CDKN2A/B的纯合缺失最近被纳入世界卫生组织对于3级脑膜瘤的分类标准。虽然这个标志物在脑膜瘤中总体罕见，但它与其他CDKN2A改变的转录组、表观遗传组和拷贝数水平的关系尚未确定。因此，我们利用来自6个独立队列共1577个临床侵袭性脑膜瘤取样的多维分子数据，通过一种综合性分子方法，全面探究了CDKN2A变化的谱系，包括DNA甲基化、拷贝数变异、转录组和蛋白质组。只有7.1%的病例中发现了纯合CDKN2A/B缺失，但与其他没有这些缺失的肿瘤相比，与显著更差的结果相关。杂合性CDKN2A/B缺失在2.6%的病例中被鉴定，并且与纯合性缺失一样存在较差的预后。在具有完好CDKN2A/B的肿瘤中（没有纯合性或杂合性缺失），我们发现基于CDKN2A的mRNA表达存在明显的预后差异，CDKN2A表达高的脑膜瘤具有较短的复发时间。在考虑了拷贝数损失后，CDKN2A的表达是独立的预后因子，并始终与WHO级别、更侵袭性的分子和甲基化组相关联，而不受队列影响。尽管这些组中的CDKN2A基因的状态不一致且互斥，但是，具有CDKN2A高表达的脑膜瘤和具有CDKN2A缺失的脑膜瘤都富集于相似的细胞周期途径，但在不同的检测点。CDKN2A的高mRNA表达还与基因高甲基化、Rb缺乏和对CDK抑制剂的缺乏反应相关。p16免疫组化不能可靠地区分具有和不具有CDKN2A缺失的脑膜瘤，但似乎更好地与mRNA表达相关。这些发现支持CDKN2A mRNA表达作为临床侵袭性脑膜瘤的生物标志物，并具有潜在的治疗意义。©2023年作者。

Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in meningiomas, its relationship to other CDKN2A alterations on a transcriptomic, epigenomic, and copy number level has not yet been determined. We therefore utilized multidimensional molecular data of 1577 meningioma samples from 6 independent cohorts enriched for clinically aggressive meningiomas to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Homozygous CDKN2A/B deletions were identified in only 7.1% of cases but were associated with significantly poorer outcomes compared to tumors without these deletions. Heterozygous CDKN2A/B deletions were identified in 2.6% of cases and had similarly poor outcomes as those with homozygous deletions. Among tumors with intact CDKN2A/B (without a homozygous or heterozygous deletion), we found a distinct difference in outcome based on mRNA expression of CDKN2A, with meningiomas that had elevated mRNA expression (CDKN2Ahigh) having a significantly shorter time to recurrence. The expression of CDKN2A was independently prognostic after accounting for copy number loss and consistently increased with WHO grade and more aggressive molecular and methylation groups irrespective of cohort. Despite the discordant and mutually exclusive status of the CDKN2A gene in these groups, both CDKN2Ahigh meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycle pathways but at different checkpoints. High mRNA expression of CDKN2A was also associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. p16 immunohistochemistry could not reliably differentiate between meningiomas with and without CDKN2A deletions but appeared to correlate better with mRNA expression. These findings support the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas with potential therapeutic implications.© 2023. The Author(s).