Serum concentrations of oncometabolite, 2-hydroxyglutarate (2HG), as biomarkers for isocitrate dehydrogenase (IDH1/2) mutations in cholangiocarcinoma (ICCA)

3049 Background: Mutations in IDH1/2 genes are common in low-grade glioma (GM) and occur in approximately 20% of intrahepatic cholangiocarcinoma (ICCA). Mutant IDHs leads to preferential accumulation of the R-relative (R2HG) to the S-enantiomer (S2HG) of 2HG. We investigated the utility of circulating R2HG, total R2HG+S2HG (tRS) and ratio of R2HG/S2HG (rRS) as biomarkers in GM and ICCA patients (pts). Methods: Blood and tumor tissues samples were obtained from pts with IDH1/2-mutant GM and ICCA. IDH mutation was confirmed by either immunohistochemistry (GM pts) or next generation sequencing (ICCA pts). Samples were analyzed for S2HG and R2HG using a validated HPLC tandem mass spectrometry method. Tissue and serum R2HG, tRS and rRS were compared with paired t-tests for GM pts. Serum S2HG, R2HG, tRS and rRS were compared with unpaired t-tests between GM and ICCA pts. A p<0.05 was considered statistically significant. Results: Blood and tumor samples were collected from 21 pts (GM = 11, ICCA=10). Tumor tissues were insufficient for analysis in 1 GM and 8 ICCA pts. Tissue S2HG, R2HG, tRS, and rRS were 0.72±0.68 ng/g, 48.92±58.92 ng/g, 66.87±80.35 ng/g and 55.77±36.23 for GM pts. There were no differences in R2HG and tRS between tissue and serum samples, while S2HG was significantly higher in serum samples ( p = 0.001) and rRS was significantly higher in tissue samples for GM pts ( p = 0.001). rRS were 144.8 and 244.9 respectively in 2 ICCA pts with sufficient tissues. There was no difference in serum S2HG between GM and ICCA pts. However, serum R2HG, tRS and rRS were significantly higher in ICCA pts. Conclusions: In IDH1/2 mutant GM and ICCA pts, R2HG was increased relative to S2HG in tumor tissues. In GM pts, the accumulation of R2HG in tumor tissues was not reflected in blood, likely due to the inability of 2HG to diffuse across the blood-brain barrier. Serum R2HG, tRS and rRS were significantly elevated in ICCA pts. These biomarkers have no clinical utilities in GM pts. However, they can potentially be used to identify IDH mutations in ICCA pts, especially given the inability to obtain tumor tissue in some ICCA pts. Clinical trial information: NCT03991832. [Table: see text]