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

Yuxuan Wang; Simeon Springer; Ming Zhang; K. Wyatt McMahon; Isaac Kinde; Lisa Dobbyn; Janine Ptak; Henry Brem; Kaisorn Chaichana; Gary L. Gallia; Ziya L. Gokaslan; Mari L. Groves; George I. Jallo; Michael Lim; Alessandro Olivi; Alfredo Quinones-Hinojosa; Daniele Rigamonti; Greg J. Riggins; Daniel M. Sciubba; Jon D. Weingart; Jean Paul Wolinsky; Xiaobu Ye; Sueli Mieko Oba-Shinjo; Suely K.N. Marie; Matthias Holdhoff; Nishant Agrawal; Luis A. Diaz; Nickolas Papadopoulos; Kenneth W. Kinzler; Bert Vogelstein; Chetan Bettegowda

doi:10.1073/pnas.1511694112

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

Yuxuan Wang, Simeon Springer, Ming Zhang, K. Wyatt McMahon, Isaac Kinde, Lisa Dobbyn, Janine Ptak, Henry Brem, Kaisorn Chaichana, Gary L. Gallia, Ziya L. Gokaslan, Mari L. Groves, George I. Jallo, Michael Lim, Alessandro Olivi, Alfredo Quinones-Hinojosa, Daniele Rigamonti, Greg J. Riggins, Daniel M. Sciubba, Jon D. WeingartJean Paul Wolinsky, Xiaobu Ye, Sueli Mieko Oba-Shinjo, Suely K.N. Marie, Matthias Holdhoff, Nishant Agrawal, Luis A. Diaz, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Chetan Bettegowda

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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.

Original language	English (US)
Pages (from-to)	9704-9709
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	112
Issue number	31
DOIs	https://doi.org/10.1073/pnas.1511694112
State	Published - Aug 4 2015

Keywords

Biomarker
CNS tumors
CSF-tDNA

ASJC Scopus subject areas

General

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10.1073/pnas.1511694112

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Wang, Y., Springer, S., Zhang, M., McMahon, K. W., Kinde, I., Dobbyn, L., Ptak, J., Brem, H., Chaichana, K., Gallia, G. L., Gokaslan, Z. L., Groves, M. L., Jallo, G. I., Lim, M., Olivi, A., Quinones-Hinojosa, A., Rigamonti, D., Riggins, G. J., Sciubba, D. M., ... Bettegowda, C. (2015). Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord. Proceedings of the National Academy of Sciences of the United States of America, 112(31), 9704-9709. https://doi.org/10.1073/pnas.1511694112

Wang, Y, Springer, S, Zhang, M, McMahon, KW, Kinde, I, Dobbyn, L, Ptak, J, Brem, H, Chaichana, K, Gallia, GL, Gokaslan, ZL, Groves, ML , Jallo, GI, Lim, M, Olivi, A, Quinones-Hinojosa, A, Rigamonti, D , Riggins, GJ, Sciubba, DM, Weingart, JD, Wolinsky, JP, Ye, X, Oba-Shinjo, SM, Marie, SKN, Holdhoff, M, Agrawal, N, Diaz, LA, Papadopoulos, N , Kinzler, KW , Vogelstein, B & Bettegowda, C 2015, 'Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 31, pp. 9704-9709. https://doi.org/10.1073/pnas.1511694112

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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.",

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AU - Wang, Yuxuan

AU - Springer, Simeon

AU - Zhang, Ming

AU - McMahon, K. Wyatt

AU - Kinde, Isaac

AU - Dobbyn, Lisa

AU - Ptak, Janine

AU - Brem, Henry

AU - Chaichana, Kaisorn

AU - Gallia, Gary L.

AU - Gokaslan, Ziya L.

AU - Groves, Mari L.

AU - Jallo, George I.

AU - Lim, Michael

AU - Olivi, Alessandro

AU - Quinones-Hinojosa, Alfredo

AU - Rigamonti, Daniele

AU - Riggins, Greg J.

AU - Sciubba, Daniel M.

AU - Weingart, Jon D.

AU - Wolinsky, Jean Paul

AU - Ye, Xiaobu

AU - Oba-Shinjo, Sueli Mieko

AU - Marie, Suely K.N.

AU - Holdhoff, Matthias

AU - Agrawal, Nishant

AU - Diaz, Luis A.

AU - Papadopoulos, Nickolas

AU - Kinzler, Kenneth W.

AU - Vogelstein, Bert

AU - Bettegowda, Chetan

PY - 2015/8/4

Y1 - 2015/8/4

N2 - 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.

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

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