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Liquid Biopsies Hold Promise for Diagnosis and Monitoring of Gliomas

Key findings

  • The advent of mutation-based therapy for glioma has created a great need for minimally invasive serial molecular analysis
  • The use of liquid biopsies as a complement to surgical biopsy could help confirm diagnosis, identify mutations present, and monitor tumor evolution and response to therapy
  • Putative biomarkers for glioma include circulating tumor cells, extracellular vesicles, circulating tumor DNA and circulating microRNA
  • The ability to obtain serial liquid biopsies would provide unique opportunities to study the evolution of tumors and mechanisms of treatment resistance

Increasingly often, drug therapy for glioma is being tailored to the genetic mutations present in the individual patient's tumor. However, most mutations are not present in every region of the tumor, and the mutations can change over time and in response to therapy. Therefore, a surgical biopsy at any given site or time point gives only limited information.

Accordingly, there is a great need for minimally invasive methods of performing serial genetic analysis. Research teams around the world are investigating whether liquid biopsy—genetic analysis of bodily fluids—is a feasible supplement to surgical biopsy for diagnosing glioma and identifying mutations. Brian V. Nahed, MD, MSc, associate director of the Mass General Neurosurgery Program, and colleagues recently reviewed the status of this research.

In Neuro-Oncology, the authors explain why circulating tumor cells, extracellular vesicles, circulating tumor DNA and circulating microRNA are considered putative biomarkers for glioma.

Circulating Tumor Cells

Circulating tumor cells can retain certain characteristics from the primary tumor, such as mutations and gene expression signatures. Several groups have identified glioma cells in blood. In one study, circulating cells showed the signature of an aggressive glioma subtype, and in another study, the presence of circulating glioma cells was correlated with amplification of epidermal growth factor receptor (EGFR, a potential drug target).

Extracellular Vesicles

Extracellular vesicles (EVs) are small lipid-enclosed structures that both cancer and noncancer cells release into the extracellular space. EVs released by gliomas can be used to detect microRNAs that are thought to promote tumor cell proliferation and resistance to apoptosis (programmed cell death). Glioblastoma EVs can also be used to detect EGFR variant III (EGFRvIII), a tumor-specific target for immunotherapy. Two groups, including one at Mass General, have developed assays that are highly specific in detecting EGFRvIII-positive glioblastoma using EVs derived from Cerebrospinal fluid (CSF).

Circulating DNA

DNA is sloughed off in great quantity by normal cells, in which case it is called circulating free DNA (cfDNA), and it is also released by tumor cells, in which case it is called circulating tumor DNA (ctDNA). Next-generation sequencing and digital polymerase chain reaction can detect ctDNA within the background of cfDNA. Blood-based detection of ctDNA is sensitive and specific for a variety of nonglial cancers, but for gliomas, ctDNA is more sensitive when derived from CSF.

Circulating MicroRNA

MicroRNAs are noncoding RNA molecules that help regulate transcription of both normal and cancer cells. Recent studies suggest that microRNAs also engage in intercellular communication as both pro- and anti-oncogenic regulators and immunosuppressors. Increased levels of some microRNAs, and decreased levels of others, have been detected in the blood of patients with glioma, and two studies linked microRNA levels to patient outcomes.

None of these biomarkers are ready for clinical use, partly because the sensitivity of most assays for detecting glioma is inadequate. In addition, more research is needed to confirm the significance of blood- or CSF-based findings during a patient's disease course.

Liquid Biopsy Applications

If these challenges can be overcome, liquid biopsies will have multiple important applications:

  • Diagnose inoperable tumors, where a safe biopsy may be difficult or impossible
  • Non-invasively identify tumor mutations and select patients who would benefit from targeted drug therapy
  • Monitor mutational changes in response to therapy
  • Distinguish between genuine tumor progression and pseudoprogression on imaging
  • Aid researchers in studying the evolution of tumors and mechanisms of treatment resistance

The authors say that a combination of techniques, such as the use of both ctDNA and EVs, might improve the potential for liquid biopsy to be used routinely in the diagnosis and monitoring of glioma.

Learn more about neuro-oncology at Mass General

Learn more about the Stephen E. and Catherine Pappas Center for Neuro-Oncology


Mass General doctors are developing a liquid biopsy for brain tumors to reduce the need for invasive tissue biopsies.


Mass General has developed a genotype-targeted therapy for glioma, designed to be given at the tumor site during surgery, and an accompanying rapid diagnostic.