKII. There were no discernible epigenetic or metabolomic differences between tumors in different glucose environments, suggesting a potential survival benefit to lowering systemic glucose in selected molecular subtypes.