LINE-1 hypomethylation in cell-free DNA of high-grade glioma patients correlates with tissue levels and is associated with reduced DNMT1 and H4K20me3 expression

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Gliomas exhibit diverse genetic, molecular, and histological profiles with limited liquid biopsy biomarkers. Loss of Long Interspersed Nuclear Element-1 (LINE-1) methylation confers to genomic instability and tumorigenesis, primarily mediated by DNA methyltransferase 1 (DNMT1) through interaction with histone H4 lysine 20 trimethylation (H4K20me3) and histone H3 lysine 9 trimethylation (H3K9me3). The present study evaluates the utility of liquid biopsy in detecting LINE-1 methylation in gliomas and potential correlations with DNMT1, H4K20me3, H3K9me3 tissue levels, clinicopathological characteristics and patients' survival. LINE-1 methylation was measured in cell-free DNA (cfDNA) of glioma patients' plasma prior to surgery or any adjuvant therapy and age-matched controls as well as in glioma tissues along with DNMT1, H4K20me3 and H3K9me3 expression. LINE-1 methylation content in plasma cfDNA and tissue samples was decreased significantly in grade 4 gliomas compared to controls (p ​< 0.0001, respectively). Similarly, DNMT1, H4K20me3 and H3K9me3 expression was significantly reduced in grade 4 cases compared to grade 2 (p ​< 0.0001). cfLINE-1 methylation was positively correlated with tissue LINE-1 methylation levels (p ​= 0.036) as well as with DNMT1 and H4K20me3 tissue expression in grade 4 samples (p ​< 0.0001, respectively). Moreover, low LINE-1 methylation plasma levels and tissue expression of DNMT1, H4K20me3 and H3K9me3 were correlated with worse overall survival in the entire cohort (p ​= 0.041, ​p ​= 0.016, ​p ​< 0.0001, ​p ​= 0.001, respectively). The present study supports the utility of liquid biopsy for the detection of LINE-1 hypomethylation, as a complementary prognostic biomarker for grade 4 tumors.

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