Pitfalls in the evaluation of CDKN2A copy number status in meningioma

Meningiomas are the most common primary intracranial tumors, with anaplastic variants linked to a poor prognosis. CDKN2A deletions are key markers of malignancy and were integrated into the 2021 WHO classification for anaplastic meningiomas. Both p16 and MTAP immunohistochemistry (IHC) are employed to assess CDKN2A loss, though each marker has limitations in accuracy to varying degrees.

This study analyzed the concordance between molecular methods - DNA methylation profiling, molecular inversion probe (MIP) analysis, targeted next-generation sequencing (NGS), and fluorescence in situ hybridization (FISH) - and protein expression of p16 and MTAP in nine anaplastic meningiomas.

We showed that while p16 loss correlated well, MTAP protein was still expressed in three cases despite homozygous CDKN2A deletions. In those three cases the MTAP gene was hemizygously deleted. Additionally, a FISH probe encompassing both genes generated misleading results.

Our results suggest that MTAP IHC can be unreliable as a sole surrogate for CDKN2A loss in anaplastic meningioma. Quantitative copy-number analysis via high-resolution chromosomal arrays enables precise determination of CDKN2A deletions. Given the therapeutic implications of WHO grading, accurate molecular testing is critical. We conclude that negative p16/MTAP IHC in high-grade meningiomas should prompt molecular analysis for CDKN2A deletions, and MTAP IHC should not be solely relied upon for classification.