A serum-based DNA methylation assay provides accurate detection of glioma

Abstract

Background The detection of somatic mutations in cell-free DNA (cfDNA) from liquid biopsy has emerged as a non-invasive tool to monitor the follow-up of cancer patients. However, the significance of cfDNA clinical utility remains uncertain in patients with brain tumors, primarily because of the limited sensitivity cfDNA has to detect real tumor-specific somatic mutations. This unresolved challenge has prevented accurate follow-up of glioma patients with non-invasive approaches. Methods Genome-wide DNA methylation profiling of tumor tissue and serum cell-free DNA of glioma patients. Results Here, we developed a non-invasive approach to profile the DNA methylation status in the serum of patients with gliomas and identified a cfDNA-derived methylation signature that is associated with the presence of gliomas and related immune features. By testing the signature in an independent discovery and validation cohorts, we developed and verified a score metric (the “glioma epigenetic liquid biopsy score” or GeLB) that optimally distinguished patients with or without glioma (sensitivity: 100%, specificity: 97.78%). Furthermore, we found that changes in GeLB score reflected clinicopathological changes during surveillance (e.g., progression, pseudoprogression or response to standard or experimental treatment). Conclusions Our results suggest that the GeLB score can be used as a complementary approach to diagnose and follow up patients with glioma.

Fragmentation patterns and personalized sequencing of cell‐free DNA in urine and plasma of glioma patients

“…These results from urine samples from glioma echoed our previous work, which identified 63% of plasma samples from glioma patients with 94% specificity using another RF model based on integration of fragmentation features in plasma cfDNA (Mouliere et al , 2018a ). Together with other studies that utilize methylation patterns in plasma (Nassiri et al , 2020 ; Sabedot et al , 2021 ), our work suggests that despite a low detection rate of mutations, epigenetic signals (i.e., fragmentation patterns) can be robustly detected in the plasma and also urine of glioma patients.…”

“…While methylation‐based detection, cell‐free DNA genome‐wide fragmentation, tumor‐derived mitochondrial DNA, exosomes, vesicles, and tumor‐educated platelets have all been proposed as alternative methods for plasma‐based detection of glioma‐derived mutant DNA, these alternative strategies provide limited information about the tumor genome (Best et al , 2015 ; Moss et al , 2018 ; Mouliere et al , 2018a ; Shen et al , 2018 ; Mair et al , 2019 ; Nørøxe et al , 2019 ; van der Pol & Mouliere, 2019 ; Sabedot et al , 2021 ). Through tumor‐guided sequencing, we have identified mutations in the plasma and urine of GBM patients and thus demonstrate the potential to track tumor‐specific mutations with a high specificity that may be important for monitoring tumor recurrence.…”

A DNA Methylation-Based Gene Signature Can Predict Triple-Negative Breast Cancer Diagnosis

“…In the last decades, whole genome strategies have dramatically expanded the identification of aberrantly methylated genes [15,47], allowing systematic approaches that seek for maximum accuracy by the generation of diagnostic signatures. Thus, in addition to classical biomarkers of diagnosis based on single methylated genes [43,48], some specific DNA-methylation-based signatures have been described for the detection of several tumours, such as prostate cancer [49,50], hepatocellular carcinoma [51], and glioma [52]. However, virtually no diagnostic biomarker or signature based on DNA methylation has been proposed for TNBC.…”

Liquid Biomarkers for Improved Diagnosis and Classification of CNS Tumors

“…Although the low ctDNA content limits the utility of WGBS or RBBS for non-invasive CNS tumor diagnosis, one recent study by Sabedot et al used 2–100 ng of serum ctDNA for WGBS and showed efficacy in discriminating and monitoring gliomas [ 71 ]. Using 38 glioma samples and 42 non-glioma control samples the authors developed a glioma epigenetic liquid biopsy score called GeLB that was highly accurate is detecting gliomas versus non-glioma patient with a sensitivity of 100% and specificity of 97.8%.…”