Detection of human brain cancers using genomic and immune cell characterization of cerebrospinal fluid through CSF-BAM.

in medRxiv : the preprint server for health sciences by Alexander H 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 M Jackson, Eric M Jackson, George I Jallo, Michael Lim, Mark Luciano, Debraj Mukherjee, Jarushka Naidoo, Sima Rozati, Cole H Sterling, Jon Weingart, Carl Koschmann, Alireza Mansoori, Michael Glantz, David Kamson, Karisa C Schreck, Carlos A Pardo, Matthias Holdhoff, Suman Paul, Kenneth W Kinzler, Nickolas Papadopoulos, Bert Vogelstein, Christopher Douville, Chetan Bettegowda

TLDR

  • A new assay, CSF-BAM, can detect brain cancers in cerebrospinal fluid samples with high sensitivity and specificity.
  • The assay identifies somatic mutations, chromosomal copy number changes, and adaptive immunoreceptor repertoires, providing comprehensive information about the tumor and immune environment.
  • CSF-BAM has the potential to revolutionize the diagnosis and management of brain cancers, and could potentially replace surgical biopsy in some cases.

Abstract

Patients who have radiographically detectable lesions in their brain or other symptoms compatible with brain tumors pose challenges for diagnosis. The only definitive way to diagnose such patients is through brain biopsy, an obviously invasive and dangerous procedure. Here we present a new workflow termed "CSF-BAM" that simultaneously identifiescell or T cell receptor rearrangements,neuploidy, andusing PCR-mediated amplification of both strands of the DNA from CSF samples. We first describe the details of the molecular genetic assessments and then establish thresholds for positivity using training sets of libraries from patients with or without cancer. We then applied CSF-BAM to an independent set of 206 DNA samples from patients with common, aggressive cancer types as well as other forms of brain cancers. Among the 126 samples from patients with the most common aggressive cancer types (high grade gliomas, medulloblastomas, or metastatic cancers to the brain), the sensitivity of detection was >81%. None of 33 CSF-BAM assays (100% specificity, 90% to 100% credible interval) were positive in CSF samples from patients without brain cancers. The sensitivity of CSF-BAM was considerably higher than that achieved with cytology. CSF-BAM provides an integrated multi-analyte approach to identify neoplasia in the central nervous system, provides information about the immune environment in patients with or without cancer, and has the potential to inform the subsequent management of such patients. There is a paucity of technologies beyond surgical biopsy that can accurately diagnose central nervous system neoplasms. We developed a novel, sensitive and highly specific assay that can detect brain cancers by comprehensively identify somatic mutations, chromosomal copy number changes, and adaptive immunoreceptor repertoires from samples of cerebrospinal fluid.

Overview

  • The study aims to develop a novel workflow, CSF-BAM, to diagnose brain tumors by identifying cell or T cell receptor rearrangements, neuploidy, and DNA mutations in cerebrospinal fluid samples.
  • The workflow was developed and validated using training sets of libraries from patients with or without cancer, and then applied to an independent set of 206 DNA samples from patients with common aggressive cancer types and other forms of brain cancers.
  • The primary objective is to provide an integrated multi-analyte approach to identify neoplasia in the central nervous system and provide information about the immune environment in patients with or without cancer.

Comparative Analysis & Findings

  • The sensitivity of detection of CSF-BAM was >81% in 126 samples from patients with high-grade gliomas, medulloblastomas, or metastatic cancers to the brain, and 100% specificity in 33 CSF-BAM assays in patients without brain cancers.
  • The sensitivity of CSF-BAM was significantly higher than that achieved with cytology.
  • The assay detected somatic mutations, chromosomal copy number changes, and adaptive immunoreceptor repertoires from samples of cerebrospinal fluid, providing comprehensive information about the tumor and the immune environment.

Implications and Future Directions

  • CSF-BAM has the potential to inform the subsequent management of patients with suspected central nervous system neoplasms, and could potentially replace surgical biopsy in some cases.
  • The assay needs to be further validated and tested in larger studies to establish its accuracy and reproducibility.
  • Future studies could explore the use of CSF-BAM in combination with other diagnostic tools to improve the accuracy and speed of diagnosis, and to monitor the effectiveness of treatment.
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