Increased mRNA expression of CDKN2A is a transcriptomic marker of clinically aggressive meningiomas

Abstract

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.

CDKN2A/B deletions are strongly associated with meningioma progression: a meta-analysis of individual patient data

“…We identified 181 records with four investigations meeting inclusion criteria (Fig. 1 ) [ 6 , 16 , 37 , 46 ].

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The importance of considering competing risks in recurrence analysis of intracranial meningioma

“…Any misclassification due to incorrect categorization based on molecular or epigenetic characteristics will impact the results, regardless of the statistical method used to analyze the data. However, due to specific molecular features, such as TERT gene alterations and CDKN2A/B homozygous deletions, is likely to impact only a minor fraction of our cohort [ 15 , 16 ]. In the present study, our primary objective was to demonstrate the implications of overlooking competing risks in the recurrence analysis of meningiomas.…”

Molecular prognostication in grade 3 meningiomas and p16/MTAP immunohistochemistry for predicting CDKN2A/B status

“…Additionally, recent studies have shown that loss of p16 expression alone is not a reliable marker for CDKN2A/B loss in histologically WHO grade 1 meningioma. 13 , 25 More work is needed to determine whether the combination of p16 and MTAP IHC could be used as a surrogate for CDKN2A/B status in WHO grade 1 and 2 meningioma. Overall, while interrogation of the CDKN2A/B locus via CNV analysis or FISH continues to be the gold standard for grading meningiomas, these molecular analyses are often unavailable and/or costly in resource-limited neuropathology centers.…”

“…CDKN2A/B copy-number status was determined as described previously. 25 In brief, CDKN2A/B deletion status was evaluated by inspection of genome-wide copy-number variation (CNV) plots for each sample. “Heterozygous deletion” was called where the depth of CDKN2A/B deletion was comparable to the depth of single copy chromosomal losses in the same sample (eg, of chr 1p, 10, 22q, etc.).…”