GENE-02. PERIPHERAL BLOOD DNA METHYLATION PROFILES IDENTIFY IDH1/2 MUTATION STATUS IN ADULTS WITH DIFFUSE GLIOMA Free

Identification of IDH1/2 mutations and association with better outcome revolutionized diagnosis and management of patients with gliomas. Liquid biopsy allows identification of driver mutations from blood; however detection of circulating tumor DNA or circulating tumor cells from patients with brain tumors is difficult due to the low amount of tumor material in the peripheral blood. We hypothesized that brain tumors alter the epigenetic profiles of circulating leukocytes and sought to identify DNA methylation patterns in peripheral blood that would identify molecular subtypes of glioma.

We analyzed brain tumors and matched whole peripheral blood collected in EDTA tubes from 63 patients with newly diagnosed diffuse glioma and whole peripheral blood from 40 individuals with no known history of brain tumor. Tumor IDH1/2 mutation status was analyzed using next-generation sequencing and circulating leukocyte genomic DNA methylation was analyzed using Illumina 850k EPIC array. Methylation data were analyzed with the R Bioconductor package minfi, including quality control, data normalization and differentially methylated CpG site analysis. Subsequent filtering was performed using a p-value cutoff = 0.01 and a minimal mean difference of the Beta-value of = 0.1.

Peripheral blood methylation profiles of patients with brain tumors were distinctly different from controls. DNA methylation profiles from peripheral leukocytes identified a total of 222 differentially methylated CpG sites in males and 515 CpG sites in females between IDH mutated versus wild-type diffuse glioma patients. Blood DNA methylation distinguished patients with IDH mutant and wildtype diffuse gliomas with 98% accuracy, nearly perfectly separating groups by clustering.

Diffuse gliomas induce epigenetic changes in the methylome of the circulating leukocytes. IDH wildtype and mutant gliomas can be distinguished with high accuracy by profiling the epigenome of circulating leukocytes. Our study demonstrates the potential of peripheral blood DNA methylation assessment for non-invasive diagnosis of brain tumors.