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Undifferentiated pleomorphic sarcomas with PRDM10 fusions have a distinct gene expression profile

Hofvander, Jakob LU ; Puls, Florian ; Pillay, Nischalan ; Steele, Christopher D. ; Flanagan, Adrienne M. ; Magnusson, Linda LU ; Nilsson, Jenny LU and Mertens, Fredrik LU (2019) In Journal of Pathology 249(4). p.425-434
Abstract

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... (More)

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.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
chromatin, CITED2, expression, fusion, PRDM10, sarcoma
in
Journal of Pathology
volume
249
issue
4
pages
425 - 434
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85071259191
  • pmid:31313299
ISSN
0022-3417
DOI
10.1002/path.5326
language
English
LU publication?
yes
id
314d6c59-b5a7-4300-9c4e-0f41ee834352
date added to LUP
2019-09-09 10:01:29
date last changed
2024-06-13 02:44:28
@article{314d6c59-b5a7-4300-9c4e-0f41ee834352,
  abstract     = {{<p>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.</p>}},
  author       = {{Hofvander, Jakob and Puls, Florian and Pillay, Nischalan and Steele, Christopher D. and Flanagan, Adrienne M. and Magnusson, Linda and Nilsson, Jenny and Mertens, Fredrik}},
  issn         = {{0022-3417}},
  keywords     = {{chromatin; CITED2; expression; fusion; PRDM10; sarcoma}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{425--434}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Journal of Pathology}},
  title        = {{Undifferentiated pleomorphic sarcomas with PRDM10 fusions have a distinct gene expression profile}},
  url          = {{http://dx.doi.org/10.1002/path.5326}},
  doi          = {{10.1002/path.5326}},
  volume       = {{249}},
  year         = {{2019}},
}