Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate. IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of IDHmt glioma and CCA patients. Results were validated in cohorts of CCA and clear cell renal cell carcinoma (ccRCC) patients. The R2HG/S2HG ratio (rRS) was significantly elevated in tumor tissues, but not in blood for IDHmt glioma patients, while circulating rRS was elevated in IDHmt CCA patients. There were overlap distributions of circulating R2HG and total 2HG (t2HG) in both IDHmt and wild-type (IDHwt) CCA patients, while there was minimal overlap in rRS values between IDHmt and IDHwt CCA patients. Using the rRS cut-off value of 1.5, the sensitivity of rRS was 90% and specificity was 96.8%. Circulating rRS is significantly increased in IDHmt CCA patients compare to IDHwt CCA patients. Circulating rRS is a sensitive and specific surrogate biomarker for IDH1/2 mutations in CCA. It can potentially be used as a tool for monitoring IDH-targeted therapy.

中文翻译：

---

循环致癌代谢物 2-羟基戊二酸 (2HG) 作为异柠檬酸脱氢酶 (IDH1/2) 突变型胆管癌的潜在生物标志物

异柠檬酸脱氢酶 (IDH) 催化异柠檬酸脱羧为 α-酮戊二酸。IDH1/2突变优先将αKG转化为R-2-羟基戊二酸(R2HG)，导致R2HG在肿瘤组织中积累。我们研究了循环 2-羟基谷氨酸 (2HG) 作为 IDH 突变 (IDHmt) 胆管癌 (CCA) 患者的潜在生物标志物。在 IDHmt 神经胶质瘤和 CCA 患者的发现队列中分析了血液和肿瘤组织中的 R2HG 和 S-2-羟基戊二酸 (S2HG) 水平。结果在 CCA 和透明细胞肾细胞癌 (ccRCC) 患者队列中得到验证。IDHmt 神经胶质瘤患者的肿瘤组织中的 R2HG/S2HG 比值 (rRS) 显着升高，但血液中的 R2HG/S2HG 比值 (rRS) 显着升高，而 IDHmt CCA 患者的循环 rRS 升高。IDHmt 和野生型 (IDHwt) CCA 患者中循环 R2HG 和总 2HG (t2HG) 存在重叠分布，而 IDHmt 和 IDHwt CCA 患者之间的 rRS 值重叠极小。使用 rRS 截止值为 1.5，rRS 的敏感性为 90%，特异性为 96.8%。与 IDHwt CCA 患者相比，IDHmt CCA 患者的循环 rRS 显着增加。循环 rRS 是 CCA 中 IDH1/2 突变的敏感且特异的替代生物标志物。它有可能用作监测 IDH 靶向治疗的工具。