Sharika Rajan, Hye‐Jung Chung, Zhichao Wu, Omkar Singh, Karen Dazelle, Zied Abdullaev, Manoj Tyagi, Christina K. Ferrone, Mark Raffeld, Ina Lee, Jeffrey Gagan, Jie Chen, Sahara Cathcart, C. Giannini, Aivi Nguyen, Murat Gökden, A. Perry, Igor Lima Fernandes, Angelica R. Putnam, Kyle C. Kurek, Richard M Green, Charles G. Eberhart, Calixto-Hope Lucas, Ignacio González-Gómez, G. Lopez, Karra A. Jones, Prayson Ra, Gabrielle Yeaney, Josephine Kam Tai Dermawan, Rati Chkheidze, Christina Appin, Erik J. Uhlmann, A Taliansky, Melissa M. Blessing, Carrie Mohila, Jennifer Cotter, Jeremy Deisch, Felipe Andreiuolo, John R Crawford, Christopher Mount, Anat Stemmer‐Rachamimov, Nelli S. Lakis, Schmidt Re, Geeta Chacko, Robert Newbury, Stewart G. Neill, Bryan Morales, Roger Fecher, Emily A. Sloan, David A Solomon, MacLean Nasrallah, Martha Quezado, Adriana Fonseca, Kenneth Aldape
BACKGROUND: Intracranial mesenchymal tumors, FET::CREB fusion-positive (ICMT), show fusions involving FET RNA-binding protein family genes (EWSR1 or FUS) and CREB family of transcription factors (ATF1, CREB1, or CREM). The methylation signature(s), gene expression characteristics, and clinical behavior of this important tumor type require further characterization. METHODS: We study the methylation profiles of 81 ICMT cases (61 newly profiled cases and 20 cases from publicly available sources). Clinicopathologic and genomic data were recorded for each case when available. RESULTS: ICMT showed a relatively distinct methylation signature compared to related tumors. Among the 65 cases where fusion types were documented, the identified fusions included EWSR1::ATF1 (25 cases), EWSR1::CREB1 (12 cases), EWSR1::CREM (21 cases), FUS::CREM (3 cases), and SMARCA2::CREM (4 cases). We confirmed the prior description of 2 distinct subgroups of ICMT (subclasses A and B). The majority of the cases belonged to subclass A (n = 69; 85%), which showed a higher median age compared to subclass B patients (26 years vs. 15 years). Subclass B cases (n = 12; 15%) showed shorter progression-free survival (P < 0.01). Gene expression analysis of ICMT showed key overexpressed markers in ICMT, with significant CREM overexpression regardless of fusion type, when compared to either meningioma alone or a larger group of CNS tumors. CONCLUSIONS: This work provides further characterization of ICMT as an important CNS mesenchymal neoplasm that is prone to tumor recurrence, showing 2 prognostically relevant methylation subclasses and warranting diagnostic distinction from other epigenetically and histologically related tumors. ICMTs show substantial overexpression of the CREM gene, independent of fusion type.