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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 2021-05-25, 00:44 authored 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 McEachronTo 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
10Issue
1Start Page
1End Page
12Number of Pages
12eISSN
2045-2322ISSN
2045-2322Location
EnglandPublisher
Nature Publishing GroupPublisher License
CC BYPublisher DOI
Full Text URL
Additional Rights
CC BY 4.0Language
engPeer Reviewed
- Yes
Open Access
- Yes
Acceptance Date
2020-07-01Era Eligible
- Yes
Medium
ElectronicJournal
Scientific ReportsArticle Number
12318Usage metrics
Categories
Keywords
CancerSarcomaDesmoplastic small round cell tumor (DSRCT)Next-generation RNA sequencingImmune therapeutic targetsAdolescentCell Line, TumorChildChild, PreschoolCluster AnalysisDesmoplastic Small Round Cell TumorFemaleGene Expression ProfilingGene Expression Regulation, NeoplasticHumansInsulin-Like Growth Factor IIMaleMedical OncologyMolecular Targeted TherapyNeoplasm ProteinsOncogene Proteins, FusionCancer Cell Biology