title: Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord.
abstract: 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.
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Simeon
authors.initials: S
authors.lastname: Springer
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: K Wyatt
authors.initials: KW
authors.lastname: McMahon
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Isaac
authors.initials: I
authors.lastname: Kinde
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Lisa
authors.initials: L
authors.lastname: Dobbyn
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Janine
authors.initials: J
authors.lastname: Ptak
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Kaisorn
authors.initials: K
authors.lastname: Chaichana
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Gary L
authors.initials: GL
authors.lastname: Gallia
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Ziya L
authors.initials: ZL
authors.lastname: Gokaslan
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Mari L
authors.initials: ML
authors.lastname: Groves
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: George I
authors.initials: GI
authors.lastname: Jallo
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Michael
authors.initials: M
authors.lastname: Lim
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Olivi
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Alfredo
authors.initials: A
authors.lastname: Quinones-Hinojosa
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Daniele
authors.initials: D
authors.lastname: Rigamonti
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Riggins
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sciubba
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Jon D
authors.initials: JD
authors.lastname: Weingart
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Wolinsky
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Xiaobu
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Neurology and Pathology, School of Medicine, University of Sao Paulo, Sao Paulo, SP 01246-903, Brazil;
authors.forename: Sueli Mieko
authors.initials: SM
authors.lastname: Oba-Shinjo
authors.affiliation: Department of Neurology and Pathology, School of Medicine, University of Sao Paulo, Sao Paulo, SP 01246-903, Brazil;
authors.forename: Suely K N
authors.initials: SK
authors.lastname: Marie
authors.affiliation: Department of Oncology, Brain Cancer Division, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Matthias
authors.initials: M
authors.lastname: Holdhoff
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287; Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
authors.forename: Nishant
authors.initials: N
authors.lastname: Agrawal
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287;
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287; bertvog@gmail.com cbetteg1@jhmi.edu.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: Ludwig Center, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287; bertvog@gmail.com cbetteg1@jhmi.edu.
authors.forename: Chetan
authors.initials: C
authors.lastname: Bettegowda
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000134:cerebrospinal fluid* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000134:cerebrospinal fluid* / Q000235:genetics; D003710:Demography; D005091:Exons / Q000235:genetics; D005260:Female; D015894:Genome, Human; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D013120:Spinal Cord Neoplasms / Q000134:cerebrospinal fluid* / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm
keywords: CNS tumors; CSF-tDNA; biomarker