Expanding the clinicopathologic spectrum and genomic landscape of tumors with SMARCA2/4::CREM fusions

Abstract CREB gene family ( ATF1 , CREB1 , CREM ) fusions with either EWSR1 or FUS gene partners drive the pathogenesis of a wide range of neoplasms, including various soft tissue tumors, intracranial myxoid mesenchymal tumors (IMMTs), hyalinizing clear cell carcinoma (HCCC), and rare mesotheliomas. Recently, a SMARCA2 :: CREM fusion was reported in one case each of IMMT and HCCC. In this study, we expand the clinicopathologic and molecular spectrum of these neoplasms by describing three additional cases with SMARCA2 :: CREM and one with a novel SMARCA4 :: CREM fusion, highlighting the recurrent potential of additional CREB gene fusion partners beyond FET family members. To evaluate if these fusions define a new pathologic entity, we performed a comprehensive genomic and methylation analysis and compared the results to other related tumors. Tumors occurred in children and young adults (median age 20 years) and spanned a broad anatomic distribution, including soft tissue, intracranial, head and neck, and prostatic urethra. Microscopically, the tumors shared an undifferentiated round to epithelioid cell phenotype and a hyalinized fibrous stroma. Immunohistochemically, a polyphenotypic profile was observed, with variable expression of SOX10, desmin, and/or epithelial markers. No targetable genomic alterations were found using panel‐based DNA sequencing. By DNA methylation and transcriptomic analyses, tumors grouped closely to FET :: CREB entities, but not with SMARCA4 / SMARCB1 ‐deficient tumors. High expression of CREM by immunohistochemistry was also documented in these tumors. Patients experienced local recurrence ( n = 2), locoregional lymph node metastases ( n = 2), and an isolated visceral metastasis ( n = 1). Overall, our study suggests that SMARCA2/4 :: CREM fusions define a distinct group of neoplasms with round cell to epithelioid histology, a variable immunoprofile, and a definite risk of malignancy. Larger studies are needed to further explore the pathogenetic relationship with the FET :: CREB family of tumors. © 2024 The Pathological Society of Great Britain and Ireland.