Analysis of data from two case-controlled studies with a total of 130 patients found that metagenomic next-generation sequencing (mNGS), which can be used to look for gene copy number variations indicating aneuploidy, had a sensitivity of 75% and a specificity of 100%, according to the results published in JAMA Neurology.
"This study builds on earlier work where we looked at DNA and RNA in the spinal fluid to see if there were infections in the CNS, which led us to a clinically validated test to look for mystery infections that affect the brain and spinal cord," said the study's lead author, Dr. Wei Gu, who was a clinical instructor in the department of laboratory medicine at the University of California, San Francisco (UCSF), at the time the research was being done.
"This current work, which I coauthored with Dr. Michael Wilson, an associate professor at the University of California, San Francisco, used the same data sets," said Dr. Gu, now an assistant professor in the department of pathology at Stanford University in California. "We sequence every piece of DNA floating in the spinal fluid and we're picking up not only undetected pathogens, but also tumor DNA."
The key new finding, Dr. Gu said, is that those pieces of human DNA can be fragments of tumor cells. In the tough to diagnose cases, it's often not possible to see intact tumor cells under a microscope, he added. "By looking at the DNA from the spinal fluid we were able to pick up cancers that you couldn't find with traditional methods."
Being able to detect cancer using spinal fluid could save patients from having more invasive tests like brain biopsies and also catch tumors that might not be detected until they are at a late stage, Dr. Gu said.
The researchers first tested their technique on cerebrospinal fluid (CSF) specimens collected at the UCSF Clinical Laboratories between July 1, 2017, and December 31, 2019, evaluating test performance in specimens from patients with a CNS malignant neoplasm (positive controls) and without the cancer (negative controls). The results of the analysis were compared with those from CSF cytologic testing and/or flow cytometry.
The second test used samples from 12 patients enrolled in an ongoing prospective study between April 1, 2014 and July 31, 2019, who had presentations that were suggestive of neuroinflammatory disease but were ultimately diagnosed with a CNS malignant neoplasm, as well as samples from 17 matched controls.
In the first test, the researchers detected aneuploidy in 64% of the patients with nondiagnostic cytologic testing and/or flow cytometry. In the second, neuroinflammatory disease test, aneuploidy was detected in 55% of the patients who were ultimately diagnosed with a CNS malignant neoplasm.
Of the patients in whom aneuploidy was detected, 38 (90.5%) had multiple copy number variations with tumor fractions ranging from 31% to 49%, the study team notes.
The new study "further demonstrates the potential applications of applying sensitive state of the art molecular technologies, such as metagenomic next generation sequencing, to help diagnose CNS tumors," said Dr. Chetan Bettegowda, a professor of neurosurgery and oncology and director of the Meningioma and Metastatic Brain Tumor Centers at Johns Hopkins Medicine in Baltimore, who wasn't involved in the study.
"There are a few very notable aspects to this study," Dr. Bettegowda said in an email. "1) The assay the authors use was designed for the detection of infection, but re-analysis of the data could detect underlying cancers and 2) the mNGS assay was far more sensitive than the traditional approaches of cytology and flow cytometry and 3) the samples were run on archived remnent samples, indicating that very little CSF is needed, suggesting such approaches can be added to existing testing without great encumbrance to the patient."
"There is burgeoning literature, including this paper, that liquid biopsy approaches such as this can help inform clinical decision making for individuals with known or suspected CNS cancers," Dr. Bettegowda said. "This field is expanding at a rapid pace but we still need prospective clinical studies to bring the technology to our patients and for integration into routine clinical use."
SOURCE: https://bit.ly/3AdS04w JAMA Neurology, online September 13, 2021.
By Linda Carroll
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