Expanding the clinicopathologic spectrum and genomic landscape of tumors with SMARCA2/4::CREM fusions Journal Article
| Authors: | Cyrta, J.; Dermawan, J. K.; Tauziède-Espariat, A.; Liu, T.; Rosenblum, M.; Shroff, S.; Katabi, N.; Cardoen, L.; Guillemot, D.; Masliah-Planchon, J.; Hoare, O.; Delattre, O.; Bale, T.; Bourdeaut, F.; Antonescu, C. R. |
| Article Title: | 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. © 2024 The Pathological Society of Great Britain and Ireland. |
| Keywords: | immunohistochemistry; adolescent; adult; child; clinical article; human tissue; school child; young adult; methylation; frameshift mutation; genetics; clinical feature; histopathology; case report; cancer risk; follow up; lymph node metastasis; paraaortic lymph node; neoplasm; neoplasms; phenotype; metabolism; nuclear protein; transcription factor; pathology; tumor marker; dna methylation; morphology; transcription factors; nuclear proteins; sarcoma; messenger rna; prostate tumor; needle biopsy; gene fusion; oncogene proteins, fusion; stroma; genomics; mitosis rate; visceral metastasis; heterozygosity loss; clear cell carcinoma; neoadjuvant chemotherapy; adjuvant radiotherapy; dna helicases; soft tissue neoplasms; soft tissue tumor; head and neck tumor; dna helicase; desmoplastic small round cell tumor; fusion; intracranial tumor; perivascular epithelioid cell tumor; urethra tumor; dimensionality reduction; brm protein; cell nucleus inclusion body; brg1 protein; maintenance chemotherapy; adjuvant chemoradiotherapy; transcription factor sox10; dna sequencing; humans; human; male; female; article; rna sequencing; smarca4; hierarchical clustering; creb; biomarkers, tumor; smarca2; crem; smarca4 protein, human; tumor mutational burden; mrna expression level; prostate urethra; epithelioid histiocyte; oncogene fusion protein; cyclic amp response element modulator; crem protein, human; cyclic amp responsive element modulator; smarca2 protein, human |
| Journal Title: | Journal of Pathology |
| Volume: | 264 |
| Issue: | 3 |
| ISSN: | 0022-3417 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2024-11-01 |
| Start Page: | 305 |
| End Page: | 317 |
| Language: | English |
| DOI: | 10.1002/path.6350 |
| PUBMED: | 39344423 |
| PROVIDER: | scopus |
| PMCID: | PMC12131337 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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