title: Expanding the molecular signature of ossifying fibromyxoid tumors with two novel gene fusions: CREBBP-BCORL1 and KDM2A-WWTR1.
abstract: Ossifying fibromyxoid tumor (OFMT) is an uncommon mesenchymal neoplasm of uncertain differentiation and intermediate malignant potential. Recurrent gene fusions involving either PHF1 or BCOR have been found in 85% of OFMT, including typical and malignant examples. As a subset of OFMT still lack known genetic abnormalities, we identified two OFMTs negative for PHF1 and BCOR rearrangements, which were subjected to transcriptome analysis for fusion discovery. The RNA sequencing found a novel CREBBP-BCORL1 fusion candidate in an axillary mass of a 51 year-old male and a KDM2A-WWTR1 in a thigh mass of a 36 year-old male. The gene fusions were validated by RT-PCR and FISH in the index cases and then screened by FISH on 4 additional OFMTs lacking known fusions. An identical CREBBP-BCORL1 fusion was found in an elbow tumor from a 30 year-old male. Both OFMTs with CREBBP-BCORL1 fusions had areas of typical OFMT morphology, exhibiting uniform round to epithelioid cells arranged in cords or nesting pattern in a fibromyxoid stroma. The OFMT with KDM2A-WWTR1 fusion involved dermis and superficial subcutis, being composed of ovoid cells in a fibromyxoid background with hyalinized giant rosettes. The S100 immunoreactivity ranged from very focal to absent. Similar to other known fusion genes in OFMT, BCORL1, CREBBP and KDM2A are also involved in histone modification. In summary, we expand the spectrum of molecular abnormalities in OFMT with 2 novel fusions, CREBBP-BCORL1 and KDM2A-WWTR1, further implicating the epigenetic deregulation as the leading pathogenetic mechanism in OFMT. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Yu-Chien
authors.initials: YC
authors.lastname: Kao
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Yun-Shao
authors.initials: YS
authors.lastname: Sung
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.|Department of Anatomical Pathology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Shih-Chiang
authors.initials: SC
authors.lastname: Huang
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology; D050882:CREB-Binding Protein / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics; D005350:Fibroma / Q000235:genetics* / Q000473:pathology; D018214:Fibroma, Ossifying / Q000235:genetics* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000473:pathology; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins
chemical_list: C521111:BCORL1 protein, human; D014408:Biomarkers, Tumor; D044783:F-Box Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; D050882:CREB-Binding Protein; C494363:CREBBP protein, human