Identification of a distinct epigenetic subgroup with inferior PFS in intracranial mesenchymal tumors with FET::CREB fusion.

Intracranial mesenchymal tumors (IMTs) with FET::CREB fusion are newly recognized molecular entities, provisionally classified into subgroups A and B. Although Group B has been partially characterized, the clinicopathological and molecular heterogeneity of Group A remains poorly defined. This study aimed to conduct an integrated analysis of 6 newly diagnosed and 20 previously reported IMTs with FET::CREB fusion. Notably, Group A was further stratified into two distinct entities A1 and A2 based on unsupervised methylation profiling. Compared to Group A1, Group A2 demonstrated significantly shorter progression-free survival (PFS), a higher proportion of male patients, and less frequent occurrence of myxoid-rich stroma. Amplification of 10p15.3 was frequently observed in Group A2. Furthermore, GLUT-1 could serve as a potential diagnostic indicator in IMTs with FET::CREB fusion. Overall, we identified a new subgroup of IMTs with FET::CREB fusion with poor PFS and distinct clinicopathological and molecular features, offering actionable insights to refine therapeutic strategies and improve risk stratification in this emerging diagnostic category.