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Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord

Yuxuan Wang,S. Springer,Ming Zhang,K. McMahon,Isaac Kinde,L. Dobbyn,Janine Ptak,H. Brem,K. Chaichana,Gary L. Gallia,Z. Gokaslan,Mari Groves,G. Jallo,M. Lim,A. Olivi,A. Quiñones‐Hinojosa,D. Rigamonti,Greg J Riggins,D. Sciubba,J. Weingart,J. Wolinsky,X. Ye,S. Oba-Shinjo,S. Marie,M. Holdhoff,N. Agrawal,Luis A. Diaz,N. Papadopoulos,K. Kinzler,B. Vogelstein,C. Bettegowda

Published 2015 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Outcomes for individuals with central nervous system (CNS) malignancies remain abysmal. A major challenge in managing these patients is the lack of reliable biomarkers to monitor tumor dynamics. Consequently, many patients undergo invasive surgical procedures to determine disease status or experience treatment delays when radiographic testing fails to show disease progression. We show here that primary CNS malignancies shed detectable levels of tumor DNA into the surrounding cerebrospinal fluid (CSF), which could serve as a sensitive and exquisitely specific marker for quantifying tumor burden without invasive biopsies. Therefore, assessment of such tumor-derived DNA in the CSF has the potential to improve the management of patients with primary CNS tumors. Cell-free DNA shed by cancer cells has been shown to be a rich source of putative tumor-specific biomarkers. Because cell-free DNA from brain and spinal cord tumors cannot usually be detected in the blood, we studied whether the cerebrospinal fluid (CSF) that bathes the CNS is enriched for tumor DNA, here termed CSF-tDNA. We analyzed 35 primary CNS malignancies and found at least one mutation in each tumor using targeted or genome-wide sequencing. Using these patient-specific mutations as biomarkers, we identified detectable levels of CSF-tDNA in 74% [95% confidence interval (95% CI) = 57–88%] of cases. All medulloblastomas, ependymomas, and high-grade gliomas that abutted a CSF space were detectable (100% of 21 cases; 95% CI = 88–100%), whereas no CSF-tDNA was detected in patients whose tumors were not directly adjacent to a CSF reservoir (P < 0.0001, Fisher’s exact test). These results suggest that CSF-tDNA could be useful for the management of patients with primary tumors of the brain or spinal cord.

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