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.

RNA sequencing of sarcomas with simple karyotypes: identification and enrichment of fusion transcripts

“…Previous reports have shown that MIR143HG exon 1 fuses with exon 29 of NOTCH3 leading to an increased expression of the 3′part of NOTCH3. 33 These results are in line with our data, although we could not identify the 5′partner. It could be noted that neither NOTCH3 nor MIR143HG maps to chromosome bands involved in the translocation t(3;7) in this case.…”

“…Glomus tumors belong to the pericytic subgroup of soft tissue tumors, and fusions involving the micro RNA MIR143HG as the 5′ gene with any of NOTCH1, NOTCH2, or NOTCH3 as the 3′partner gene have previously been reported in these tumors. 33 We thus investigated the fusion further. Visualizing the reads generated from RNA-Seq in the Integrative Genomics Viewer (IGV; https://www.broadinstitute.org/igv/home) showed that there were more reads in the 3′part of the NOTCH3 gene, exons 25-33, indicating that this part was expressed at higher levels than the rest of the gene (Supplementary Figure 1) and in agreement with a rearrangement resulting in a split of the gene.…”

Nuclear expression and gain-of-function β-catenin mutation in glomangiopericytoma (sinonasal-type hemangiopericytoma): insight into pathogenesis and a diagnostic marker

“…3 However, MIR143-NOTCH gene fusion often seen in glomus tumor has not been found in glomangiopericytoma. 27 In this study, further differences between glomangiopericytoma and glomus tumor included nuclear b-catenin expression and gain-of-function CTNNB1 mutations in glomangiopericytoma. Previous studies on glomus tumor, by contrast, showed a lack of b-catenin nuclear expression and CTNNB1 activating mutations.…”

Recurrent Mutations within the Amino-Terminal Region of β-Catenin Are Probable Key Molecular Driver Events in Sinonasal Hemangiopericytoma

“…9 Another recent study failed to demonstrate any rearrangements of NOTCH1-3 genes in five cases of SN-HPCs analyzed. 24 Accordingly, absence of similar alterations in SN-HPCs suggested a different, albeit yet unknown, molecular pathway involved in these morphologically distinctive tumors confined to the sinonasal tract.…”