PATH-62. Intracranial mesenchymal tumor, FET-CREB fusion-positive: an integrative analysis of 81 cases

Intracranial mesenchymal tumors, FET-CREB fusion-positive, are well circumscribed extra-axial tumors often reported in children and young adults, with fusions involving FET RNA-binding protein family gene (EWSR1 or FUS) and CREB family of transcription factors (ATF1, CREB1 or CREM). The DKFZ methylation classifiers don’t recognize this tumor group, thus often resulting in their classification as meningioma. Here, we studied 81 cases of intracranial mesenchymal tumors (ICMT) with FET-CREB fusion, including 61 newly profiled cases and 20 cases from publicly available sources. Fusions found in 64 available cases included EWSR1-ATF1 (n=25), EWSR1-CREB1 (n=12), EWSR1-CREM (n=20), FUS-CREM (n=3) and SMARCA2-CREM (n=4). Positive immunohistochemical markers included Desmin, EMA and CD99. SSTR2A was positive in about one-third of cases (9 positive vs. 21 negative). Notably, Synaptophysin was positive in more than 50% of cases (14 vs. 10) and GFAP was occasionally positive (5 vs. 30). Recurrent copy number alterations were losses of chromosomes 10p, 19 and 22q. Elder ICMT patients age >40 years old were observed in 18.5% of the cohort. We confirmed the prior description of two distinct epigenetic subgroups of ICMT methylation class (subclass A and B). The majority of the cases belonged to subclass A (n=69; 85%). Subclass B cases (n=12; 15%) showed CREM as the fusion partner more often than ATF1, and interestingly contained all of the GFAP-positive cases. Gene expression profile differentiated ICMT tumors from other epigenetically related tumors, such as meningioma and schwannoma. Differential gene expression analysis revealed that genes enriched in epithelial mesenchymal transition, KRAS signaling, INFA-alpha signaling and immune activity, were highly expressed in ICMT tumors. Further subdivision of the subclass A was supported by t-SNE. These results support ICMT as a distinct tumor class and provide an insight to its diagnostic differentiation from meningioma and other tumors.