WFRF:(Fletcher Christopher D M)
Sökning: WFRF:(Fletcher Christopher D M) > (2020-2023) > PHF1 fusions cause ...
PHF1 fusions cause distinct gene expression and chromatin accessibility profiles in ossifying fibromyxoid tumors and mesenchymal cells
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- Hofvander, Jakob (författare)
- Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Genetiska avvikelser i mjukdelstumörer,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine,The genetics of soft tissue tumors,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Jo, Vickie Y. (författare)
- Harvard Medical School
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- Fletcher, Christopher D.M. (författare)
- Harvard Medical School
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- (creator_code:org_t)
- Elsevier BV, 2020
- 2020
- Engelska 10 s.
- Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 33:7, s. 1331-1340
- Tidskriftsartikel (refereegranskat)
Abstract
Ämnesord
Stäng
- 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 (EP400–PHF1, MEAF6–PHF1, 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 CSMD1–MEAF6. 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
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- Hofvander, Jakob
- Jo, Vickie Y.
- Fletcher, Christ ...
- Puls, Florian
- Flucke, Uta
- Nilsson, Jenny
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- Magnusson, Linda
- Mertens, Fredrik
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