Secondary Genetic Alterations in Extraskeletal Myxoid Chondrosarcoma

Extraskeletal myxoid chondrosarcoma (EMC) is a rare mesenchymal neoplasm of uncertain histogenesis, characterized by recurrent gene fusions involving NR4A3 with various gene partners (EWSR1, TAF15, FUS, etc.). Although the impact of fusion variants has been linked to histology and prognosis, no study to date has comprehensively investigated the incidence and spectrum of secondary genetic alterations (SGAs) in EMC with regard to their association with fusion type and clinical impact. Our molecular database was searched for EMC tested on a hybridization capture-based targeted matched tumor-normal DNA NGS assay (MSK-IMPACT, 341-505 gene panel). All tumors had their fusion subtype confirmed either by Archer FusionPlex and/or fluorescence in situ hybridization (FISH). Clinicopathologic data was reviewed. Eighteen EMC patients (20 samples) were selected, with a mean age of 61 years and a male: female ratio of 5:1. By molecular testing, the most common NR4A3 fusion subtype involved EWSR1 (14/18, 78%), while two cases involved TAF15 gene partner, and one each TCF12 and FUS genes, respectively. All cases showed a low tumor mutation burden (TMB) (0–2, mean 0.83). Two-thirds of cases had concurrent SGAs, while the remaining showed only the driver NR4A3 fusion (0–8, mean 1.67 mut/case). Among the detected SGAs, only TP53 alterations were recurrent, seen in 2 cases with EWSR1::NR4A3 and TAF15::NR4A3 fusions, respectively. Other non-recurrent alterations involved CDKN1B, TERT, and MET genes, among others. Non-EWSR1 fusion variant tumors showed a tendency for a higher number of SGAs compared to EWSR1-rearranged tumors (mean 2.75 versus 1.36 mut/case). Patients with ≥ 1 SGA showed lower disease-free survival (DFS) (p = 0.022) and poor overall survival (OS) (p = 0.014), while no statistically significant correlation was detected between OS and fusion subtypes. Most patients (83%) developed distant metastases, which did not correlate with the SGA status. This is the first study addressing the genomic landscape in EMC with regard to prognostication beyond fusion subtypes and histology. Similar to other translocation-associated sarcomas, the number of co-occurring SGAs in EMC is low; however, when present, they are associated with worse survival. Although a higher number of SGAs showed a trend to be associated with non-EWSR1 fusion variants, larger multi-institutional studies are needed to further evaluate the correlation between fusion variants with SGAs and survival.