Farshad Nassiri1,2,3, Justin Z Wang1,2,3, Olivia Singh1, Shirin Karimi1, Tatyana Dalcourt1, Nazanin Ijad1, Neda Pirouzmand1, Ho-Keung Ng4, Andrea Saladino5, Bianca Pollo6, Francesco Dimeco5, Stephen Yip7, Andrew Gao8, Kenneth D Aldape9, Gelareh Zadeh1,2,3. 1. MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, Ontario, Canada. 2. Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada. 3. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. 4. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin N.T., Hong Kong SAR, People's Republic of China. 5. Unit of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 6. Unit of Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 7. Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 8. Department of Pathology & Laboratory Medicine, University Health Network, Toronto, Ontario, Canada. 9. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
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.
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.
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