In-depth Genetic Analysis of Sclerosing Epithelioid Fibrosarcoma Reveals Recurrent Genomic Alterations and Potential Treatment Targets.

Sclerosing epithelioid fibrosarcoma (SEF) is a highly aggressive soft tissue sarcoma closely related to low-grade fibromyxoid sarcoma (LGFMS). Some tumors display morphologic characteristics of both SEF and LGFMS, hence they are known as hybrid SEF/LGFMS. Despite the overlap of gene fusion variants between these two tumor types, SEF is much more aggressive. The current study aimed to further characterize SEF and hybrid SEF/LGFMS genetically to better understand the role of the characteristic fusion genes and possible additional genetic alterations in tumorigenesis. We performed whole-exome sequencing, SNP array analysis, RNA sequencing (RNA-seq), global gene expression analyses, and/or IHC on a series of 13 SEFs and 6 hybrid SEF/LGFMS. We also expressed the and fusion genes conditionally in a fibroblast cell line; these cells were subsequently analyzed by RNA-seq, and expression of the CD24 protein was assessed by FACS analysis. The SNP array analysis detected a large number of structural aberrations in SEF and SEF/LGFMS, many of which were recurrent, notably microdeletions. RNA-seq identified and as alternative fusion genes in one SEF each. was strongly upregulated, presumably a direct target of the fusion proteins. This was further confirmed by the gene expression analysis and FACS analysis on Tet-On 3G cells expressing Although gene fusions are the primary tumorigenic events in both SEF and LGFMS, additional genomic changes explain the differences in aggressiveness and clinical outcome between the two types. CD24 and DMD constitute potential therapeutic targets. .