PHF1 fusions cause distinct gene expression and chromatin accessibility profiles in ossifying fibromyxoid tumors and mesenchymal cells


Ossifying fibromyxoid tumor (OFMT) is a soft tissue tumor frequently displaying gene fusions, most of which affect the PHF1 gene. PHF1 encodes plant homeodomain finger protein 1, which is involved in various processes regulating gene transcription, including those orchestrated by the polycomb repressor complex 2. Here, a series of 37 OFMTs, including 18 typical, 9 atypical, and 10 malignant variants, was analyzed with regard to transcriptomic features, gene fusion and copy number status, and/or single-nucleotide variants. The effects on gene expression and chromatin accessibility of three detected fusions (EP400PHF1, MEAF6PHF1, and PHF1–TFE3) were further evaluated in fibroblasts. Genomic imbalances showed a progression-related pattern, with more extensive copy number changes among atypical/malignant lesions than among typical OFMTs; loss of the RB1 gene was restricted to atypical/malignant OFMTs, occurring in one-third of the cases. RNA sequencing identified fusion transcripts in >80% of the cases analyzed, including a novel CSMD1MEAF6. The gene-expression profile of OFMT was distinct from that of other soft tissue tumors, with extensive transcriptional upregulation of genes in OFMT. These findings were largely recapitulated in gene fusion-expressing fibroblast lines, suggesting that genes involved in, e.g., Wnt signaling and/or being regulated through trimethylation of lysine 27 in histone 3 (H3K27me3) are pivotal for OFMT development. The genes showing differentially higher expression in fusion-expressing cells paralleled increased chromatin accessibility, as revealed by ATAC sequencing. Thus, the present study suggests that OFMT develops through gene fusions that have extensive epigenetic consequences.

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Fig. 1: Circos plot showing SNP-array results in OFMT.
Fig. 2: OFMT forms a distinct expression cluster by unsupervised hierarchical clustering of 1568 genes.
Fig. 3: Analysis of overexpressed genes and differentially open promoter regions in the TERT-immortalized Bj5ta human fibroblast cell line with the EP400PPHF1 (E–P), MEAF6–PHF1 (M–P), PHF1–TFE3 (P–T), or empty vector (EV) plasmids.


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The kits for the TruSight Fusion RNA Fusion Panel library preparation were kindly provided by Illumina, San Diego, USA.


This study was supported by the Swedish Cancer Society and Region Skåne.

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Correspondence to Fredrik Mertens.

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Hofvander, J., Jo, V.Y., Fletcher, C.D.M. et al. PHF1 fusions cause distinct gene expression and chromatin accessibility profiles in ossifying fibromyxoid tumors and mesenchymal cells. Mod Pathol (2020).

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