Super-enhancer-drivenCACNA2D2is an EWSR1::WT1 signature gene encoding a diagnostic marker for desmoplastic small round cell tumor (DSRCT)

Author:

Geyer Florian H.,Ritter Alina,Kinn-Gurzo Seneca,Faehling Tobias,Li Jing,Jarosch Armin,Ngo Carine,Vinca Endrit,Aljakouch Karim,Orynbek Azhar,Ohmura Shunya,Kirchner Thomas,Imle Roland,Romero-Pérez Laura,Bertram Stefanie,de Álava Enrique,Postel-Vilnay Sophie,Banito Ana,Sill Martin,Versleijen-Jonkers Yvonne M.H.,Mayer Benjamin F.B.,Ebinger Martin,Sparber-Sauer Monika,Stegmaier Sabine,Baumhoer Daniel,Hartmann Wolfgang,Krijgsveld Jeroen,Horst David,Delattre Olivier,Grohar Patrick J.,Grünewald Thomas G. P.ORCID,Cidre-Aranaz Florencia

Abstract

ABSTRACTDesmoplastic small round cell tumor (DSRCT) is a highly aggressive cancer predominantly occurring in male adolescents and young adults. The lack of a comprehensive understanding on the biology of the disease is paralleled by its dismal survival rates (5–20%). To overcome this challenge, we first identified and prioritized urgently needed resources for clinicians and researchers. Thus, we established genome-wide single-cell RNA-sequencing and bulk proteomic data of in vitro and in vivo-generated knockdown models of the pathognomonic DSRCT fusion oncoprotein (EWSR1::WT1) and combined them with an original systems-biology-based pipeline including patient data and the largest histology collection of DSRCTs and morphological mimics available to date. These novel tools were enriched with curated public datasets including patient- and cell line-derived ChIP-seq, bulk and single-cell RNA-seq studies resulting in a multi-model and multi-omic toolbox for discovery analyses. As a proof of concept, our approach revealed the alpha-2/delta subunit of the voltage-dependent calcium channel complex, CACNA2D2, as a highly overexpressed, super-enhancer driven, direct target of EWSR1::WT1. Single-cell and bulk-level analyses of patient samples and xenografted cell lines highlighted CACNA2D2 as a critical component of our newly established EWSR1::WT1 oncogenic signature, that can be employed to robustly identify DSRCT in reference sets. Finally, we show that CACNA2D2 is a highly sensitive and specific single biomarker for fast, simple, and cost-efficient diagnosis of DSRCT. Collectively, we establish a large-scale multi-omics dataset for this devastating disease and provide a blueprint of how such toolbox can be used to identify new and clinically relevant diagnostic markers, which may significantly reduce misdiagnoses, and thus improve patient care.

Publisher

Cold Spring Harbor Laboratory

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