Seq-ing the SINEs of central nervous system tumors in cerebrospinal fluid (CSF)
Authors:
Christopher Douville, Samuel Curtis, Mahmoud Summers, Tej D. Azad, Jordina Rincon-Torroella, Yuxuan Wang, Austin Mattox, Bracha Avigdor, Jonathan Dudley, Joshua Materi, Divyaansh Raj, Sumil Nair, Debarati Bhanja, Kyle Tuohy, Lisa Dobbyn, Maria Popoli, Janine Ptak, Nadine Nehme, Natalie Silliman, Cherie Blair, Kathy Judge, Gary L. Gallia, Mari Groves, Christopher M. Jackson, Eric M. Jackson, John Laterra, Michael Lim, Debraj Mukherjee, Jon Weingart, Jarushka Naidoo, Carl Koschmann, Natalya Smith, Karisa C. Schreck, Carlos A. Pardo, Michael Glantz, Matthias Holdhoff, Kenneth W. Kinzler, Nickolas Papadopoulos, Bert Vogelstein, Chetan Bettegowda
Journal:
Cell Reports Medicine, Volume 4, Issue 8, 15 August 2023, 101148.
Abstract:
It is often challenging to distinguish cancerous from non-cancerous lesions in the brain using conventional diagnostic approaches. We introduce an analytic technique called Real-CSF (repetitive element aneuploidy sequencing in CSF) to detect cancers of the central nervous system from evaluation of DNA in the cerebrospinal fluid (CSF). Short interspersed nuclear elements (SINEs) are PCR amplified with a single primer pair, and the PCR products are evaluated by next-generation sequencing. Real-CSF assesses genome-wide copy-number alterations as well as focal amplifications of selected oncogenes. Real-CSF was applied to 280 CSF samples and correctly identified 67% of 184 cancerous and 96% of 96 non-cancerous brain lesions. CSF analysis was considerably more sensitive than standard-of-care cytology and plasma cell-free DNA analysis in the same patients. Real-CSF therefore has the capacity to be used in combination with other clinical, radiologic, and laboratory-based data to inform the diagnosis and management of patients with suspected cancers of the brain.
Detection of tumor-derived DNA in cerebrospinal fluid (CSF) of patients with primary tumors of the brain and spinal cord
Authors:
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 Jr, Nickolas Papadopoulos, Kenneth W Kinzler, Bert Vogelstein, Chetan Bettegowda
Journal:
Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):9704-9. doi: 10.1073/pnas.1511694112.Epub 2015 Jul 20.
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.