Abstract
Genome-wide DNA methylation signatures correlate with and distinguish central nervous system (CNS) tumor types. Since the publication of the initial CNS tumor DNA methylation classifier in 2018, this platform has been increasingly used as a diagnostic tool for CNS tumors, with multiple studies showing the value and utility of DNA methylation-based classification of CNS tumors. A Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) Working Group was therefore convened to describe the current state of the field and to provide advice based on lessons learned to date. Here, we provide recommendations for the use of DNA methylation-based classification in CNS tumor diagnostics, emphasizing the attributes and limitations of the modality. We emphasize that the methylation classifier is one diagnostic tool to be used alongside previously established diagnostic tools in a fully integrated fashion. In addition, we provide examples of the inclusion of DNA methylation data within the layered diagnostic reporting format endorsed by the World Health Organization (WHO) and the International Collaboration on Cancer Reporting. We emphasize the need for backward compatibility of future platforms to enable accumulated data to be compatible with new versions of the array. Finally, we outline the specific connections between methylation classes and CNS WHO tumor types to aid in the interpretation of classifier results. It is hoped that this update will assist the neuro-oncology community in the interpretation of DNA methylation classifier results to facilitate the accurate diagnosis of CNS tumors and thereby help guide patient management. • DNA methylation profiling is a valuable tool for the diagnosis of central nervous system tumors. • Results should be interpreted within the entire context of the case. • Inclusion of methylation results into a layered diagnostic format is recommended. DNA methylation profiling has emerged as a practical platform for the classification of central nervous system (CNS) tumors. Since the initial description of its potential across CNS tumor types and the development of a classifier by the Heidelberg group in 2018, 1 use of this diagnostic strategy has expanded to additional centers. Notably, The World Health Organization (WHO) 2021 Classification of Tumours of the Central Nervous System (WHO CNS "Blue Book") 2 highlights the utility of DNA methylation profiling by indicating this modality as either an "essential" or "desirable" diagnostic criterion in a large proportion of tumor types. Key attributes of DNA methylation profiling include the generation of objective, reproducible, and cIMPACT-NOW update 9: Recommendations on utilization of genome-wide DNA methylation profiling for central nervous system tumor diagnostics transferable data metrics that contribute to more precise and accurate tumor classification, prognostic information (in some tumor types), and the potential to discover new tumor types/subtypes. With the increasing use of DNA methylation-based classification in clinical diagnostics, and in line with previous updates, [3] [4] [5] [6] [7] [8] [9] [10] the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) assembled a group of experienced neuropathologists and clinical neuro-oncologists to provide recommendations regarding the use of genome-wide DNA methylation profiling in CNS tumor diagnostics. These recommendations, based on the literature and collective experience, relate to methylation classifier results in daily practice, observed attributes and limitations of the classifier, and selection of cases for methylation profiling.
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