A novel, multi-analyte test developed by researchers at the Johns Hopkins Kimmel Cancer Center, its Ludwig Center and the Johns Hopkins Department of Neurosurgery can accurately identify brain cancers using small samples of cerebrospinal fluid (CSF), offering a promising new tool to guide clinical decision-making.
The findings, supported by funding from the National Institutes of Health, were published Aug. 25 in Cancer Discovery and demonstrate that combining multiple biological markers, including tumor-derived DNA and immune cell signatures, is more effective for diagnosing central nervous system cancers than using any one marker alone.
"This study highlights how much more information we can gain when we evaluate several analytes together," says senior study author Chetan Bettegowda, M.D., Ph.D., Harvey Cushing Professor and Director of the Department of Neurosurgery at the Johns Hopkins University School of Medicine, director of the Reza Khatib Brain Tumor Research Center at Johns Hopkins, medical director of the Ludwig Center, and a senior author on the study. "The ability to detect cancers with high specificity and also gain insight into the immune environment of the brain could be an important advance in the care of patients with brain tumors."
To evaluate the potential of a multi-analyte approach, investigators analyzed 206 CSF samples, including samples from patients with high-grade gliomas, medulloblastomas, metastases and central nervous system lymphomas. Their test, called CSF-BAM (cerebrospinal fluid–B/T cell receptor, aneuploidy and mutation), measured chromosomal abnormalities, tumor-specific mutations, and T and B cell receptor sequences. In combination, these markers identified brain cancers with more than 80% sensitivity (ability to detect cancer) and 100% specificity (correctly identified those who were cancer-free) in the validation cohort. The 100% specificity means no false positives were recorded among individuals with noncancerous conditions.
The study also showed that the assay could distinguish between the immune cell populations present in cancer and noncancer cases, offering additional biological context that could be helpful in more-challenging clinical scenarios. Investigators say this ability to categorize T and B cell populations in the CSF provides insights into both disease presence and immune response.
"Many patients with brain lesions face invasive diagnostic procedures to confirm a cancer diagnosis," says Christopher Douville, M.D., assistant professor of oncology and a senior study author. "A tool like this could help us make better-informed decisions about who really needs a biopsy and who doesn't."
Researchers say the test could be particularly useful for cases in which conventional imaging or cytology is inconclusive, or in situations when obtaining tissue for diagnosis is risky or not possible. The multi-analyte approach, they say, enables clinicians to better detect cancer and better understand the disease status, supporting a more tailored approach to patient care.
In addition to Bettegowda and Douville, other researchers on the study were Maximilian Konig, Peter Calabresi, Alexander Pearlman, Yuxuan Wang, Anita Kalluri, Megan Parker, Joshua D Cohen, Jonathan Dudley, Jordina Rincon-Torroella, Yuanxuan Xia, Ryan Gensler, Melanie Alfonzo Horwitz, John Theodore, Lisa Dobbyn, Maria Popoli, Janine Ptak, Natalie Silliman, Kathy Judge, Mari Groves, Christopher Jackson, Eric Jackson, George Jallo, Michael Lim, Mark Luciano, Debraj Mukherjee, Jarushka Naidoo, Sima Rozati, Cole Sterling, Jon Weingart, Carl Koschmann, Alireza Mansouri, Michael Glantz, David Kamson, Karisa Schreck, Carlos Pardo, Matthias Holdhoff, Suman Paul, Kenneth Kinzler, Nickolas Papadopoulos, and Bert Vogelstein.
The research was supported by the National Cancer Institute grants T32 CA009071, CA0973, DRP80057309, K08CA240403, RA37CA230400, RO1CA276221, R21TR004059, T32GM136577, U01CA230691; Alex's Lemonade Stand Foundation; American Society of Hematology Scholar Award; Benjamin Baker Endowment 80049589; Burroughs Wellcome Carer Award for Medical Scientists; Commonwealth Fund; Conrad R. Hilton Foundation; DOD award W81XWH-21-1-0251; Doris Duke Career Development Award; Jerome Greene Foundation; Leukemia Lymphoma Society Translation Research Program award; Lustgarten Foundation for Pancreatic Cancer Research; Sol Goldman Sequencing Facility at Johns Hopkins; Swim Across America/Baltimore; Thomas M. Hohman Memorial Cancer Research Fund; and the Virginia and D.K. Ludwig Fund for Cancer Research.
On the Web
