Sequencing Detects Oncogenic Alterations in Cerebrospinal Fluid

Tumors affecting the central nervous system (CNS) are challenging to treat, and little is known about the mechanisms of CNS tumor evolution in part because of the difficulty of accessing tumor tissue. Recent studies have indicated that tumor DNA can be detected in the cerebrospinal fluid (CSF) from some patients with CNS cancers, but it is not clear whether detection of clinically relevant genomic alterations by CSF sequencing would be feasible. Pentsova and colleagues performed targeted next-generation sequencing of 341 cancer-associated genes in cell-free DNA (cfDNA) from the CSF of 53 patients and identified clinically relevant somatic alterations that were concordant with the primary tumors in 20 of 32 (63%) of patients with CNS metastases and 6 of 12 (50%) of patients with primary brain tumors, but none in 9 patients without CNS involvement. To determine if drug resistance–associated mutations could be identified in CSF, 12 patients whose CNS tumors progressed during kinase inhibitor treatment were analyzed. Mutations were detected in the CSF of 4 (33%) of these patients that were undetectable prior to treatment, including EGFR^T790M mutations in two patients and a KRAS^G12A mutation in one patient with erlotinib-resistant EGFR-mutant non–small cell lung cancer and an acquired NRAS^G12R mutation in a patient with dabrafenib- and trametinib-resistant melanoma. CSF sequencing also identified mutations in patients with primary brain tumors despite the absence of malignant cells on cytopathological evaluation of the CSF. In one patient, the CSF mutation profile could be compared to that of the original tumor and a recurrent tumor sample obtained 3 weeks after CSF collection. All three samples shared several common mutations, whereas the CSF and recurrent tumor samples harbored distinct mutations. Collectively, these findings demonstrate the feasibility of next-generation sequencing of CSF and indicate that liquid biopsies of the CSF may potentially be used to monitor CNS tumor progression.

Pentsova EI, Shah RH, Tang J, Boire A, You D, Briggs S, et al. Evaluating cancer of the central nervous system through next-generation sequencing of cerebrospinal fluid. J Clin Oncol 2016 May 9 [Epub ahead of print].

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