The prognostic impact of CDKN2A/B hemizygous deletions in meningioma

BACKGROUND: Meningiomas are the most common adult brain tumors. While homozygous deletions of CDKN2A/B are linked to early recurrence and hence serve as CNS WHO grade 3 criterion, the clinical impact of hemizygous deletions remains unclear-especially since distinguishing between hemi- and homozygous losses can be technically challenging. METHODS: DNA methylation data, copy-number, and mutation data were evaluated on a multicenter cohort of 970 meningiomas. Each sample's CDKN2A/B status was manually classified by visual inspection in relation to whole chromosomal losses and gains in the copy number profile generated from global methylation array data in relation to other copy number events. Progression probabilities were determined using the Kaplan-Meier method. RESULTS: Among 970 meningiomas, n = 30 had homozygous, n = 114 hemizygous (n = 31 segmental; n = 83 focal), and n = 826 CDKN2A/B balanced status. In cases with hemizygous deletions in general, an association with increased progression risk compared to balanced cases was observed, although this did not reach statistical significance (log-rank P = .074; HR = 1.36, 95% CI [0.97, 1.90]; P = .07). However, segmental hemizygous losses were linked to a significantly worse prognosis (log-rank P = .0023), but focal hemizygous deletions were not (log-rank P = .523). Segmental hemizygous CDKN2A/B deletions were more frequently associated with a higher amount of high-risk copy number variations than focal losses. CONCLUSION: Our findings suggest that hemizygous CDKN2A/B deletions overall do not confer worse risks for progression in meningiomas. The signal for segmental deletions may not be locus-specific but just one representation of the generally instable genome of aggressive meningiomas.