The genomics of desmoplastic small round cell tumor reveals the deregulation of genes related to DNA damage response, epithelial–mesenchymal transition, and immune response

Abstract

BackgroundDesmoplastic small round cell tumor (DSRCT) is a rare, aggressive, and poorly investigated simple sarcoma with a low frequency of genetic deregulation other than an Ewing sarcoma RNA binding protein 1 (EWSR1)-Wilm’s tumor suppressor (WT1) translocation. We used whole-exome sequencing to interrogate six consecutive pre-treated DSRCTs whose gene expression was previously investigated.MethodsDNA libraries were prepared from formalin-fixed, paraffin-embedded archival tissue specimens following the Agilent SureSelectXT2 target enrichment protocol and sequenced on Illumina NextSeq 500. Raw sequence data were aligned to the reference genome with Burrows–Wheeler Aligner algorithm. Somatic mutations and copy number alterations (CNAs) were identified using MuTect2 and EXCAVATOR2, respectively. Biological functions associated with altered genes were investigated through Ingenuity Pathway Analysis (IPA) software.ResultsA total of 137 unique somatic mutations were identified: 133 mutated genes were case-specific, and 2 were mutated in two cases but in different positions. Among the 135 mutated genes, 27% were related to two biological categories: DNA damage-response (DDR) network that was also identified through IPA and mesenchymal–epithelial reverse transition (MErT)/epithelial–mesenchymal transition (EMT) already demonstrated to be relevant in DSRCT. The mutated genes in the DDR network were involved in various steps of transcription and particularly affected pre-mRNA. Half of these genes encoded RNA-binding proteins or DNA/RNA-binding proteins, which were recently recognized as a new class of DDR players. CNAs in genes/gene families, involved in MErT/EMT and DDR, were recurrent across patients and mostly segregated in the MErT/EMT category. In addition, recurrent gains of regions in chromosome 1 involving many MErT/EMT gene families and loss of one arm or the entire chromosome 6 affecting relevant immune-regulatory genes were recorded.ConclusionsThe emerging picture is an extreme inter-tumor heterogeneity, characterized by the concurrent deregulation of the DDR and MErT/EMT dynamic and plastic programs that could favour genomic instability and explain the refractory DSRCT profile.Electronic supplementary materialThe online version of this article (10.1186/s40880-018-0339-3) contains supplementary material, which is available to authorized users.

Clinicopathologic and molecular features of intracranial desmoplastic small round cell tumors

“…Inactivating mutations in STAG2 are the most frequent accompanying somatic mutation in Ewing sarcoma, occurring in approximately 17% of cases, and are associated with poor outcome (10,51). To the best of our knowledge, among the relatively few cases of DSRCT that have either undergone extensive genetic sequencing (13,16,46) or sequencing focused specifically on accompanying STAG2 or TP53 mutations (45), only one additional case with a STAG2 mutation has been reported (45). This patient's EWSR1-WT1 gene fusion and accompanying inactivating STAG2 splice site mutation were detected within tumor tissue and within plasma derived cell free DNA (45).…”

Olaparib and temozolomide in desmoplastic small round cell tumors: a promising combination in vitro and in vivo

“…Given the need for novel treatments, we looked towards targeted therapy directed against the DNA damage response (DDR) machinery. The DDR network appears to be a potential target for DSRCTs since the EWSR1-WT1 translocation already involves two DDR network proteins (Gorthi and Bishop 2018;Oji et al 2015) and the recent detection of multiple mutated genes belonging to the DDR network (Devecchi et al 2018) by whole-exome sequencing of 6 DSRCT samples. We hypothesize that the presence of aberrations in the DDR pathway will most probably make DSRCTs more vulnerable for additional inhibition of the DDR system.…”

Desmoplastic small round cell tumor (DSRCT): emerging therapeutic targets and future directions for potential therapies

“…Among the 135 mutated genes, 27% were related to EMT/ mesenchymal-epithelial reverse transition (MErT) and the DDR network. These include proteins with a crucial function in the cell cycle such as Ataxia telangiectasia and Rad3-related protein (ATR) and Ribonucleoside-diphosphate reductase subunit M2 (RRM2) [12]. Consistent with the latter, Mellado et al demonstrated the sensitivity of DSRCT to PARP inhibition combination therapy in patient-derived xenograft models.…”

“…Recent analyses of mutational profiles revealed the deregulation of genes related to immune response, epithelial-mesenchymal transition (EMT), and the DNA damage response (DDR) in DSRCT [12]. Whole-exome sequencing of six DSRCT samples identified a total of 137 unique somatic mutations, of which 133 mutated genes were case-specific, and two genes were mutated in two cases but in different positions.…”

“…Polyspecific organic cation transporter DNA damage repair pathways Ataxia telangiectasia and Rad3-related protein (ATR) Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses [12] Poly(ADP-ribose)-polymerase (PARP)…”