Seq-ing the SINEs of central nervous system tumors in cerebrospinal fluid

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

doi:10.1016/j.xcrm.2023.101148

Seq-ing the SINEs of central nervous system tumors in cerebrospinal fluid

Cell Rep Med. 2023 Aug 15;4(8):101148. doi: 10.1016/j.xcrm.2023.101148. Epub 2023 Aug 7.

Authors

Christopher Douville¹, Samuel Curtis¹, Mahmoud Summers¹, Tej D Azad², Jordina Rincon-Torroella³, Yuxuan Wang¹, Austin Mattox¹, Bracha Avigdor¹, Jonathan Dudley⁴, Joshua Materi², Divyaansh Raj², Sumil Nair², Debarati Bhanja⁵, Kyle Tuohy⁵, Lisa Dobbyn¹, Maria Popoli¹, Janine Ptak¹, Nadine Nehme¹, Natalie Silliman¹, Cherie Blair¹, Kathy Judge¹, Gary L Gallia², Mari Groves², Christopher M Jackson², Eric M Jackson², John Laterra⁶, Michael Lim⁷, Debraj Mukherjee², Jon Weingart², Jarushka Naidoo⁸, Carl Koschmann⁹, Natalya Smith⁵, Karisa C Schreck¹⁰, Carlos A Pardo⁶, Michael Glantz⁵, Matthias Holdhoff¹¹, Kenneth W Kinzler¹, Nickolas Papadopoulos¹, Bert Vogelstein¹², Chetan Bettegowda¹³

Affiliations

¹ Department of Oncology, The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; The Ludwig Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
² Department of Neurosurgery, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
³ Department of Oncology, The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; The Ludwig Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Neurosurgery, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
⁴ Department of Oncology, The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; The Ludwig Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pathology, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
⁵ Department of Neurosurgery, Pennsylvania State University, Hershey, PA, USA.
⁶ Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
⁷ Department of Neurosurgery, Stanford University, Palo Alto, CA, USA.
⁸ Department of Oncology, Beaumont Hospital, Dublin, Ireland.
⁹ Division of Pediatric Oncology, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Department of Oncology, The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
¹¹ Department of Oncology, The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
¹² Department of Oncology, The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; The Ludwig Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
¹³ Department of Oncology, The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; The Ludwig Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Neurosurgery, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA. Electronic address: cbetteg1@jhmi.edu.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Central Nervous System
Central Nervous System Neoplasms* / cerebrospinal fluid
Central Nervous System Neoplasms* / diagnosis
Central Nervous System Neoplasms* / genetics
Humans
Nucleic Acid Amplification Techniques
Polymerase Chain Reaction / methods
Short Interspersed Nucleotide Elements

Abstract

Publication types

MeSH terms

Grants and funding