Loss of H3K27me3 in meningiomas

Abstract

Background: There is a critical need for objective and reliable biomarkers of outcome in meningiomas beyond WHO classification. Loss of H3K27me3 has been reported as a prognostically unfavorable alteration in meningiomas. We sought to independently evaluate the reproducibility and prognostic value of H3K27me3 loss by immunohistochemistry (IHC) in a multicenter study.

Methods: IHC staining for H3K27me3 and analyses of whole slides from 181 meningiomas across three centers was performed. Staining was analyzed by dichotomization into loss and retained immunoreactivity, and using a 3-tiered scoring system in 151 cases with clear staining. Associations of grouping with outcome were performed using Kaplan-Meier survival estimates.

Results: A total of 21 of 151 tumors (13.9%) demonstrated complete loss of H3K27me3 staining in tumor with retained endothelial staining. Overall, loss of H3K27me3 portended a worse outcome with shorter times to recurrence in our cohort, particularly for WHO grade 2 tumors which were enriched in our study. There were no differences in recurrence-free survival (RFS) for WHO grade 3 patients with retained vs loss of H3K27me3. Scoring by a 3-tiered system did not add further insights into the prognostic value of this H3K27me3 loss. Overall, loss of H3K27me3 was not independently associated with RFS after controlling for WHO grade, extent of resection, sex, age, and recurrence status of tumor on multivariable Cox regression analysis.

Conclusions: Loss of H3K27me3 identifies a subset of WHO grade 2 and possibly WHO grade 1 meningiomas with increased recurrence risk. Pooled analyses of a larger cohort of samples with standardized reporting of clinical definitions and staining patterns are warranted.

Keywords: H3K27; immunohistochemistry; meningioma; trimethylation.

Fig. 1

(A-F) Representative patterns of H3K27me3 staining in meningioma. (A) Distinct and strong brown nuclear and endothelial staining suggestive of retained trimethylation. (B) Clear loss of trimethylation with immunopositivity restricted only to endothelial cells as an internal positive control without any tumor cell staining. (C-F) Representative ambiguous staining whereby (C) some tumor cells stained weakly without consistent endothelial cell staining, (D) weak nuclear staining with some cytoplasmic background staining, (E) majority but not all tumor cells with clear immunopositivity, and (F) minority (less than half) of tumor cells demonstrating immunopositivity with other adjacent cells being immunonegative. Only (B) was considered to have unequivocal loss of trimethylation, with other representative images counted as having retained trimethylation.

Fig. 2

Kaplan-Meier survival curve with log-rank test showing recurrence-free survival stratified by (A) WHO grade and (B) H3K27me3 status in all patients, and (C) H3K27me3 status in primary tumors only.

Fig. 3

Kaplan-Meier survival curves with log-rank test showing recurrence-free survival stratified by degree of H3K27me3 staining, with 0 denoting complete loss, 1 denoting minority staining (<50% of all tumor cells on the slide), and 2 denoting majority staining (>50% of all tumor cells on slide).

Fig. 4

Kaplan-Meier survival curve with log-rank test showing recurrence-free survival stratified by H3K27me3 status in all WHO grade (A) 1, (B) 2, and (C) 3 patients.