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Study Suggests Cerebrospinal Fluid as Potential Liquid Biopsy Source for Brain Tumors

NEW YORK (GenomeWeb) – A research team from Spain and the US has found that circulating tumor DNA (ctDNA) can be detected in the cerebrospinal fluid of individuals with brain tumors or brain metastases, offering a potential opportunity for liquid biopsies from CSF, resembling those from blood.

"[W]e found circulating tumor DNA in CSF at such high levels that we were able to detect and characterize tumors with a high degree of sensitivity," Joan Seoane, director of translational research at Vall d'Hebron Institute of Oncology in Barcelona, Spain, said in a statement.

Seoane and his colleagues sequenced several hundred cancer genes in tumor, germline, blood, and cerebrospinal samples from a dozen individuals with glioblastoma or brain metastases from lung or breast cancers. Their results, appearing online today in Nature Communications, suggested tumor-associated mutations can be picked up in CSF. They further verified them using samples from individuals with medullobastoma or brain metastases from other cancer types.

The team found that CSF typically contained levels of ctDNA that corresponded with the size of the tumor during treatment. The approach also showed promise for picking up a cancer complication called leptomeningeal carcinomatosis (LC), where the cancer affects the membrane around the brain and spinal cord.

While a growing body of research has focused on detecting ctDNA from solid tumors in blood, , it has proven difficult to reliably detect DNA from brain tumors due to the organ's relative insulation from the blood, the team explained.

"[C]irculating tumor DNA levels for brain tumors are very low in plasma," Seoane noted. "But the brain has its own closed circuit of fluid, cerebrospinal fluid, which bathes the brain and spinal cord, and is therefore in direct contact with tumor cells."

With that in mind, the researchers used the Integrated Mutation Profiling of Actionable Cancer Targets platform from Memorial Sloan Kettering Cancer Center to target the coding sequences of more than 300 genes in samples from 12 cancer cases: four glioblastomas, six breast cancers with brain metastasis, and two cases of lung cancer with brain metastasis.

For each individual, the team tested and compared tumor samples, peripheral blood lymphocytes cells containing germline DNA, blood plasma, and CSF. 

Within the CSF samples, the researchers saw somatic point mutations insertions, deletions, and copy number changes that matched those found in the tumor sample itself. In another 11 individuals with brain-restricted medulloblastoma or metastatic brain disease, they successfully detected ctDNA in the CSF even when little or no tumor DNA could be found in plasma.

In general, the team detected fewer mutations in ctDNA from CSF when glioblastoma tumors were involved. Nevertheless, results so far hint that CSF might offer a window to brain cancer, which is prone to recurrence and difficult to sample directly.

For example, when the researchers assessed blood and CSF samples over time in six of the glioblastoma or brain metastasis cases, they found that the levels of ctDNA in CSF declined in response to waning tumor size after surgery or other treatment. On the other hand, ctDNA in the CSF inched up as tumors progressed.

Based on their findings so far, the team noted that CSF may be particularly useful for peeking at the mutation patterns in tumors restricted to the brain. The group also saw signs that the approach may compare favorably to cytological approaches for finding LC complications, though additional work is needed to distinguish between DNA from LC and genetic material from the tumor itself.

"Altogether, our results indicate that CSP ctDNA can be exploited as a 'liquid biopsy' of brain tumors," the study's authors concluded, "opening a novel avenue of research in [central nervous system] circulating biomarkers with an important impact in the future characterization, diagnosis, prognosis, and clinical managing of brain cancer."