Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors - A prospective study and guidelines for clinical testing

Kristyn Galbraith, Varshini Vasudevaraja, Jonathan Serrano, Guomiao Shen, Ivy Tran, Nancy Abdallat, Mandisa Wen, Seema Patel, Misha Movahed-Ezazi, Arline Faustin, Marissa Spino-Keeton, Leah Geiser Roberts, Ekrem Maloku, Steven A. Drexler, Benjamin L. Liechty, David Pisapia, Olga Krasnozhen-Ratush, Marc Rosenblum, Seema Shroff, Daniel R. BouéChristian Davidson, Qinwen Mao, Mariko Suchi, Paula North, Amanda Hopp, Annette Segura, Jason A. Jarzembowski, Lauren Parsons, Mahlon D. Johnson, Bret Mobley, Wesley Samore, Declan McGuone, Pallavi P. Gopal, Peter D. Canoll, Craig Horbinski, Joseph M. Fullmer, Midhat S. Farooqui, Murat Gokden, Nitin R. Wadhwani, Timothy E. Richardson, Melissa Umphlett, Nadejda M. Tsankova, John C. Dewitt, Chandra Sen, Dimitris G. Placantonakis, Donato Pacione, Jeffrey H. Wisoff, Eveline Teresa Hidalgo, David Harter, Christopher M. William, Christine Cordova, Sylvia C. Kurz, Marissa Barbaro, Daniel A. Orringer, Matthias A. Karajannis, Erik P. Sulman, Sharon L. Gardner, David Zagzag, Aristotelis Tsirigos, Jeffrey C. Allen, John G. Golfinos, Matija Snuderl

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

Original languageEnglish
Article numbervdad076
JournalNeuro-Oncology Advances
Issue number1
StatePublished - 1 Jan 2023


  • DNA methylation
  • central nervous system tumors
  • guidelines
  • molecular
  • tumor classification


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