MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada.
Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
Acta Neuropathol. 2023 Jul;146(1):145-162. doi: 10.1007/s00401-023-02571-3. Epub 2023 Apr 24.
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 (CDKN2A) 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 CDKN2A 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.
CDKN2A/B 纯合缺失最近被纳入世界卫生组织 3 级脑膜瘤分类。虽然这种标志物在脑膜瘤中总体较为罕见，但它与转录组、表观遗传学和拷贝数水平上其他 CDKN2A 改变的关系尚未确定。因此，我们利用来自 6 个独立队列的 1577 例脑膜瘤样本的多维分子数据，这些队列均富含临床侵袭性脑膜瘤，通过整合分子方法，利用 DNA 甲基化、拷贝数变异、转录组学和蛋白质组学全面探究 CDKN2A 改变的谱。仅在 7.1%的病例中发现 CDKN2A/B 纯合缺失，但与没有这些缺失的肿瘤相比，预后显著较差。在 2.6%的病例中发现杂合性 CDKN2A/B 缺失，其结果与纯合缺失相似。在 CDKN2A/B 完整的肿瘤（无纯合或杂合缺失）中，我们根据 CDKN2A 的 mRNA 表达发现了截然不同的预后差异，CDKN2A 高表达（CDKN2A）的脑膜瘤复发时间明显缩短。在考虑到拷贝数丢失后，CDKN2A 的表达是独立的预后因素，并且与 WHO 分级和更具侵袭性的分子和甲基化组一致增加，与队列无关。尽管在这些组中 CDKN2A 基因的状态存在差异和相互排斥，但 CDKN2A 脑膜瘤和 CDKN2A 缺失的脑膜瘤都富集了相似的细胞周期途径，但在不同的检查点。CDKN2A 的高 mRNA 表达也与基因高甲基化、Rb 缺陷和对 CDK 抑制无反应有关。p16 免疫组化不能可靠地区分有和无 CDKN2A 缺失的脑膜瘤，但似乎与 mRNA 表达相关性更好。这些发现支持 CDKN2A mRNA 表达作为具有潜在治疗意义的临床侵袭性脑膜瘤的生物标志物的作用。
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