Clinicopathological significance of loss of Y chromosome in male meningiomas

Male meningiomas, comprising approximately 30% of all meningiomas, are more frequently high-grade and associated with poorer clinical outcomes compared to their female counterparts. Although Y chromosome alterations have been studied in various male-predominant tumors, a limited number of studies have evaluated their role in meningiomas. To evaluate the clinicopathological significance of Y chromosome loss in male meningiomas, we assessed the frequency of loss of the Y chromosome (LOY) using droplet digital polymerase chain reaction on tumor DNA from 93 male meningioma samples. LOY, detected in 15 cases (16.1%), was significantly associated with a higher World Health Organization (WHO) tumor grade (grade 2: 40.0% vs. 14.1%; grade 1: 60.0% vs. 85.9%; p = 0.028), and loss of the NF2 gene-encoded protein, merlin (loss: 80.0% vs. 48.7%; retained: 20.0% vs. 51.3%; p = 0.045). RNA in situ hybridization performed on formalin-fixed paraffin-embedded tissue sections proved to be a reliable method for the accurate evaluation of LOY. Moreover, spatial transcriptomic analysis revealed significant differences in the expression of genes associated with epithelial–mesenchymal transition and extracellular matrix organization between LOY and non-LOY meningioma tumor cells. Our findings emphasize the presence of atypical pathological features and distinct transcriptional profiles in LOY-associated meningiomas. LOY may serve as both a prognostic biomarker and a mechanistic contributor to sex-based differences in meningioma biology.