A High MCM6 Proliferative Index in Atypical Meningioma Is Associated with Shorter Progression Free and Overall Survivals

SIMPLE SUMMARY: The aim of this study was to evaluate the prognostic value of MCM6 relative to that of Ki-67 in a series of grade 1 (World Health Organization 2021; n = 100) and grade 2 (atypical) meningiomas (n = 69), using immunohistochemistry, and to evaluate its correlation with methylation classes. In a multivariate model, the LI (Labeling Index) of MCM6 correlated with progression free survival of grade 2, but not grade 1 meningiomas. MCM6 was also correlated with overall survival in univariate analysis. No correlation was found with the methylation classes and subclasses returned by the meningioma algorithm MNGv2.4. We found a significant correlation between PTEN loss and high MCM6 or Ki-67 LI. Our evidence here suggests that MCM6 is a relevant and reproducible marker in atypical meningiomas. It is also easy-to use and could also allow to identify a highly aggressive subtype of proliferative meningiomas. ABSTRACT: The aim of this study was to evaluate the prognostic value of MCM6, in comparison with Ki-67, in two series of grade 1 and 2 meningiomas, and to evaluate its correlation with methylation classes. The first cohort included 100 benign (grade 1, World Health Organization 2021) meningiomas, and the second 69 atypical meningiomas (grade 2). Immunohistochemical Ki-67 and MCM6 labeling indices (LI) were evaluated independently by two observers. Among the atypical meningiomas, 33 cases were also studied by genome-wide DNA methylation. In grade 2 meningiomas, but not grade 1, both Ki-67 and MCM6 LIs were correlated with PFS (p = 0.004 and p = 0.005, respectively; Cox univariate analyses). Additionally, MCM6 was correlated with overall survival only in univariate analysis. In a multivariate model, including mitotic index, Ki-67, MCM6, age, sex, and the quality of surgical resection, only MCM6 was correlated with PFS (p = 0.046). Additionally, we found a significant correlation between PTEN loss and high MCM6 or Ki-67 LIs. Although no correlation was found with the methylation classes and subtypes returned by the meningioma algorithm MNGv2.4., MCM6 LI was significantly correlated with the methylation of 2 MCM6 gene body loci. In conclusion, MCM6 is a relevant prognostic marker in atypical meningiomas. This reproducible and easy-to-use marker allows the identification of a highly aggressive subtype of proliferative meningiomas, characterized notably by frequent PTEN losses, which was previously reported to be sensitive to histone deacetylase inhibitors.