| 1. |
- Gebre-Medhin, Samuel, et al.
(författare)
-
Recurrent Rearrangement of the PHF1 Gene in Ossifying Fibromyxoid Tumors.
- 2012
-
Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 181:3, s. 1069-1077
-
Tidskriftsartikel (refereegranskat)abstract
- Ossifying fibromyxoid tumor (OFMT) is a soft tissue tumor of unknown lineage. Although most cases are histologically and clinically benign, some show malignant morphological features and local recurrences are not uncommon; a few may even metastasize. In the present study, cytogenetic analysis identified different structural rearrangements of chromosome band 6p21 in tumor cells from three cases of OFMT, including one with typical, one with atypical, and one with malignant morphological features. Mapping of the 6p21 breakpoint by fluorescence in situ hybridization (FISH) indicated that the PHF1 gene was rearranged in all three cases. Further FISH, 5'-rapid amplification of cDNA ends, and RT-PCR analyses disclosed an EP400/PHF1 fusion transcript in one of the cases. Interphase FISH on tumor sections from 13 additional cases of OFMT showed rearrangement of the PHF1 locus in four of four typical, two of three atypical, and one of six malignant lesions. Thus, the PHF1 gene, previously shown to be the 3'-partner of fusion genes in endometrial stromal tumors, is also recurrently involved in the pathogenesis of OFMTs, irrespective of whether they are diagnosed as typical, atypical, or malignant lesions. The PHF1 protein interacts with the polycomb-repressive complex 2 (PRC2), which, in turn, regulates the expression of a variety of developmental genes. Thus, the results indicate that deregulation of PRC2 target genes is crucial for OFMT development.
|
|
| 2. |
- Hofvander, Jakob, et al.
(författare)
-
Comprehensive genetic analysis of a pediatric pleomorphic myxoid liposarcoma reveals near-haploidization and loss of the RB1 gene.
- 2016
-
Ingår i: Histopathology. - : Wiley. - 0309-0167. ; 69:1, s. 141-147
-
Tidskriftsartikel (refereegranskat)abstract
- Pleomorphic myxoid liposarcoma (PML) is an exceptionally rare and poorly studied subtype of liposarcoma, typically occurring in children and adolescents. The few previous genetic studies have shown that PML lacks the gene fusions and amplifications that characterize myxoid liposarcoma, atypical lipomatous tumor, and dedifferentiated liposarcoma. To learn more about its pathogenesis, we performed a comprehensive genetic analysis, including chromosome banding, fluorescence in situ hybridization, single nucleotide polymorphism (SNP) array analysis, deep sequencing of the exome (WES) complemented by targeted sequencing of hotspot regions of selected cancer-associated genes, and transcriptome sequencing (RNA-seq), of a PML in a 10-year-old boy.
|
|
| 3. |
- Hofvander, Jakob, et al.
(författare)
-
PHF1 fusions cause distinct gene expression and chromatin accessibility profiles in ossifying fibromyxoid tumors and mesenchymal cells
- 2020
-
Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 33:7, s. 1331-1340
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
