Novel Molecular Markers in Glioblastoma—Benefits of Liquid Biopsy

Abstract

: Glioblastoma is a primary Central Nervous System (CNS) malignancy with poor survival. Treatment options are scarce and despite the extremely heterogeneous nature of the disease, clinicians lack prognostic and predictive markers to characterize patients with different outcomes. Certain immunohistochemistry, FISH, or PCR-based molecular markers, including isocitrate dehydrogenase1/2 (IDH1/2) mutations, epidermal growth factor receptor variant III (EGFRvIII) mutation, vascular endothelial growth factor overexpression (VEGF) overexpression, or (O6-Methylguanine-DNA methyltransferase promoter) MGMT promoter methylation status, are well-described; however, their clinical usefulness and accuracy is limited, and tumor tissue samples are always necessary. Liquid biopsy is a developing field of diagnostics and patient follow up in multiple types of cancer. Fragments of circulating nucleic acids are collected in various forms from different bodily fluids, including serum, urine, or cerebrospinal fluid in order to measure the quality and quantity of these markers. Multiple types of nucleic acids can be analyzed using liquid biopsy. Circulating cell-free DNA, mitochondrial DNA, or the more stable long and small non-coding RNAs, circular RNAs, or microRNAs can be identified and measured by novel PCR and next-generation sequencing-based methods. These markers can be used to detect the previously described alterations in a minimally invasive method. These markers can be used to differentiate patients with poor or better prognosis, or to identify patients who do not respond to therapy. Liquid biopsy can be used to detect recurrent disease, often earlier than using imaging modalities. Liquid biopsy is a rapidly developing field, and similarly to other types of cancer, measuring circulating tumor-derived nucleic acids from biological fluid samples could be the future of differential diagnostics, patient stratification, and follow up in the future in glioblastoma as well.

Noninvasive Urine-Based Tests to Diagnose or Detect Recurrence of Bladder Cancer

“…Indeed, urine and blood are largely used as liquid biopsies to detect markers, such as circulating cell free DNA, microRNA, circular RNA, non-coding RNA, proteins, cells etc. [ 124 , 125 , 126 ]. Urine is a body fluid that can be used to detect cancers and others diseases.…”

“…It is noninvasive and easy to collect. Other types of cancer, completely independent of the genitourinary system, can also be detected using urine, such as breast cancer or Glioblastoma [ 124 ]. To detect BC, cytology is the first assay used.…”

Advancements in Neuroimaging to Unravel Biological and Molecular Features of Brain Tumors

“…EGFR modifications are believed to have a role in tumor invasiveness (regulating proliferation and motility of tumor cells) and often occur in the infiltrating periphery of GBM, accounting for the fuzzier appearance of tumor margins [ 55 ]. Despite not representing a diagnostic criterion for WHO 2016 GBM classification, the identification of EGFR modifications (and specifically EGFRvIII) may have prognostic and therapeutic implications (even though the exact prognostic meaning of EGFRvIII is still controversial) [ 57 , 58 , 59 ]. EGFR alterations have been associated with lower ADC [ 60 ], higher rCBV, and lower PSR (percentage signal recovery, a DSC-derived metric reflecting contrast leakage) [ 61 ], as well as higher rV p and rK trans [ 62 ].…”

Mitochondrial DNA Alterations in Glioblastoma (GBM)

“…Liquid biopsies are based on the fact that tumors can eliminate several compounds in the blood circulation, such as circulating tumor cells (CTCs), cell-free nucleic acids (cfDNA and cfRNA), extracellular vesicles (EVs) [ 68 , 69 , 70 , 71 , 72 ], proteins [ 68 , 73 ], and tumor-educated metabolites and platelets (TEPs) [ 68 ], which can cross the blood-brain barrier [ 68 , 70 ] due to changes in its permeability [ 70 , 71 ].…”