cIMPACT-NOW update 9: Recommendations on utilization of genome-wide DNA methylation profiling for central nervous system tumor diagnostics

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.

Keywords: CNS tumors; DNA methylation profiling; molecular classification; neuropathology.

Figure 1.

Layered diagnosis example: high-confidence match to family and class.

Figure 2.

Layered diagnosis example: no match on methylation-based classification, with sufficient orthogonal data for definitive diagnosis.

Figure 3.

Layered diagnosis example: match to a methylation family, no match to a methylation class; descriptive diagnosis warranted.

Figure 4.

Layered diagnosis example: high-confidence match to a class that does not correspond to a current WHO tumor type.

Figure 5.

Layered diagnosis example: high-confidence match to meningioma with reference to recent cIMPACT-NOW Working Group recommendations.

Figure 6.

Additional reporting recommendations: (A) classifier detailed results; (B) methylation testing parameters.

Figure 7.

Layered diagnosis example: high-confidence match to the glioblastoma IDH-wildtype methylation family, but low-confidence matches to glioblastoma classes.