Minimally Invasive Detection of IDH1 Mutation With Cell-Free Circulating Tumor DNA and D-2-Hydroxyglutarate, D/L-2-Hydroxyglutarate Ratio in Gliomas

Abstract

Isocitrate dehydrogenase-1 (IDH1) mutation is accepted as one of the earliest events in tumorigenesis in gliomas. This mutation causes preferential accumulation of D- relative to L-enantiomer of 2-hydroxyglutarate (2-HG). Minimally invasive techniques to detect IDH1 mutation may prove useful for clinical practice. We adopted 2 different diagnostic approaches to detect IDH1 mutation status in glioma patients: Evaluation of D- and L-2-HG levels in cerebrospinal fluid (CSF), urine, and plasma, and identification of IDH1 mutation using cell-free circulating tumor DNA (ctDNA) in CSF and plasma. Forty-nine glioma patients in different stages were included. Levels of D- and L-2-HG were determined using liquid chromatography-tandem mass spectrometry; IDH1 R132H mutation was determined by digital-PCR. D-2-HG levels and D/L-2-HG ratio (rDL) in CSF and rDL in plasma were significantly higher in the mutant group than in the wild-type group (p = 0.029, 0.032, 0.001, respectively). The IDH1 mutation detection rates in CSF- and plasma-ctDNA were 63.2% and 25.0%, respectively. These data indicate that D-2-HG values in CSF and rDL in plasma and CSF can be considered as significant contributors to the identification of IDH1 mutation status. In addition, detection of IDH1 mutation in CSF-ctDNA from glioma patients provides a basis for future use of ctDNA for minimally invasive clinical assessment of gliomas.

Systematic Review of Cerebrospinal Fluid Biomarker Discovery in Neuro-Oncology: A Roadmap to Standardization and Clinical Application

“…17 This translates to improved mutation detection rates in CSF, including epidermal growth factor receptor in BrM and glioblastoma (GBM), 18,19 MYD88 in primary CNSL (PCNSL), 20 and IDH1 in gliomas (Data Supplement). 21 This improved performance with CSF also holds true for protein and miRNA biomarkers (Data Supplement).…”

“…In IDH-mutant gliomas, D-2HG levels are elevated in CSF, but not in serum or urine (Data Supplement, Table S8). 21,63,81 Despite variable diagnostic performance (AUROC, 0.701-0.934), CSF D-2HG levels are more sensitive to IDH-mutant status than the detection of IDH1 mutations in CSF (Table 2). 21,81 CSF D-2HG levels also correlate with IDH-mutant tumor volume, 81 thereby enabling surveillance of tumor progression in addition to diagnosis of IDH-mutant gliomas.…”

Clinical applications of cerebrospinal fluid liquid biopsies in central nervous system tumors

“…In cases where a biopsy is risky or not feasible, CSF ctDNA can capitalize on this molecular approach and provide a less invasive means of arriving at a specific diagnosis, which will then have therapeutic and prognostic implications. Several studies have preliminarily demonstrated the feasibility of classifying gliomas using CSF ctDNA data, in particular in regard to IDH [ 6 , [61] , [62] , [63] , [64] ] and H3 mutations [ [61] , [62] , [63] , 65 , 66 ]; H3 K27M-mutant diffuse midline gliomas are an especially interesting target for this approach, as their location frequently makes surgical access difficult. It is important to note that many of these studies utilized intracranial CSF (obtained intraoperatively or from a ventricular shunt or reservoir), and the diagnostic sensitivity of a lumbar puncture may be lower [66] .…”

“…In addition, in the case of metastatic tumors, this physical proximity may be the key to obtaining information specific to the CNS compartment: CNS metastases may have a different genomic evolution than the primary tumors they derive from [2] , which—due to the blood-brain barrier—may not be appropriately captured by liquid biopsies in plasma, but can be detected in CSF. Lastly, CSF has a low baseline cellularity that notably decreases the “noise” that needs to be filtered to detect true tumor material, and numerous studies directly comparing CSF and plasma samples have demonstrated a higher yield for the detection of tumor genomic material in CSF [3] , [4] , [5] , [6] .…”

Detection of IDH1 Mutation in cfDNA and Tissue of Adult Diffuse Glioma with Allele-Specific qPCR

“…In recent years, various approaches have been developed, including "liquid biopsies" (nucleic acid extracted from biological fluids such as plasma, urine, and cerebrospinal fluid (CSF)) for detecting the IDH mutation (Satomi et al, 2022); D2HG detection in body fluids; and advanced MRI imaging with specific D2HG detection by magnetic resonance spectroscopy (MRS) (Fujita et al, 2022;Mithraprabhu et al, 2021;Tuna et al, 2022). However, none of them is currently used in clinical practice.…”