Transcriptome analysis of desmoplastic small round cell tumors identifies actionable therapeutic targets: a report from the Children's Oncology Group.
Adolescent
Cell Line, Tumor
Child
Child, Preschool
Cluster Analysis
Desmoplastic Small Round Cell Tumor
/ genetics
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Insulin-Like Growth Factor II
/ genetics
Male
Medical Oncology
Molecular Targeted Therapy
Neoplasm Proteins
/ metabolism
Oncogene Proteins, Fusion
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
23 07 2020
23 07 2020
Historique:
received:
19
02
2019
accepted:
01
07
2020
entrez:
25
7
2020
pubmed:
25
7
2020
medline:
15
12
2020
Statut:
epublish
Résumé
To further understand the molecular pathogenesis of desmoplastic small round cell tumor (DSRCT), a fatal malignancy occurring primarily in adolescent/young adult males, we used next-generation RNA sequencing to investigate the gene expression profiles intrinsic to this disease. RNA from DSRCT specimens obtained from the Children's Oncology Group was sequenced using the Illumina HiSeq 2000 system and subjected to bioinformatic analyses. Validation and functional studies included WT1 ChIP-seq, EWS-WT1 knockdown using JN-DSRCT-1 cells and immunohistochemistry. A panel of immune signature genes was also evaluated to identify possible immune therapeutic targets. Twelve of 14 tumor samples demonstrated presence of the diagnostic EWSR1-WT1 translocation and these 12 samples were used for the remainder of the analysis. RNA sequencing confirmed the lack of full-length WT1 in all fusion positive samples as well as the JN-DSRCT-1 cell line. ChIP-seq for WT1 showed significant overlap with genes found to be highly expressed, including IGF2 and FGFR4, which were both highly expressed and targets of the EWS-WT1 fusion protein. In addition, we identified CD200 and CD276 as potentially targetable immune checkpoints whose expression is independent of the EWS-WT1 fusion gene in cultured DSCRT cells. In conclusion, we identified IGF2, FGFR4, CD200, and CD276 as potential therapeutic targets with clinical relevance for patients with DSRCT.
Identifiants
pubmed: 32703985
doi: 10.1038/s41598-020-69015-w
pii: 10.1038/s41598-020-69015-w
pmc: PMC7378211
doi:
Substances chimiques
Neoplasm Proteins
0
Oncogene Proteins, Fusion
0
Insulin-Like Growth Factor II
67763-97-7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12318Subventions
Organisme : NIH HHS
ID : NCI U10CA180884
Pays : United States
Organisme : NIH HHS
ID : U24CA114766
Pays : United States
Organisme : NIH HHS
ID : U10CA180886
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180884
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180899
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180886
Pays : United States
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