Abstract
Serum and cerebrospinal fluid (CSF) levels of α-fetoprotein and β-subunit of human chorionic gonadotropin are used as biomarkers for the management of central nervous system (CNS) germ cell tumors (GCTs). However, additional discriminating biomarkers are required. Especially, biomarkers to differentiate non-germinomatous germ cell tumors (NGGCTs) from germinomas are critical, as these have a distinct prognosis. We investigated CSF samples from 12 patients with CNS-GCT patients (8 germinomas and 4 NGGCTs). We analyzed circulating tumor DNA (ctDNA) in CSF to detect mutated genes. We also used liquid chromatography-mass spectrometry to characterize metabolites in CSF. We detected KIT and/or NRAS mutation, known as frequently mutated genes in GCTs, in 3/12 (25%) patients. We also found significant differences in the abundance of 15 metabolites between control and GCT, with unsupervised hierarchical clustering analysis. Metabolites related to the TCA cycle were increased in GCTs. Urea, ornithine, and short-chain acylcarnitines were decreased in GCTs. Moreover, we also detected several metabolites (e.g., betaine, guanidine acetic acid, and 2-aminoheptanoic acid) that displayed significant differences in abundance in patients with germinomas and NGGCTs. Our results suggest that ctDNA and metabolites in CSF can serve as novel biomarkers for CNS-GCTs and can be useful to differentiate germinomas from NGGCTs.
Highlights
CtDNA Circulating tumor DNA normal pressure hydrocephalus (NPH) Normal pressure hydrocephalus lumbar puncture (LP) Lumbar puncture cell-free DNA (cfDNA) Cell-free DNA next-generation sequencing (NGS) Next-generation sequencing electro spray ionization (ESI) Electro spray ionization Single Reaction Monitoring (SRM) Single reaction monitoring false discovery rate (FDR) False discovery rate mutant allele fraction (MAF) Mutant allele fraction TCA Tricarboxylic acid PEP Phosphoenolpyruvate SAH S-adenosylhomocysteine NAA N-acetylaspartic acid aspartate N-acetyltransferase (Asp-NAT) Aspartate N-acetyltransferase
Serum and cerebrospinal fluid (CSF) levels of α-fetoprotein (AFP) and β-subunit of human chorionic gonadotropin (β-HCG), and placental alkaline phosphatase (PLAP) levels in CSF are used as biomarkers for current clinical management of central nervous system (CNS) GCTs4–6 and in some cases, initial treatment is based on the levels of AFP, β-HCG, and PLAP without tissue confirmation
We have previously reported on the analysis of circulating tumor DNA and metabolites in the CSF of patients with lymphoma, gliomas, and metastatic CNS tumors[14,15,16]
Summary
CtDNA Circulating tumor DNA NPH Normal pressure hydrocephalus LP Lumbar puncture cfDNA Cell-free DNA NGS Next-generation sequencing ESI Electro spray ionization SRM Single reaction monitoring FDR False discovery rate MAF Mutant allele fraction TCA Tricarboxylic acid PEP Phosphoenolpyruvate SAH S-adenosylhomocysteine NAA N-acetylaspartic acid Asp-NAT Aspartate N-acetyltransferase. Non-germinomatous GCTs (NGGCTs) require intense chemotherapy, craniospinal irradiation, and sometimes salvage surgical resection[4,5], and have an unfavorable prognosis with a 5-year survival rate of 71.4–87.3%3. Distinguishing between these tumor types is essential to determine the appropriate treatment strategy. GCTs are classified as pure germinoma or non-germinomatous germ cell tumors (NGGCT). We have previously reported on the analysis of circulating tumor DNA (ctDNA) and metabolites in the CSF of patients with lymphoma, gliomas, and metastatic CNS tumors[14,15,16]. We analyzed both ctDNA and metabolites in CSF from CNS GCT patients, with the aim of identifying biomarkers that could potentially be utilized in clinical practice
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