TMET-31. CHOLESTEROL ESTERIFICATION IN A PATIENT WITH DIFFUSE ASTROCYTOMA PROGRESSING TO GLIOBLASTOMA

Abstract

Abstract Metabolic profiles of diffuse astrocytoma and recurrent tumor tissues were compared in a patient with diffuse astrocytoma who showed tumor recurrence and progressed to glioblastoma (GBM). The patient presented with a diffuse infiltrating tumor and was operated in April 2018. The pathology report showed that the tumor was a diffusely infiltrating astrocytoma with Ki-67 of 5% (WHO Grade II). In addition, the molecular testing results indicated that the tumor was IDH1wt with TERTp mutation and showed an indeterminate MGMT promoter status. Given diffuse brain involvement and IDH1wt status, an aggressive behavior was suggested for this tumor. After ~3.5 years (January 2022), the MRI examination showed tumor recurrence and the patient underwent craniotomy for the resection of the recurrent tumor. The pathology report showed a high-grade glial neoplasm composed of ovoid tumor cells with nuclear pleomorphism (GBM, WHO Grade IV). We collected the tumor specimens from both surgeries and compared the metabolic profiles using 1H NMR spectroscopy. The tumor specimens were extracted using methanol-chloroform (2:1 ratio) extraction-method. The methanol-layer of the recurrent tumor showed decreased levels of N-acetylaspartate (NAA) and myo-inositol, and the elevated levels of phosphocholine (PC) and glycine, compared to the diffuse astrocytoma. Decreased NAA and elevated PC and glycine are metabolic features of high-grade gliomas, suggesting progression of the low-grade astrocytoma to GBM. The chloroform-layers of both tumors showed the presence of cholesterol; however, cholesteryl ester (CE) was detected only in the recurrent tumor (GBM). The ratio of CE to cholesterol was 0.44, suggesting that 44% of cholesterol pool was esterified in GBM. Cholesterol esterification is dysregulated in GBM and targeting this metabolic pathway using AcylCoA:cholesterol acyltransferase (ACAT) inhibitors would be promising in the treatment of GBM and astrocytomas with TERTp mutation which transform to GBM.