title: Novel ZC3H7B-BCOR, MEAF6-PHF1, and EPC1-PHF1 fusions in ossifying fibromyxoid tumors--molecular characterization shows genetic overlap with endometrial stromal sarcoma.
abstract: PHF1 gene rearrangements have been recently described in around 50% of ossifying fibromyxoid tumors (OFMT) including benign and malignant cases, with a small subset showing EP400-PHF1 fusions. In the remaining cases no alternative gene fusions have been identified. PHF1-negative OFMT, especially if lacking S100 protein staining or peripheral ossification, are difficult to diagnose and distinguish from other soft tissue mimics. In seeking more comprehensive molecular characterization, we investigated a large cohort of 39 OFMT of various anatomic sites, immunoprofiles and grades of malignancy. Tumors were screened for PHF1 and EP400 rearrangements by FISH. RNA sequencing was performed in two index cases (OFMT1, OFMT3), negative for EP400-PHF1 fusions, followed by FusionSeq data analysis, a modular computational tool developed to discover gene fusions from paired-end RNA-seq data. Two novel fusions were identified ZC3H7B-BCOR in OFMT1 and MEAF6-PHF1 in OFMT3. After being validated by FISH and RT-PCR, these abnormalities were screened on the remaining cases. With these additional gene fusions, 33/39 (85%) of OFMTs demonstrated recurrent gene rearrangements, which can be used as molecular markers in challenging cases. The most common abnormality is PHF1 gene rearrangement (80%), being present in benign, atypical and malignant lesions, with fusion to EP400 in 44% of cases. ZC3H7B-BCOR and MEAF6-PHF1 fusions occurred predominantly in S100 protein-negative and malignant OFMT. As similar gene fusions were reported in endometrial stromal sarcomas, we screened for potential gene abnormalities in JAZF1 and EPC1 by FISH and found two additional cases with EPC1-PHF1 fusions.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Yun-Shao
authors.initials: YS
authors.lastname: Sung
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Hsiao-Wei
authors.initials: HW
authors.lastname: Chen
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: Narasimhan P
authors.initials: NP
authors.lastname: Agaram
authors.forename: Andrea
authors.initials: A
authors.lastname: Sboner
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Fletcher
mesh_terms: D002114:Calcinosis / Q000378:metabolism* / Q000473:pathology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D050939:Gene Fusion; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D009418:S100 Proteins / Q000235:genetics; D018203:Sarcoma, Endometrial Stromal / Q000378:metabolism* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C411984:BCOR protein, human; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C485469:EPC1 protein, human; D015514:Oncogene Proteins, Fusion; C112309:PHF1 protein, human; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D009418:S100 Proteins; D014157:Transcription Factors; C484647:ZC3H7B protein, human