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This summary outlines the strong association between NR4A3 (HGNC:7982) and extraskeletal myxoid chondrosarcoma (MONDO_0012825). Multiple independent studies have identified NR4A3 rearrangements, such as fusion events with TAF15, EWSR1, and LSM14A, in patients with this rare soft tissue sarcoma. These gene fusion events serve as a molecular hallmark for diagnosis and have been detected in both isolated case reports and larger multi‐patient cohorts (PMID:14708728, PMID:22743288).
Detailed case reports describe unique phenotypic presentations including extraskeletal myxoid chondrosarcoma with neuroendocrine differentiation and with massive pulmonary metastases. In these reports, NR4A3 fusion events were identified as the primary genetic alteration, underscoring its utility as a diagnostic marker. The recurrent observation of these fusions across independent clinical series reinforces the clinical validity of NR4A3 in this disease context (PMID:30534357).
Multi‐patient studies have further cemented the role of NR4A3 by demonstrating its involvement in a wide spectrum of EMC cases, including rare osseous presentations. In one study, molecular confirmation of NR4A3 rearrangements was achieved in a cohort that included five bone cases, with detailed analyses emphasizing the fusion with EWSR1 and other partners (PMID:23588370). The consistency of these molecular findings across diverse settings supports the reliability of using NR4A3 as a key diagnostic marker.
At the genetic level, the detection of multiple recurrent fusion variants—namely TAF15::NR4A3, EWSR1::NR4A3, and LSM14A::NR4A3—illustrates the heterogeneity yet specificity of the molecular alterations underlying EMC. These fusion events not only serve diagnostic purposes but may also define subgroups with distinct clinical behaviors, as suggested by correlations with tumor size and metastatic potential (PMID:35932215, PMID:36948401).
The combination of robust genetic data from both isolated case studies and comprehensive multi‐patient analyses contributes to a strong gene–disease association. The recurrent presence of NR4A3 fusions provides critical support for its incorporation into diagnostic workflows, thereby enhancing clinical confidence in the molecular diagnosis of EMC.
Functional studies, though primarily focused on elucidating fusion-driven oncogenesis rather than classical loss‐of‐function or gain‐of‐function paradigms, reveal that the pathogenic mechanism likely involves aberrant transcriptional regulation. While direct experimental models specific to EMC remain limited, the available data suggest that the chimeric proteins alter downstream signaling pathways to promote tumorigenesis (PMID:30534357).
In conclusion, the integration of clinical, genetic, and preliminary functional evidence supports a strong association between NR4A3 and extraskeletal myxoid chondrosarcoma. This association is critical for diagnostic decision‑making and highlights the potential for targeted research into therapeutic strategies.
Key Take‑home sentence: The consistent detection of NR4A3 fusion events in EMC empowers precise molecular diagnosis and sets the stage for future clinical interventions.
Gene–Disease AssociationStrongMultiple case reports and multi‐patient studies report NR4A3 rearrangements in extraskeletal myxoid chondrosarcoma, with molecular confirmation in cohorts totaling over 50 cases (PMID:36948401, PMID:14708728, PMID:23588370). Genetic EvidenceStrongGenetic evidence is robust, with recurrent detection of fusion events such as TAF15::NR4A3, EWSR1::NR4A3, and LSM14A::NR4A3 in multiple independent probands and studies (PMID:22743288, PMID:35932215). Functional EvidenceModerateFunctional studies indicate that NR4A3 fusion proteins likely drive oncogenesis through aberrant transcriptional regulation; however, direct experimental validation in EMC-specific models remains somewhat limited (PMID:30534357). |