Comprehensive Molecular Profiling of Desmoplastic Small Round Cell Tumor.

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive sarcoma characterized by the EWSR1-WT1 translocation.
• Limited understanding of DSRCT's genomic landscape and lack of effective model systems have hindered research.
• Previous next-generation sequencing (NGS) studies may have overestimated somatic mutation rates.

Purpose of the Study:

• To comprehensively characterize the genomic profile of DSRCT using integrated multi-omics data.
• To establish and validate patient-derived xenograft (PDX) models for DSRCT research.
• To identify potential therapeutic targets by analyzing recurrent genetic alterations and gene expression.

Main Methods:

• Next-generation sequencing (NGS) on 68 matched tumor-normal samples.
• Whole-genome sequencing, transcriptomic, and Affymetrix array analyses.
• Development and characterization of DSRCT patient-derived xenograft (PDX) models.

Main Results:

• DSRCT genome is largely quiescent, dominated by the EWSR1-WT1 translocation with few secondary mutations.
• Recurrent mutations were identified in TERT, ARID1A, HRAS, and TP53; significant copy number alterations were found at 11p, 11q, and 16q.
• Fibroblast growth factor receptor 4 (FGFR4) showed recurrent activating alterations and high expression, suggesting its importance.

Conclusions:

• DSRCT is characterized by a quiet genome with a paucity of secondary mutations but notable copy number alterations.
• Established PDX models accurately represent DSRCT biology and are valuable for preclinical studies.
• FGFR4 is a key receptor tyrosine kinase in DSRCT, presenting a promising therapeutic target due to its recurrent alterations and overexpression.