A novel fusion variant LSM14A::NR4A3 in extraskeletal myxoid chondrosarcoma

Abstract

Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue neoplasm of uncertain lineage characterized by the pathognomonic rearrangement of the NR4A3 gene, which in most cases is fused with EWSR1. Other NR4A3 fusion partners have been described, namely TAF15, FUS, TCF12, and TGF. Some studies suggest that EMCs with non‐EWSR1 variant fusion are associated with high‐grade morphology and worst clinical behavior compared to EWSR1::NR4A3 tumors, supporting the potential significance of particular fusion variant in EMC. We report a case of a 34‐year‐old male who presented with calf EMC and subsequently developed a slowly progressive metastatic disease 3 years after diagnosis. Whole‐transcriptome analysis with total RNA sequencing enabled identification of a novel fusion transcript LSM14A::NR4A3, expanding the molecular spectrum of EMC.

Extraskeletal myxoid chondrosarcoma of the gingival: a rare case report and review of the literature

“…FISH detection plays an increasingly important role in diagnosing EMC. Rearrangement of NR4A3 has been found exclusively in EMC and is considered a hallmark of EMC according to the WHO [ 12 ]. In EMC, the major fusion partners of NR4A3 described so far belong to TET family genes: EWSR1 (over 70%), TAF15 (about 20% of cases), and FUS.…”

NR4A3 fusions characterize a distinctive peritoneal mesothelial neoplasm of uncertain biological potential with pure adenomatoid/microcystic morphology

“…However, the roles of NR4A3 seem to vary with the histogenetic origin of neoplasms, the cellular context, and the presence or absence of other co‐factors, so that both oncogenic and tumor suppressor roles have been ascribed to this protein in different malignancies 31–35 . The majority of extraskeletal myxoid chondrosarcoma cases harbor the canonical EWSR1::NR4A3 fusion, while <30% of cases may show rare non‐ EWSR1 fusion partners including TAF15 , TCF12 , FUS , HSPA8 , S MARAC2 , and LSM14A 35–41 …”

“…[31][32][33][34][35] The majority of extraskeletal myxoid chondrosarcoma cases harbor the canonical EWSR1::NR4A3 fusion, while <30% of cases may show rare non-EWSR1 fusion partners including TAF15, TCF12, FUS, HSPA8, SMARAC2, and LSM14A. [35][36][37][38][39][40][41] Employing comprehensive genomic, transcriptomic, and epigenomic profiling, we recently identified recurrent rearrangements [t(4;9)(q13;q31)] in 98% of salivary gland acinic cell carcinoma. 42 Translocation of highly active enhancer regions from the SCPP gene cluster at 4q13 to upstream of NR4A3 at 9q31 results in highly expressed NR4A3 as a major oncogenic driver of acinic cell carcinoma.…”

TAF15::NR4A3 gene fusion identifies a morphologically distinct subset of extraskeletal myxoid chondrosarcoma mimicking myoepithelial tumors

“…A genetic hallmark of EMC has long been considered the pathognomonic rearrangements involving NR4A3 (9q22.33), 7 which are identified in more than 90% of EMC 8 . Although EWSR1 (22q12) is the most common fusion partner for NR4A3 , genetic heterogeneity exists, with alternative fusion partners described including TAF15 (17q12), 9 FUS (16p11.2), 10 TCF12 (15q21), 11 TGF (3q12.2), 12 SMARCA2 (9p24.3), 13 LSM14A (19q13.11) 14 and HSPA8 (11q24.1) 15 …”

“…6 A genetic hallmark of EMC has long been considered the pathognomonic rearrangements involving NR4A3 (9q22.33), 7 which are identified in more than 90% of EMC. 8 Although EWSR1 (22q12) is the most common fusion partner for NR4A3, genetic heterogeneity exists, with alternative fusion partners described including TAF15 (17q12), 9 FUS (16p11.2), 10 TCF12 (15q21), 11 TGF (3q12.2), 12 SMARCA2 (9p24.3), 13 LSM14A (19q13.11) 14 and HSPA8 (11q24.1). 15 In 75%-80% of cases of EMC, NR4A3 is fused with EWSR1, 7,16 and this is accompanied by a conventional morphologic appearance, manifesting as a relatively well-circumscribed, multilobular tumor composed of uniform short spindle-to-ovoid primitive mesenchymal cells with a modest amount of deeply eosinophilic to vacuolated cytoplasm arranged in anastomosing cords, forming a complex interconnecting reticular network enmeshed in an abundant basophilic myxoid matrix.…”