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Comprehensive Molecular Profiling of Desmoplastic Small Round Cell Tumor
- Source :
- Mol Cancer Res
- Publication Year :
- 2021
- Publisher :
- American Association for Cancer Research (AACR), 2021.
-
Abstract
- Desmoplastic small round cell tumor (DSRCT) is characterized by the EWSR1–WT1 t(11;22) (p13:q12) translocation. Few additional putative drivers have been identified, and research has suffered from a lack of model systems. Next-generation sequencing (NGS) data from 68 matched tumor-normal samples, whole-genome sequencing data from 10 samples, transcriptomic and affymetrix array data, and a bank of DSRCT patient-derived xenograft (PDX) are presented. EWSR1–WT1 fusions were noted to be simple, balanced events. Recurrent mutations were uncommon, but were noted in TERT (3%), ARID1A (6%), HRAS (5%), and TP53 (3%), and recurrent loss of heterozygosity (LOH) at 11p, 11q, and 16q was identified in 18%, 22%, and 34% of samples, respectively. Comparison of tumor-normal matched versus unmatched analysis suggests overcalling of somatic mutations in prior publications of DSRCT NGS data. Alterations in fibroblast growth factor receptor 4 (FGFR4) were identified in 5 of 68 (7%) of tumor samples, whereas differential overexpression of FGFR4 was confirmed orthogonally using 2 platforms. PDX models harbored the pathognomic EWSR1–WT1 fusion and were highly representative of corresponding tumors. Our analyses confirm DSRCT as a genomically quiet cancer defined by the balanced translocation, t(11;22)(p13:q12), characterized by a paucity of secondary mutations but a significant number of copy number alterations. Against this genomically quiet background, recurrent activating alterations of FGFR4 stood out, and suggest that this receptor tyrosine kinase, also noted to be highly expressed in DSRCT, should be further investigated. Future studies of DSRCT biology and preclinical therapeutic strategies should benefit from the PDX models characterized in this study.Implications:These data describe the general quiescence of the desmoplastic small round cell tumor (DSRCT) genome, present the first available bank of DSRCT model systems, and nominate FGFR4 as a key receptor tyrosine kinase in DSRCT, based on high expression, recurrent amplification, and recurrent activating mutations.
- Subjects :
- Adult
Male
0301 basic medicine
Cancer Research
Adolescent
DNA Copy Number Variations
Oncogene Proteins, Fusion
Desmoplastic small-round-cell tumor
ARID1A
Chromosomal translocation
Desmoplastic Small Round Cell Tumor
Article
Receptor tyrosine kinase
Loss of heterozygosity
Young Adult
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
medicine
Humans
Receptor, Fibroblast Growth Factor, Type 4
HRAS
Child
WT1 Proteins
Molecular Biology
biology
Gene Expression Profiling
High-Throughput Nucleotide Sequencing
Cancer
Fibroblast growth factor receptor 4
Middle Aged
medicine.disease
Gene Expression Regulation, Neoplastic
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
biology.protein
Cancer research
Female
RNA-Binding Protein EWS
Multiplex Polymerase Chain Reaction
Subjects
Details
- ISSN :
- 15573125 and 15417786
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer Research
- Accession number :
- edsair.doi.dedup.....2ac1c7939c3d9200ba4a58d45d791710