ABSTRACT: Myxofibrosarcoma (MFS) is a common adult soft tissue sarcoma characterized by an infiltrative growth pattern and a high local recurrence rate and high propensity for local recurrence. Using 41 MFSs as a discovery set, we underwent whole exome sequencing (N=41), RNA sequencing (N=29), and methylation analysis (N=41). We subsequently performed targeted sequencing of 140 genes in the entire cohort of 99 MFSs to validate the results in the discovery samples. We also combined 17 MFSs data from TCGA to characterize the molecular features of MFS. Fourteen driver genes were identified, including potentially actionable therapeutic targets seen in 37% of cases. There were frequent alterations in p53 signaling (51%; TP53 and MDM2) and cell cycle checkpoint genes (43%; RB1, CDKN2A/CDKN2B, CDK6, and CCND1) genes. Other conceivably actionable driver genes including ATRX, JAK1, NF1, NTRK1 and novel oncogenic BRAF fusion gene were identified and a novel oncogenic BRAF fusion gene, SLC37A3-BRAF, which could potentially be targeted with BRAF inhibitors, and other conceivably actionable driver genes (ATRX, JAK1, NF1, and NTRK1) were identified. Methylation patterns clustered into three subtypes associated with unique combinations of MFS driver mutations. This cluster was also associated with clinical outcomes, and immune cell compositions. Our results provide a valuable genomic resource to enable the design of precision medicine for MFS. Here, based on these analyses, we identified recurrent driver genes, including novel BRAF fusion gene, and novel methylation clusters associated with unique combinations of driver mutations, clinical outcomes, and immune cell compositions.
