Undifferentiated pleomorphic sarcomas with PRDM10 fusions have a distinct gene expression profile.
Biomarkers, Tumor
/ genetics
Cell Adhesion Molecules
/ genetics
Cell Differentiation
Cell Line
DNA-Binding Proteins
/ genetics
Fibroblasts
/ enzymology
Gene Expression Profiling
Gene Fusion
Genetic Predisposition to Disease
Humans
Immunoglobulins
/ genetics
Mutation
Phenotype
Polymorphism, Single Nucleotide
Repressor Proteins
/ genetics
Sarcoma
/ enzymology
Soft Tissue Neoplasms
/ enzymology
Trans-Activators
/ genetics
Transcription Factors
/ genetics
Transcriptome
CITED2
PRDM10
chromatin
expression
fusion
sarcoma
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
31
05
2019
revised:
27
06
2019
accepted:
12
07
2019
pubmed:
18
7
2019
medline:
21
4
2020
entrez:
18
7
2019
Statut:
ppublish
Résumé
Undifferentiated pleomorphic sarcoma (UPS) is a highly aggressive soft tissue tumor. A subset of UPS is characterized by a CITED2-PRDM10 or a MED12-PRDM10 gene fusion. Preliminary data suggest that these so-called PRDM10-rearranged tumors (PRT) are clinically more indolent than classical high-grade UPS, and hence important to recognize. Here, we assessed the spectrum of accompanying mutations and the gene expression profile in PRT using genomic arrays and sequencing of the genome (WGS) and transcriptome (RNA-seq). The fusion protein's function was further investigated by conditional expression of the CITED2-PRDM10 fusion in a fibroblast cell line, followed by RNA-seq and an assay for transposase-accessible chromatin (ATAC-seq). The CADM3 gene was found to be differentially up-regulated in PRT and cell lines and was also evaluated for expression at the protein level using immunohistochemistry (IHC). The genomic analyses identified few and nonrecurrent mutations in addition to the structural variants giving rise to the gene fusions, strongly indicating that the PRDM10-fusions represent the critical driver mutations. RNA-seq of tumors showed a distinct gene expression profile, separating PRT from high-grade UPS and other soft tissue tumors. CADM3 was among the genes that was consistently and highly expressed in both PRT and fibroblasts expressing CITED2-PRDM10, suggesting that it is a direct target of the PRDM10 transcription factor. This conclusion is in line with sequencing data from ATAC-seq, showing enrichment of PRDM10 binding sites, suggesting that the amino-terminal fusion partner contributes by making the DNA more accessible to PRDM10 binding. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Substances chimiques
Biomarkers, Tumor
0
CADM3 protein, human
0
CITED2 protein, human
0
Cell Adhesion Molecules
0
DNA-Binding Proteins
0
Immunoglobulins
0
PRDM10 protein, human
0
Repressor Proteins
0
Trans-Activators
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
425-434Informations de copyright
© 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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