Tumor infiltration into brain tissue usually remains undetected even by high-resolution imaging. Molecular markers are used to increase diagnostic accuracy, but with limited continuous monitoring application. We evaluated the potential of circulating cell-free DNA (cfDNA) as a molecular indicator of the response to therapy by the intranasal administration (ITN) of perillyl alcohol (POH) in brain tumors. The cohort included 130 healthy subjects arranged as control-paired groups and patients at terminal stages with glioblastoma (GBM, n = 122) or brain metastasis (BM, n = 55) from stage IV adenocarcinomas. Serum cfDNA was isolated and quantified by fluorimetry. Compared with the controls (40 ng/mL), patients with brain tumors before ITN-POH treatment had increased (p < 0.0001) cfDNA median levels: GBM (286 ng/mL) and BM (588 ng/mL). ITN-POH treatment was significantly correlated (rho = −0.225; p = 0.024) with survival of >6 months at a concentration of 599 ± 221 ng/mL and of <6 months at 1626 ± 505 ng/mL, but a sharp and abrupt increase of cfDNA and tumor recurrence occurred after ITN-POH discontinuation. Patients under continuous ITN-POH treatment and checked with brain magnetic resonance imaging (MRI) compatible with complete response had cfDNA levels similar to the controls. cfDNA may be used as a noninvasive prognostic and molecular marker for POH-based therapy in brain tumors and as an accurate screening tool for the early detection of tumor progression.

Background: Polymorphisms in MTHFR gene influence risk and overall survival of patients with brain tumor. Global genomic DNA (gDNA) methylation profile from tumor tissues is replicated in peripheral leukocytes. This study aimed to draw a correlation between rs1801133 MTHFR variants, gDNA methylation and overall survival of patients with recurrent glioblastoma (rGBM) under perillyl alcohol (POH) treatment. Methods: gDNA from whole blood was extracted using a commercially available kit (Axygen) and quantified by spectrophotometry. Global gDNA methylation was determined by ELISA and rs1801133 polymorphism by PCR-RFLP. Statistical analysis of gDNA methylation profile and rs1801133 variants included Mann-Whitney, Kruskal-Wallis, Spearman point-biserial correlation tests (SPSS and Graphpad Prism packages; significant results for effect size higher than 0.4). Prognostic value of gDNA methylation and rs1801133 variants considered survival profiles at 25 weeks of POH treatment, having the date of protocol adhesion as starting count and death as the final event.

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