AnEWSR1-CREB3L1Fusion Gene in Extraskeletal Undifferentiated Round Cell Sarcoma Expands the Spectrum of Genetic Landscape in the “Ewing-Like” Undifferentiated Round Cell Sarcomas

Abstract

The molecular findings in Ewing sarcoma have greatly expanded in recent years. Furthermore, this is particularly true for the subset termed “Ewing-like” undifferentiated round cell sarcomas in which new translocations have been reported since the fourth edition of the WHO Classification of Tumours of Soft Tissue and Bone. Amid this expanding genetic landscape, we report a case of extraskeletal undifferentiated round cell “Ewing-like” sarcoma in a 27-year-old female. The patient presented with a large lung mass accompanied on staging imaging by deposits suspicious for metastatic disease in the humerus, calvarium, and lymph nodes of the neck and chest. Biopsy of the lung mass revealed a densely packed monotonous proliferation of round, uniform neoplastic cells with scant cytoplasm. By immunohistochemistry, the tumor cells were diffusely positive for CD99, synaptophysin, TLE1, EMA, and MUC4 and negative for FLI1, PAX7, AE1/3, S100, SOX10, WT1, p63, desmin, and HMB45. Fluorescence in situ hybridization demonstrated rearrangement of the EWSR1 gene. Next-generation sequencing based assay revealed an EWSR1-CREB3L1 fusion. Taken together, the histomorphologic and molecular findings were considered consistent with an undifferentiated round cell sarcoma with an EWSR1-CREB3L1 fusion. Although described in entities such as sclerosing epithelioid fibrosarcoma, low-grade fibromyxoid sarcoma, and small cell osteosarcoma, this has not been previously described in undifferentiated round cell (“Ewing-like”) sarcoma. This finding adds to the growing list of undifferentiated round cell sarcomas with Ewing-like morphologic phenotype–associated fusion genes and may contribute to further defining and characterizing the different subset of tumors in the Ewing family of tumors.

Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin‐like enhancer 1 in primary intracranial sarcoma, DICER1‐mutant

“…26,27 TLE1 is increasingly recognised as staining positively in BCOR-related tumours of the kidney and soft tissue 28 ; other primitive sarcomas and spindle-cell neoplasms of childhood that can show positive TLE1 staining include nerve sheath tumours, Ewing sarcomas/ Ewing-like tumours, and melanomas. [29][30][31][32][33][34] Its staining characteristics in DICER1-related tumours and primary tumours of the paediatric CNS are not well explored. TLE1 is one of the four members of the TLE gene family encoding transcriptional corepressors homologous to the Drosophila groucho gene.…”

“…TLE1 has been described as an immunomarker mainly associated with synovial sarcoma 26,27 . TLE1 is increasingly recognised as staining positively in BCOR ‐related tumours of the kidney and soft tissue 28 ; other primitive sarcomas and spindle‐cell neoplasms of childhood that can show positive TLE1 staining include nerve sheath tumours, Ewing sarcomas/Ewing‐like tumours, and melanomas 29–34 . Its staining characteristics in DICER1 ‐related tumours and primary tumours of the paediatric CNS are not well explored.…”

Pan-cancer analysis of CREB3L1 as biomarker in the prediction of prognosis and immunotherapeutic efficacy

“…In addition, a recent study conducting scRNA-seq analysis has revealed the critical biomarkers and process of the differentiation of fibroblasts into myofibroblasts in systemic sclerosis, and CREB3L1 may be a critical upstream transcription factor in promoting systemic sclerosis myofibroblast differentiation ( Tabib et al, 2021 ). Notably, it has been reported that CREB3L1 expression is frequently altered in many cancers, and complex functions and mechanisms of CREB3L1 in cancer development have been clarified in several studies ( Feng et al, 2017 ; Liu et al, 2018 ; Bissonnette et al, 2021 ; Morishita et al, 2021 ). Xu et al have recently explored the cellular composition of thyroid cancer and found that CREB3L1 was upregulated in anaplastic thyroid cancer (ATC)-derived thyroid cancer cells by scRNA-seq.…”

“…The results revealed that the total alteration rate of CREB3L1 was 1.4% in pan-cancer with various alternation types, such as amplification, miss mutation, and deep deletion, and patients with SKCM has the highest CREB3L1 mutation rate. To date, the biological functions of CREB3L1 mutations are mostly investigated in modulating osteogenesis process, and only few studies have reported that EWSR1-CREB3L1 fusion mutation in sarcomas ( Keller et al, 2018 ; Bissonnette et al, 2021 ). The functions and mechanisms of CREB3L1 mutations are largely unknown in human neoplasms, and our investigation shed highlights on the potential roles of CREB3L1 mutations in cancer initiation and progression.…”

Prognostic Nomogram of Osteocarcinoma after Surgical Treatment

“…e aetiology of osteosarcoma primarily includes epidemiological, genetic, and environmental factors. To date, the globally recognised risk factors related to osteosarcoma progression include Paget's disease, hereditary retinoblastoma, chromosome abnormalities, and the e ects of ionising radiation and alkylating agents [3]. With the development of surgical techniques and the application of neoadjuvant chemotherapy, limb-salvage surgery combined with systemic chemotherapy has become a better choice than simple amputation.…”