New transcriptional-based insights into the pathogenesis of desmoplastic small round cell tumors (DSRCTs)

Negri, Tiziana; Brich, Silvia; Bozzi, Fabio; Volpi, Chiara Costanza; Gualeni, Ambra Vittoria; Stacchiotti, Silvia; Cecco, Loris De; Canevari, Silvana; Gloghini, Annunziata; Pilotti, Silvana

doi:10.18632/oncotarget.16477

Cited by 17 publications

(25 citation statements)

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“…We performed WES in six cases of DSRCT that, on the basis of previously published results of transcriptome profiling, microRNA (miRNA) in situ hybridisation (ISH), and IHC assays, were divided into three groups that recapitulated the traits of mesenchymal–epithelial reverse transition (MErT), hybrid/partial EMT, and EMT [ 9 ]. After alignment of raw reads, we evaluated the quality of data in terms of coverage and sample purity.…”

Section: Resultsmentioning

confidence: 99%

“…Before surgery, all patients had received 3–6 cycles of multi-drug chemotherapy including one or two alkylating agents [ 9 ]. To evaluate whether the identified mutations may have been due to the dominant effect of chemotherapy, we tested 30 mutational signatures from COSMIC in the aggregated list of our 137 somatic mutations.…”

Section: Resultsmentioning

confidence: 99%

“…Seven consecutive cases of primary DSRCT that were surgically removed after multi-drug chemotherapy between 2000 and 2016 were analyzed. The presence of the EWSR1 - WT1 translocation was detected using fluorescent in situ hybridisation coupled with immunolabeling restricted to WT-C19 [ 9 ]. The clinical data (including follow-up data when available) were obtained from the patients’ records and were previously described [ 9 ].…”

Section: Methodsmentioning

confidence: 99%

“…The presence of the EWSR1 - WT1 translocation was detected using fluorescent in situ hybridisation coupled with immunolabeling restricted to WT-C19 [ 9 ]. The clinical data (including follow-up data when available) were obtained from the patients’ records and were previously described [ 9 ]. The study was approved by the Independent Ethics Committee of the Fondazione IRCCS Istituto Nazionale dei Tumori di Milano.…”

Section: Methodsmentioning

confidence: 99%

“…Finally, amplification of aurora kinase B ( AURKB ) and MCL1, BCL2 family apoptosis regulator 1 ( MCL1 ) has been reported in one case of DSRCT interrogated using targeted NGS [ 6 ], and gains in chromosome 5 and 18 and loss at 13q have been detected in one case interrogated using WES and comparative genomic hybridization [ 7 ]. In the present study, we used WES to investigate six cases of DSRCT known to carry the specific EWSR1 - WT1 translocation and was previously investigated using gene expression profiling complemented by immunophenotyping, microRNA (miRNA) in situ hybridisation (ISH), and a cancer stem cell array analysis [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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

Devecchi

Cecco

Dugo

et al. 2018

Cancer Communications

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%