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

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Undifferentiated pleomorphic sarcomas with PRDM10 fusions have a distinct gene expression profile. / Hofvander, Jakob; Puls, Florian; Pillay, Nischalan; Steele, Christopher D.; Flanagan, Adrienne M.; Magnusson, Linda; Nilsson, Jenny; Mertens, Fredrik.

I: Journal of Pathology, 2019.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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Hofvander, Jakob ; Puls, Florian ; Pillay, Nischalan ; Steele, Christopher D. ; Flanagan, Adrienne M. ; Magnusson, Linda ; Nilsson, Jenny ; Mertens, Fredrik. / Undifferentiated pleomorphic sarcomas with PRDM10 fusions have a distinct gene expression profile. I: Journal of Pathology. 2019.

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TY - JOUR

T1 - Undifferentiated pleomorphic sarcomas with PRDM10 fusions have a distinct gene expression profile

AU - Hofvander, Jakob

AU - Puls, Florian

AU - Pillay, Nischalan

AU - Steele, Christopher D.

AU - Flanagan, Adrienne M.

AU - Magnusson, Linda

AU - Nilsson, Jenny

AU - Mertens, Fredrik

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - chromatin

KW - CITED2

KW - expression

KW - fusion

KW - PRDM10

KW - sarcoma

U2 - 10.1002/path.5326

DO - 10.1002/path.5326

M3 - Article

JO - Journal of Pathology

T2 - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

ER -