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Updated: Jul 23, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Genomic Breakpoint Characterization and Transcriptome Analysis of Metastatic, Recurrent Desmoplastic Small Round Cell
Justin W Magrath1, Dane A Flinchum1, Alifiani B Hartono1
1Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Ave. New Orleans, LA, USA.
Abstract:
Desmoplastic small round cell tumor (DSRCT) is a rare pediatric cancer caused by the EWSR1-WT1 fusion oncogene. Despite initial response to chemotherapy, DSRCT has a recurrence rate of over 80% leading to poor patient prognosis with a 5-year survival rate of only 15-25%. Owing to the rarity of DSRCT, sample scarcity is a barrier in understanding DSRCT biology and developing effective therapies. Utilizing a novel pair of primary and recurrent DSRCTs, we present the first map of DSRCT genomic breakpoints and the first comparison of gene expression alterations between primary and recurrent DSRCT. Our genomic breakpoint map includes the lone previously published DSRCT genomic breakpoint, the breakpoint from our novel primary/recurrent DSRCT pair, as well as the breakpoints of five available DSRCT cell lines and five additional DSRCTs. All mapped breakpoints were unique and most breakpoints included a 1-3 base pair microhomology suggesting microhomology-mediated end-joining as the mechanism of translocation fusion and providing novel insights into the etiology of DSRCT. Through RNA-sequencing analysis, we identified altered genes and pathways between primary and recurrent DSRCTs. Upregulated pathways in the recurrent tumor included several DNA repair and mRNA splicing-related pathways, while downregulated pathways included immune system function and focal adhesion. We further found higher expression of the EWSR1-WT1 upregulated gene set in the recurrent tumor as compared to the primary tumor and lower expression of the EWSR1-WT1 downregulated gene set, suggesting the EWSR1-WT1 fusion continues to play a prominent role in recurrent tumors. The identified pathways including upregulation of DNA repair and downregulation of immune system function may help explain DSRCT's high rate of recurrence and can be utilized to improve the understanding of DSRCT biology and identify novel therapies to both help prevent recurrence and treat recurrent tumors.
Insights
Desmoplastic small round cell tumor (DSRCT) recurrence is linked to DNA repair pathway upregulation and immune system downregulation. This study maps DSRCT genomic breakpoints and compares primary to recurrent tumor gene expression, offering insights into DSRCT biology and potential therapies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Desmoplastic small round cell tumor (DSRCT) is a rare pediatric cancer driven by the EWSR1-WT1 fusion oncogene.
- High recurrence rates (over 80%) and poor prognosis (15-25% 5-year survival) underscore the need for better therapeutic strategies.
- Sample scarcity hinders understanding of DSRCT biology and the development of effective treatments.
Purpose of the Study:
- To create the first comprehensive map of genomic breakpoints in DSRCT.
- To compare gene expression alterations between primary and recurrent DSRCT.
- To identify molecular mechanisms contributing to DSRCT recurrence and inform therapeutic development.
Main Methods:
- Genomic breakpoint mapping using a novel primary/recurrent DSRCT pair, existing cell lines, and additional DSRCT samples.
- RNA-sequencing to analyze gene expression differences between primary and recurrent tumors.
- Analysis of DNA repair, mRNA splicing, immune function, and focal adhesion pathways.
Main Results:
- A unique genomic breakpoint map for DSRCT was generated, suggesting microhomology-mediated end-joining in translocation fusion.
- Recurrent DSRCT showed upregulated DNA repair and mRNA splicing pathways, and downregulated immune system function and focal adhesion.
- The EWSR1-WT1 fusion oncogene remained prominent, with altered expression patterns in recurrent tumors.
Conclusions:
- Genomic breakpoint analysis provides insights into DSRCT etiology.
- Upregulation of DNA repair and downregulation of immune function in recurrent DSRCT may explain treatment resistance and recurrence.
- Findings offer potential therapeutic targets for preventing and treating DSRCT recurrence.
