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Transcriptome analysis of desmoplastic small round cell tumors identifies actionable therapeutic targets: A report from the Children’s Oncology Group

journal contribution
posted on 25.05.2021, 00:44 by Pooja Hingorani, Valentin Dinu, Xiyuan Zhang, Haiyan Lei, Jack F Shern, Jin Park, Jason SteelJason Steel, Femina Rauf, David Parham, Julie Gastier-Foster, David Hall, Douglas S Hawkins, Stephen X Skapek, Joshua Labaer, Troy A McEachron
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.

Funding

Category 1 - Australian Competitive Grants (this includes ARC, NHMRC)

History

Volume

10

Issue

1

Start Page

1

End Page

12

Number of Pages

12

eISSN

2045-2322

ISSN

2045-2322

Location

England

Publisher

Nature Publishing Group

Publisher License

CC BY

Additional Rights

CC BY 4.0

Language

eng

Peer Reviewed

Yes

Open Access

Yes

Acceptance Date

01/07/2020

Era Eligible

Yes

Medium

Electronic

Journal

Scientific Reports

Article Number

12318