PATH-56. LOSS OF HETEROZYGOSITY OF CDKN2A/B DEFINES AN AGGRESSIVE SUBSET OF RECURRENT, HIGH-GRADE MENINGIOMAS

Abstract INTRODUCTION Loss of heterozygosity (LOH) occurs when one gene allele is lost, leaving the cell with a single functional copy. This genetic alteration drives tumor progression by disabling critical regulatory pathways. Currently, CDKN2A/B homozygous loss is a criterion for WHO Grade 3 meningiomas. However, the impact of CDKN2A/B LOH and other copy-number alterations remains unclear. This study investigates the effects of LOH in the CDKN2A/B tumor suppressor gene on progression-free survival (PFS) and overall survival (OS) in meningiomas. METHODS The study included adult patients with sporadic primary or recurrent meningiomas who underwent resection and whole exome sequencing. LOH and copy-number alterations were confirmed on visual inspection of b-allele frequency and mean ratio graphs. Samples of unsuitable quality for evaluation were excluded. CDKN2A/B copy number and LOH were associated with PFS and OS. RESULTS The sample included 333 meningiomas (64.6% female [n=215], 18.8% recurrent meningiomas [n=61], and 50 cases of postoperative recurrence [15%]). CDKN2A/B was intact in 88.5% of samples (n=295), while 38 samples (11.4%) exhibited CDKN2A/B LOH. This included homozygous deletions (n=2, 5.2%), heterozygous deletions (n=11, 28.9%), amplifications (n=12, 31.6%), and copy-neutral LOH (n=13, 34.2%). All copy-number alterations were associated with an increased risk of recurrence compared to CDKN2A/B intact samples, so CDKN2A/B LOH was used for subsequent analysis. CDKN2A/B LOH was more frequently associated with prior recurrence (22.9% vs. 8.8%; p=0.004), prior radiation (46% vs. 15.6%; p<0.0001), and WHO Grade 2 and 3 tumors (63.2% vs. 42.7%; p=0.02). CDKN2A/B LOH was associated with worse PFS (HR 3.97 [1.3-11.9]; p=0.01) and worse OS (HR 2.9 [1.03-8.2]; p=0.0429) only in recurrent, high-grade meningiomas, independent of the fraction of the genome altered, mutation count, and Simpson grade. Postoperative radiation therapy did not improve PFS (HR 3.24 [1.06-9.85]; p=0.038). CONCLUSION CDKN2A/B LOH is enriched in high-grade, recurrent meningiomas and confers worse PFS and OS despite postoperative radiotherapy. CDKN2A/B LOH is a high-risk biomarker that predicts tumor behavior and patient outcome.