Cerebrospinal fluid methylome-based liquid biopsies for accurate malignant brain neoplasm classification

Jeffrey A. Zuccato, Vikas Patil, Sheila Mansouri, Mathew Voisin, Ankur Chakravarthy, Shu Yi Shen, Farshad Nassiri, Nicholas Mikolajewicz, Mara Trifoi, Anna Skakodub, Brad Zacharia, Michael Glantz, Daniel D. De Carvalho, Alireza Mansouri, Gelareh Zadeh

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Background. Resolving the differential diagnosis between brain metastases (BM), glioblastomas (GBM), and central nervous system lymphomas (CNSL) is an important dilemma for the clinical management of the main three intra-axial brain tumor types. Currently, treatment decisions require invasive diagnostic surgical biopsies that carry risks and morbidity. This study aimed to utilize methylomes from cerebrospinal fluid (CSF), a biofluid proximal to brain tumors, for reliable non-invasive classification that addresses limitations associated with low target abundance in existing approaches. Methods. Binomial GLMnet classifiers of tumor type were built, in fifty iterations of 80% discovery sets, using CSF methylomes obtained from 57 BM, GBM, CNSL, and non-neoplastic control patients. Publicly-available tissue methylation profiles (N = 197) on these entities and normal brain parenchyma were used for validation and model optimization. Results. Models reliably distinguished between BM (area under receiver operating characteristic curve [AUROC] = 0.93, 95% confidence interval [CI]: 0.71–1.0), GBM (AUROC = 0.83, 95% CI: 0.63–1.0), and CNSL (AUROC = 0.91, 95% CI: 0.66–1.0) in independent 20% validation sets. For validation, CSF-based methylome signatures reliably distinguished between tumor types within external tissue samples and tumors from non-neoplastic controls in CSF and tissue. CSF methylome signals were observed to align closely with tissue signatures for each entity. An additional set of optimized CSF-based models, built using tumor-specific features present in tissue data, showed enhanced classification accuracy. Conclusions. CSF methylomes are reliable for liquid biopsy-based classification of the major three malignant brain tumor types. We discuss how liquid biopsies may impact brain cancer management in the future by avoiding surgical risks, classifying unbiopsiable tumors, and guiding surgical planning when resection is indicated.

Original languageEnglish (US)
Pages (from-to)1452-1460
Number of pages9
Issue number8
StatePublished - Aug 1 2023

All Science Journal Classification (ASJC) codes

  • Oncology
  • Clinical Neurology
  • Cancer Research

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