E. Circulating free DNA

Cell-free DNA (cfDNA) as a double-stranded, DNA fragments released for the breakdown of cancer tissue by bloodstream that is approximately 150 to 200 base pairs in length, corresponding to nucleosome-associated DNA, can be released by cells under physiological and pathological conditions as well. It is suggested that cfDNA could be derived from apoptotic or necrotic cells, rapidly dividing cells, or CTCs [4]. Blood cfDNA is mostly derived from genomic DNA released during inflammation or cell death in people without cancer. Due to phagocyte clearance, the concentration of cfDNA in the blood is low in physiological settings. Circulating protein markers may be used to track the efficacy of therapy in patients with brain tumors. Current MR imaging techniques cannot effectively detect the unique biological tumor characteristics and complicated tissue changes produced by various cancer treatments [26, 27].

The incidence of detectable ctDNA varies significantly across patients with various tumor types. The concentration of cancer cell-generated ctDNA in plasma in glioblastoma is low when compared to other cancer types, which might be due to the existence of the blood–brain barrier. In glioblastoma, ctDNA analysis presents a number of difficulties. Aside from the common issues of short half-lives (1.5 h) of ctDNA fragments, distinguishing mutant from wild-type alleles, and developing mutation thresholds, the primary issue is the low amount of ctDNA in the samples [28].

F. Circulating proteins

Several tumor-derived circulating nucleic acids (e.g., ctDNA, cmtDNA, mRNA, non-coding RNAs including miRNAs, long non-coding RNAs) that can be detected from blood or other types of body fluids like urine, cerebrospinal fluid (CSF), saliva, pleural fluid, and ascites. In brain tumor patients, the secretion of the proteins may lead to an increase in the level of circulating proteins (CPs) in the blood and urine and/or CSF [4]. Angiogenesis-related protein markers were discovered in malignancies. The amount of vascular endothelial growth factor was shown to be substantially greater in brain tumor patients than in healthy persons, and even higher in patients with brain metastases [29]. There are two types of prognostic CP indicators: tumor-associated markers and related markers with endogenous systemic stress responses. Overall survival was adversely associated with the tumor-related plasma markers YKL-40, the extracellular domain of EGFR, and osteopontin [30, 31].
