Loss of histone H3K27me3 identifies a subset of meningiomas with increased risk of recurrence

Abstract

Epigenetic patterns on the level of DNA methylation have already been shown to separate clinically relevant subgroups of meningiomas. We here set out to identify potential prognostic implications of epigenetic modification on the level of histones with focus on H3K27 trimethylation (H3K27me3). H3K27me3 was assessed by immunohistochemistry on 232 meningiomas from 232 patients. In 194 cases, trimethylation was detected in tumor cells. In 25 cases, staining was limited to vessels while all tumor cells were negative. Finally, 13 cases yielded equivocal staining patterns. Reduced abundance of H3K27me3 in cases with staining limited to vessels was confirmed by mass spectrometry on a subset of cases. Lack of staining for H3K27me3 in all tumor cells was significantly associated with more rapid progression (p = 0.009). In line, H3K27me3-negative cases were associated with a DNA methylation pattern of the more aggressive types among the recently introduced DNA methylation groups. Also, NF2 and SUFU mutations were enriched among cases with complete lack of H3K27me3 staining in tumor cells (p < 0.0001 and p = 0.029, respectively). H3K27me3 staining pattern added significant prognostic insight into WHO grade II cases and in the compound subset of WHO grade I and II cases (p = 0.04 and p = 0.007, respectively). However, it did not further stratify within WHO grade III cases. Collectively, these data indicate that epigenetic modifications beyond DNA methylation are involved in the aggressiveness of meningioma. It also suggests that H3K27me3 immunohistochemistry might be a useful adjunct in meningioma diagnostics, particularly for cases with WHO grade II histology or at the borderline between WHO grade I and II.

Basis for Immunotherapy for Treatment of Meningiomas

“…Sahm et al devised a DNA methylation-based grading system for meningioma that accurately stratified risk of recurrence in meningiomas more accurately than current WHO grading by analyzing methylation patterns in 40 genes known to contribute to meningioma genesis and progression ( 23 ). Similarly, Katz et al also demonstrate that methylation patterns on the H3 histone could predict recurrence of WHO grade I and II meningiomas ( 25 ). One recent study highlighted the use of RNA sequencing and whole-exome sequencing to predict recurrence more accurately than current WHO criteria ( 24 ).…”

“…One recent study highlighted the use of RNA sequencing and whole-exome sequencing to predict recurrence more accurately than current WHO criteria ( 24 ). Interestingly, in all these studies, the authors report that their methods accurately predicted recurrence in a significant subset of WHO Grade I tumors where recurrence is typically low ( 23 – 25 ). Studies with larger sample sizes are needed to assess how tumor microenvironment and immune infiltrate impact meningioma recurrence and progression.…”

Global DNA 5hmC and CK19 with 5hmC positives cell contents represent a promising biomarker for predicting prognosis in small hepatocellular carcinoma

“…H3K27me3 and DNA hypomethylation decreases without recurrent genetic alterations in HCC displays that epigenetic mechanisms are the core of HCC occurrence [29][30][31][32][33][34][35]. Further, some studies indicated that decreased H3K27me3 is not deregulated by genes but epigenetics [36,37].…”

Biomarkers in tumors of the central nervous system – a review

“…Katz et al. reported that complete loss of nuclear staining for H3K27 trimethylation (H3K27me3) was closely associated with more aggressive DNA‐methylation subgroups, and hence a potential biomarker in the routine diagnostic work‐up of meningiomas.…”

“…A study by Olar et al (161) also found that DNA methylation analysis of meningiomas reliably identified patients with risk of tumor recurrence. Katz et al (167) reported that complete loss of nuclear staining for H3K27 trimethylation (H3K27me3) was closely associated with more aggressive DNA-methylation subgroups, and hence a potential biomarker in the routine diagnostic work-up of meningiomas.…”