301 Even Heterozygous Loss of CDKN2A B Greatly Accelerates Recurrence in Aggressive Meningioma

INTRODUCTION: In the WHO 2021 criteria, homozygous deletion of cyclin-dependent kinase-inhibitor 2A and/or B (CDKN2A/B) qualifies meningiomas as Grade 3. We assessed the effect of heterozygous CDKN2A/B loss, which was not addressed by the WHO, on recurrence-free survival (RFS), and evaluated the relationship of CDKN2A/B losses with our MenG classification. METHODS: Methylation and RNA-profiling were used to assign MenG. Methylation data identified heterozygous or homozygous loss of CDKN2A/B in 776 meningiomas. Clinical data for 659 tumors were used for survival analysis. RESULTS: Of the 776 tumors, 738 (95.1%) had intact CDKN2A/B, 20 (2.5%) had heterozygous loss of both CDKN2A/B, 3 (0.4%) had homozygous CDKN2A and heterozygous CDKN2B loss, and 15 (1.9%) had homozygous loss of both CDKN2A/B. Of the 659 tumors with clinical data, 28 (4.2%) showed any CDKN2A/B loss. RFS was based on concordant CDKN2A/B status. Tumors with intact CDKN2A/B (n = 631, mRFS not reached) had improved RFS compared to those with heterozygous loss (n = 15, mRFS = 29.1 mo) and homozygous loss (n = 11, mRFS = 10.5mo; p < 0.0001 all groups, homozygous vs. heterozygous p = 0.4, Log-rank). Nearly all tumors with CDKN2A/B loss (27/28) were MenG C, the most aggressive group. Among MenG C tumors, presence of either homozygous (n = 11, mRFS 10.5mo) or heterozygous (n = 14, mRFS 25.1 mo) CDKN2A/B loss led to shortened RFS than those with intact CDKN2A/B (n = 198, mRFS 61.4 mo; p < 0.0001 Log-rank). Median RFS was not reached in MenG A (n = 173) or MenG B (n = 259). Tumors with any CDKN2A/B loss had worse survival when controlling for WHO Grade (Grade: 2 p < 0.0001, 3 p = 0.035, Log-rank). CONCLUSIONS: Heterozygous CDKN2A/B loss (not addressed in the 2021 WHO criteria) leads to poor outcome in meningioma even when controlling for molecular subgroup (MenG C) or WHO grade (2/3). All but 1 tumor (27/28) with any type of CDKN2A/B loss were MenG C.