Papillary thyroid carcinoma shows elevated levels of 2-hydroxyglutarate

Abstract

Elevated levels of D: -2-hydroxyglutarate (D: -2-HG) occur in gliomas and myeloid leukemias associated with mutations of IDH1 and IDH2. L: -2-Hydroxyglutaric aciduria, an inherited metabolic disorder, predisposes to brain tumors. Therefore, we asked whether sporadic cancers, without IDH1 or IDH2 hot-spot mutations, show elevated 2-hydroxyglutarate levels. We retrieved 15 pairs of frozen papillary thyroid carcinoma (PTC) and adjacent non-neoplastic thyroid, and 14 pairs of hyperplastic nodule (HN) and adjacent non-hyperplastic thyroid. In all lesions, exon 4 sequencing confirmed the absence of known mutations of IDH1 and IDH2. We measured 2-hydroxyglutarate by liquid chromatography-tandem mass spectrometry. Compared to normal thyroid, PTCs had significantly higher D: -2-HG and L: -2-hydroxyglutarate (L: -2-HG) levels, and compared to HNs, PTCs had significantly higher D: -2-HG levels. D: -2-HG/L: -2-HG levels were not significantly different between HNs and normal thyroid. Further studies should clarify if elevated 2-hydroxyglutarate in PTC may be useful as cancer biomarker and evaluate the role of 2-hydroxyglutarate in cancer biology.

IDH mutations in acute myeloid leukemia

“…IDH mutations can be detected by different methods including polymerase chain reaction (PCR)-based assays [20,[55][56][57], expression of IDH1 mutant protein in the tumor tissue by immunohistochemistry [58,59], and detection of the putative oncometabolite, D-2HG, by gas chromatography/ mass spectrometry in vitro or by magnetic resonance spectroscopy in vivo [8,60,61].…”

Citrate – new functions for an old metabolite

“…Although the source of 2-HG is not fully understood, experimental evidences indicate that IDH1 and IDH2 have a role in the production of d-2-HG (Matsunaga et al, 2012). d-2-HG and its enantiomer l-2-HG are linked to the Krebs cycle (Raimundo et al, 2011) and are found to be elevated in certain types of cancer (Dang et al, 2009;Rakheja et al, 2011) and in different variants of the neurometabolic 2-hydroxyglutaric aciduria. In relation to the latter defect, a recent study from Nota et al (2013) reported 12 recessive mutations (Ser193Trp, Arg282Gly, Arg282Cys, Gly167Arg, Pro45Leu, Glu144Gln, Met202Thr, Tyr297Cys, Tyr256*, Ala9Profs*82, A274Ilefs*24, and Arg173Glyfs*2) found in the CIC gene of three individuals and their families that cause combined d-2-and l-2-hydroxyglutaric aciduria.…”

Deficiency in SLC25A1, Encoding the Mitochondrial Citrate Carrier, Causes Combined D-2- and L-2-Hydroxyglutaric Aciduria

“…2 Moreover, certain cancer types show elevated levels of 2-HG but contain no mutations in IDH1 or IDH2. 4 It would therefore be interesting to further investigate the role of citrate and SLC25A1 in these cancer types.…”