Heterozygous CDKN2A Loss is Associated with Recurrence and Survival in High, But Not Low Grade Meningiomas

INTRODUCTION: Homozygous loss of CDKN2A/B is associated with more aggressive meningiomas and is now considered in the updated WHO grading criteria. The relevance of heterozygous loss (hetloss) of CDKN2A/B is less clear and the potential association of hetloss CDKN2A with aggressive meningioma phenotype remains underexplored. METHODS: Clinical and whole exome sequencing data for patients who underwent resection of sporadic meningiomas were analyzed. RESULTS: Of the 564 meningiomas included, 16 tumors harbored hetloss of CDKN2A; 7 of these were low grade (WHO grade I) and 9 high grade (grade II or III). Compared to high-grade hetloss meningiomas, low-grade ones were less likely to have an NF2 somatic driver mutation (p = 0.041) and were more common along the skull base (p = 0.005). Low-grade meningiomas with hetloss CDKN2A had more aggressive clinical characteristics compared to wild type (WT), with higher proliferative indices (p = 0.044), increased cellularity (p = 0.032) and higher copy number variations (p = 0.004) and patients were more likely to be symptomatic (p = 0.007); there was no difference in progression-free survival (PFS) (p = 0.4). High-grade hetloss CDKN2A meningiomas, however, had higher mitotic count (p = 0.014), increased chromosomal instability (p = 0.004), and higher recurrence rates (p < 0.001), as well as decreased PFS (p < 0.001) and overall survival (OS) (p = 0.002), compared to high-grade WT. Interestingly, these findings remained significant amongst high-grade hetloss CDKN2A meningiomas even when controlling for underlying NF2 mutation. CONCLUSIONS: Hetloss of CDKN2A is associated with more aggressive histological and genomic characteristics in both low- and high-grade meningiomas. Only high-grade meningiomas with hetloss CDKN2A, however, differ from those without the mutation in recurrence and PFS. This effect does not seem related to underlying somatic NF2 mutation. These findings may have clinical implications for high-grade meningiomas harboring heterozygous CDKN2A mutations.