脑膜瘤的代谢谱分析揭示了新的亚组特异性生物学见解和预后相关性。

Landry Alexander P, Wang Justin Z, Yefet Leeor S, Liu Jeff, Patil Vikas, Zhang Wen-Jiang, Sosa Julio, Ellenbogen Yosef, Gui Chloe, Ajisebutu Andrew, Aldape Kenneth, Gao Andrew, Kislinger Thomas, Chen Eric X, Nassiri Farshad, Zadeh Gelareh

MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada.

Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.

Neuro Oncol. 2025 Jan 24. doi: 10.1093/neuonc/noae281.

BACKGROUND

Our group and others have recently identified four molecular groups of meningioma, with unique underlying biology and outcomes. The relevance of group-specific metabolite profiles (particularly among hypermetabolic tumours), has not been explored.

METHODS

We performed untargeted metabolic profiling of meningiomas representing each molecular group and WHO grade. Prognostic biochemicals were identified using Cox regression and their biological importance was explored using RNA and protein-based pathway analyses. Validation was performed using targeted high performance liquid chromatography-mass spectrometry (HPLC-MS/MS).

RESULTS

Global metabolic profiling identified 560 unique biochemicals. We identified a 21-metabolite outcome signatures which is strongly predictive of outcome after adjusting for WHO grade, extent of resection, and receipt of adjuvant radiotherapy (HR 326.49, 95%CI 16.72-6375.48, p < 0.0001). The abundance of N6-trimethyllysine was associated with earlier time to recurrence on our whole cohort (log-rank p = 0.009) and within hypermetabolic and WHO grade 2 tumours specifically; this was validated using targeted HPLC-MS/MS on two cohorts. Consensus RNA and protein expression analysis demonstrated as association between N6-trimethyllysine abundance and activation of oxidative phosphorylation pathways, which portended worse outcomes in the hypermetabolic subgroup but, interestingly, better outcomes in the proliferative subgroup. By contrast, upregulated pyruvate and lactate transporters were associated with worse outcomes in proliferative meningiomas specifically.

CONCLUSIONS

This is the first study to demonstrate a subgroup-specific prognostic role of N6-trimethyllysine in hypermetabolic meningiomas, offering increasingly granular outcome predictions using a widely accessible technique (HPLC-MS/MS). We also suggest fundamental differences in preferred energy utilization between and a potential need for subgroup-specific therapies.

背景

我们团队及其他研究团队最近鉴定出了脑膜瘤的四个分子亚组，它们具有独特的潜在生物学特性和预后情况。但尚未探究亚组特异性代谢物谱的相关性（尤其是在高代谢肿瘤中）。

方法

我们对代表每个分子亚组和世界卫生组织（WHO）分级的脑膜瘤进行了非靶向代谢谱分析。使用Cox回归确定预后生化物质，并通过基于RNA和蛋白质的通路分析探究其生物学重要性。使用靶向高效液相色谱 - 质谱联用仪（HPLC-MS/MS）进行验证。

结果

整体代谢谱分析鉴定出560种独特的生化物质。我们确定了一个由21种代谢物组成的预后特征，在对WHO分级、切除范围和辅助放疗进行校正后，该特征对预后具有很强的预测性（风险比326.49，95%置信区间16.72 - 6375.48，p < 0.0001）。在我们的整个队列中，N6 - 三甲基赖氨酸的丰度与复发时间较早相关（对数秩检验p = 0.009），在高代谢肿瘤和WHO 2级肿瘤中尤其如此；这在两个队列中通过靶向HPLC-MS/MS得到了验证。一致性RNA和蛋白质表达分析表明，N6 - 三甲基赖氨酸丰度与氧化磷酸化途径的激活之间存在关联，这在高代谢亚组中预示着更差的预后，但有趣的是，在增殖亚组中预示着更好的预后。相比之下，丙酮酸和乳酸转运蛋白上调与增殖性脑膜瘤的预后较差具有特异性关联。