Department of Biophysics and Nuclear Medicine, University Hospitals of Strasbourg, Strasbourg, France ; ICube, UMR (Unité Mixte de Recherche) 7357 University of Strasbourg/CNRS (Centre National de la Recherche Scientifique) and FMTS (Fédération de médecine translationnelle de Strasbourg), Faculty of Medicine, Strasbourg, France.
PLoS One. 2013 Nov 27;8(11):e80539. doi: 10.1371/journal.pone.0080539. eCollection 2013.
Paragangliomas (PGLs) are frequently associated with germline mutations in genes involved in energy metabolism. The purpose of the present study was to assess whether the tumor metabolomic profile of patients with hereditary and apparently sporadic PGLs enables the distinction of different subtypes of tumors. Twenty-eight unrelated patients with a histological diagnosis of PGLs were included in the present study. Twelve had germline mutations in SDHx genes (5 SDHB, 7 SDHD), 6 VHL, and 10 were apparently sporadic. Intact tumor samples from these patients (one per patient) were evaluated with (1)H high-resolution magic angle spinning (HRMAS) NMR spectroscopy. SDHx-related tumors were characterized by an increase in succinate levels in comparison to other tumor subtypes (p = 0.0001 vs VHL and p = 0.000003 vs apparently sporadic). Furthermore, we found significantly lower values of glutamate in SDHx-related tumors compared to other subtypes (p = 0.0007 vs VHL and p = 0.003 vs apparently sporadic). Moreover, SDHx-tumors also exhibited lower values of ATP/ADP/AMP (p = 0.01) compared to VHL. VHL tumors were found to have the highest values of glutathione (GSH) compared to other tumors. Based on 4 metabolites (succinate, glutamate, GSH, and ATP/ADP/AMP), tumors were accurately distinguished from the other ones on both 3- and 2-class PLS-DA models. The present study shows that HRMAS NMR spectroscopy is a very promising method for investigating the metabolomic profile of various PGLs. The present data suggest the existence of a specific succinate-glutamate hallmark of SDHx PGLs. The relevance of such a metabolomic hallmark is expected to be very useful in designing novel treatment options as well as improving the diagnosis and follow-up of these tumors, including metastatic ones.
嗜铬细胞瘤（PGL）常与涉及能量代谢的基因的种系突变相关。本研究的目的是评估遗传性和明显散发性 PGL 患者的肿瘤代谢组学特征是否能够区分不同的肿瘤亚型。本研究纳入了 28 名组织学诊断为 PGL 的无关联患者。其中 12 名患者存在 SDHx 基因（5 名 SDHB，7 名 SDHD）、6 名 VHL 的种系突变，10 名患者为明显散发性。对这些患者的完整肿瘤样本（每位患者一个样本）进行了（1）H 高分辨率魔角旋转（HRMAS）NMR 波谱分析。与其他肿瘤亚型相比，SDHx 相关肿瘤的琥珀酸水平升高（p = 0.0001 与 VHL 相比，p = 0.000003 与明显散发性相比）。此外，我们发现 SDHx 相关肿瘤中的谷氨酸水平明显低于其他亚型（与 VHL 相比，p = 0.0007，与明显散发性相比，p = 0.003）。此外，SDHx 肿瘤的 ATP/ADP/AMP 值也低于 VHL（p = 0.01）。与其他肿瘤相比，VHL 肿瘤的谷胱甘肽（GSH）值最高。基于 4 种代谢物（琥珀酸、谷氨酸、GSH 和 ATP/ADP/AMP），在 3 类和 2 类 PLS-DA 模型中，肿瘤均能准确地与其他肿瘤区分开来。本研究表明，HRMAS NMR 波谱是研究各种 PGL 代谢组学特征的一种很有前途的方法。本研究数据表明，SDHx PGL 存在特定的琥珀酸-谷氨酸特征。这种代谢组学特征的相关性有望在设计新的治疗方案以及改善这些肿瘤的诊断和随访方面非常有用，包括转移性肿瘤。
