Imaging and histopathologic correlates of plasma cell-free DNA concentration and circulating tumor DNA in adult patients with newly diagnosed glioblastoma

Abstract

Background Plasma cell-free DNA (cfDNA) concentration is lower in glioblastoma (GBM) compared to other solid tumors, which can lead to low circulating tumor DNA (ctDNA) detection. In this study, we investigated the relationship between multimodality magnetic resonance imaging (MRI) and histopathologic features with plasma cfDNA concentration and ctDNA detection in patients with treatment-naive GBM. Methods We analyzed plasma cfDNA concentration, MRI scans, and tumor histopathology from 42 adult patients with newly diagnosed GBM. Linear regression analysis was used to examine the relationship of plasma cfDNA concentration before surgery to imaging and histopathologic characteristics. In a subset of patients, imaging and histopathologic metrics were also compared between patients with and without a detected tumor somatic mutation. Results Tumor volume with elevated (>1.5 times contralateral white matter) rate transfer constant (Kep, a surrogate of blood–brain barrier [BBB] permeability) was independently associated with plasma cfDNA concentration (P = .001). Histopathologic characteristics independently associated with plasma cfDNA concentration included CD68+ macrophage density (P = .01) and size of tumor vessels (P = .01). Patients with higher (grade ≥3) perivascular CD68+ macrophage density had lower volume transfer constant (Ktrans, P = .01) compared to those with lower perivascular CD68+ macrophage density. Detection of at least 1 somatic mutation in plasma cfDNA was associated with significantly lower perivascular CD68+ macrophages (P = .01). Conclusions Metrics of BBB disruption and quantity and distribution of tumor-associated macrophages are associated with plasma cfDNA concentration and ctDNA detection in GBM patients. These findings represent an important step in understanding the factors that determine plasma cfDNA concentration and ctDNA detection.

Cell-free DNA and circulating TERT promoter mutation for disease monitoring in newly-diagnosed glioblastoma

“…Moreover, the interest of cfDNA as a reflection of tumor burden was previously reported in a series showing that its level may correlate with radiological parameters. Taken together, these findings support the hypothesis that cfDNA is released from the vascularized part of the tumor [ 20 ] and that this marker might be a useful tool for disease monitoring in the TMZ maintenance phase.…”

Blood-Based Biomarkers for Glioma in the Context of Gliomagenesis: A Systematic Review

“…First, it has been shown that total number of cfDNA molecules can be used as diagnostic marker to differentiate between glioma patients and controls (163,164), tumor type differentiating marker (163), tumor progression marker (165), and prognostic marker (164). However, it remains unclear whether total cfDNA can also be used as a marker to estimate and monitor tumor burden (164)(165)(166). Furthermore, mutations and copy number variations in cfDNA can also be utilized to differentiate between glioma patients and controls (164,(166)(167)(168)(169)(170).…”

“…However, it remains unclear whether total cfDNA can also be used as a marker to estimate and monitor tumor burden (164)(165)(166). Furthermore, mutations and copy number variations in cfDNA can also be utilized to differentiate between glioma patients and controls (164,(166)(167)(168)(169)(170). Diagnostic sensitivities ranged from 50% to near perfect accuracies.…”

Cell-free DNA technologies for the analysis of brain cancer

“…The overall load of cfDNA molecules in plasma (or other bio-fluids) from patients with brain tumours can be recovered quickly and at minimal cost (via spectrofluorometer methods or PCR quantification) and has recently regained interest [15]. Multiple studies have explored the difference in concentration of cfDNA between various types of gliomas and healthy controls, alone or in combination with other methods [16][17][18]. In a prospective study, glioma patients had higher plasma cfDNA concentration than age-matched healthy controls prior to initial surgery (mean 13.4 vs. 6.7 ng/mL, respectively) and this correlated with tumour burden on preirradiation MRI [16].…”