Loss of H3K27me3 in meningiomas
Authors: Nassiri Farshad , Wang Justin Z , Singh Olivia , Karimi Shirin , Dalcourt Tatyana , Ijad Nazanin , Pirouzmand Neda , Ng Ho-Keung , Saladino Andrea , Pollo Bianca , Dimeco Francesco , Yip Stephen , Gao Andrew , Aldape Kenneth D , Zadeh Gelareh ,   The International Consortium on Meningiomas, Aldape Kenneth , Au Karolyn , Barnholtz-Sloan Jill , Behling Felix , (Linda) Bi Wenya , Brastianos Priscilla , Butowski Nicholas , Brodie Chaya , Cohen-Gadol Aaron , Couce Marta , Dimeco Francesco , Drummond Kate , Dunn Ian , Cohen-Gadol Aaron , Galanis Eva , Galldiks Norbert , Giannini Caterina , Goldbrunner Roland , Hanemann Oliver , Herold-Mende Christel , Horbinski Craig , Huang Raymond , Javadpour Mohsen , Jenkinson Michael , Jungk Christine , Kaufmann Timothy , Krischek Boris , Kurz Sylvia , Lachance Daniel , Lafougere Christian , Lamszus Katrin , Lee Ian , Malta Tathiana , Makarenko Serge , Mawrin Christian , McDermott Michael , Millward Christopher , Moliterno-Gunel Jennifer , Morokoff Andrew , Nassiri Farshad , Ng H K , Noushmehr Houtan , Perry Arie , Poisson Laila , Pollo Bianco , Ragunathan Aditya , Raleigh David , Renovanz Mirjam , Ricklefs Franz , Sahm Felix , Saladino Andrea , Santacroce Antonio , Santarius Thomas , Schichor Christian , Schimdt Nils , Schittenhelm Jens , Selman Warren , Shih Helen , Snyder Jim , Snuderl Matja , Sloan Andrew , Suppiah Suganth , Sulman Erik , Tabatabai Ghazaleh , Tatagiba Marcos , Timmer Marcos , Tonn Joerg-Christian , Von Deimling Andreas , Vogelbaum Michael , Walbert Tobias , Wang Justin , Wen Patrick , Westphal Manfred , Yip Stephen , Zadeh Gelareh 
Published: May 2021

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.