Evaluating Cancer of the Central Nervous System Through Next-Generation Sequencing of Cerebrospinal Fluid

Abstract

PurposeCancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of limited access to tumor tissue.Materials and MethodsWe sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer.ResultsWe detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations.ConclusionThe study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS.

Cell-Cycle and DNA-Damage Response Pathway Is Involved in Leptomeningeal Metastasis of Non–Small Cell Lung Cancer

“…There are two types of DNA sources in CSF-cell-free DNA (cfDNA) from supernatants and genomic DNA from cell pellets. It was reported that a higher fraction of cfDNA is tumor-derived than pellet DNA samples (20). However, in our experience, the EGFR mutation type(s) in CSF cfDNA and pellet DNA sometimes can be different and complement each other (Supplementary Table S8).…”

“…However, due to blood-brain barrier (BBB), patients with brain tumors do not present with or present with only low amounts of ctDNA in plasma (17). Recently, a few studies have demonstrated that tumor mutations are detectable in the CSF of patients with various primary and metastatic brain tumors, and ctDNA in CSF recapitulates the genomic landscape of brain tumors better than plasma (18)(19)(20). Therefore, CSF may serve as liquid biopsy to monitor brain tumor evolution.…”

Molecular Diagnosis of Diffuse Gliomas through Sequencing of Cell-Free Circulating Tumor DNA from Cerebrospinal Fluid

“…Furthermore, we could identify ctDNA in a large proportion of patients with diffuse glioma (17 of 20 patients). A lack of ctDNA in the CSF may depend on the aggressiveness of the tumor or the anatomical location (18)(19)(20). In our cohort, the three patients without CSF ctDNA (one diffuse astrocytoma and two oligodendrogliomas) were all grade II gliomas.…”

“…We and others have reported the presence of cell-free circulating tumor DNA (ctDNA) in the cerebrospinal fluid (CSF) of patients with brain tumors (18)(19)(20). While absent or low levels of ctDNA are found in the plasma of these patients, ctDNA is frequently present in the CSF and can be used to characterize brain tumors (18).…”

Advancements in diagnosis and treatment of meningeal carcinomatosis in solid cancer

“…Sasaki et al [29] analyzed the EGFR mutation status of CSF straightly using real-time polymerase chain reaction that was more sensitive than cytology to diagnose MC in seven patients with non-small cell lung carcinoma (NSCLC) harboring an EGFR mutation (sensitivity of 100% vs. 28.6%). A separate study used nextgeneration sequencing by Pentsova et al [30] to reveal somatic alterations in tumor-derived DNA from CSF in patients with CNS metastases of solid tumors and primary brain tumors. These studies demonstrated that identification of genomic mutations in tumorderived cell-free DNA from CSF using a sufficiently sensitive platform in patients with CNS involvement.…”