In-depth genetic analysis of sclerosing epithelioid fibrosarcoma reveals recurrent genomic alterations and potential treatment targets Journal Article


Authors: Arbajian, E.; Puls, F.; Antonescu, C. R.; Amary, F.; Sciot, R.; Debiec-Rychter, M.; Sumathi, V. P.; Järås, M.; Magnusson, L.; Nilsson, J.; Hofvander, J.; Mertens, F.
Article Title: In-depth genetic analysis of sclerosing epithelioid fibrosarcoma reveals recurrent genomic alterations and potential treatment targets
Abstract: Purpose: 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. Experimental Design: 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 FUS-CREB3L2 and EWSR1-CREB3L1 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. Results: The SNP array analysis detected a large number of structural aberrations in SEF and SEF/LGFMS, many of which were recurrent, notably DMD microdeletions. RNA-seq identified FUS-CREM and PAX5-CREB3L1 as alternative fusion genes in one SEF each. CD24 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 EWSR1-CREB3L1. Conclusions: 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. ©2017 AACR.
Keywords: immunohistochemistry; clinical article; controlled study; gene mutation; single nucleotide polymorphism; gene deletion; genetic analysis; gene expression; carcinogenesis; rna; fibrosarcoma; gene fusion; fusion gene; soft tissue sarcoma; fibroblast; cd24 antigen; fluorescence activated cell sorting; rna sequence; human; priority journal; article; whole exome sequencing; sclerosing epitheloid fibrosarcoma
Journal Title: Clinical Cancer Research
Volume: 23
Issue: 23
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2017-12-01
Start Page: 7426
End Page: 7434
Language: English
DOI: 10.1158/1078-0432.ccr-17-1856
PROVIDER: scopus
PUBMED: 28939748
DOI/URL:
Notes: Article -- Export Date: 2 January 2018 -- Source: Scopus
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MSK Authors
  1. Cristina R Antonescu
    606 Antonescu