title: Novel MIR143-NOTCH fusions in benign and malignant glomus tumors.
abstract: Glomus tumors (GT) have been classified among tumors of perivascular smooth muscle differentiation, together with myopericytoma, myofibroma/tosis, and angioleiomyoma, based on their morphologic overlap. However, no molecular studies have been carried out to date to investigate their genetic phenotype and to confirm their shared pathogenesis. RNA sequencing was performed in three index cases (GT1, malignant GT; GT2, benign GT and M1, multifocal myopericytoma), followed by FusionSeq data analysis, a modular computational tool developed to discover gene fusions from paired-end RNA-seq data. A gene fusion involving MIR143 in band 5q32 was identified in both GTs with either NOTCH2 in 1p13 in GT1 or NOTCH1 in 9q34 in GT2, but none in M1. After being validated by FISH and RT-PCR, these abnormalities were screened on 33 GTs, 6 myopericytomas, 9 myofibroma/toses, 18 angioleiomyomas and in a control group of 5 sino-nasal hemangiopericytomas. Overall NOTCH2 gene rearrangements were identified in 52% of GT, including all malignant cases and one NF1-related GT. No additional cases showed NOTCH1 rearrangement. As NOTCH3 shares similar functions with NOTCH2 in regulating vascular smooth muscle development, the study group was also investigated for abnormalities in this gene by FISH. Indeed, NOTCH3 rearrangements were identified in 9% of GTs, all present in benign soft tissue GT, one case being fused to MIR143. Only 1/18 angioleiomyomas showed NOTCH2 gene rearrangement, while all the myopericytomas and myofibroma/toses were negative. In summary, we describe novel NOTCH1-3 rearrangements in benign and malignant, visceral, and soft tissue GTs.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, NY.
authors.forename: Juan-Miguel
authors.initials: JM
authors.lastname: Mosquera
authors.forename: Andrea
authors.initials: A
authors.lastname: Sboner
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chen
authors.forename: Yun-Shao
authors.initials: YS
authors.lastname: Sung
authors.forename: Hsiao-Wei
authors.initials: HW
authors.lastname: Chen
authors.forename: Narasimhan P
authors.initials: NP
authors.lastname: Agaram
authors.forename: Daniel
authors.initials: D
authors.lastname: Briskin
authors.forename: Basma M
authors.initials: BM
authors.lastname: Basha
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D050939:Gene Fusion; D015321:Gene Rearrangement; D005918:Glomus Tumor / Q000235:genetics* / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D051880:Receptors, Notch / Q000235:genetics*; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C542359:MIRN143 microRNA, human; D035683:MicroRNAs; D051880:Receptors, Notch