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, 00:44authored byPooja 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)