CARMN‐NOTCH2 fusion transcript drives high NOTCH2 expression in glomus tumors of the upper digestive tract

Abstract

Glomus tumors (GTs) are perivascular tumors mostly occurring in the distal extremities. Rare cases arise in the digestive tract and may be misdiagnosed with neuroendocrine or gastrointestinal stromal tumors. We aimed to specify the features of GT of the upper digestive tract. Clinical, histological, phenotypic, and molecular features of 16 digestive GTs were analyzed, of whom two underwent whole exome and RNA sequencing to search for gene alterations. RNA‐sequencing disclosed a t(1:5)(p13;q32) translocation, which resulted in the fusion of CARMN and NOTCH2 in two GTs. The fusion gene encoded a protein sequence corresponding to the NOTCH2 intracellular domain that functions as transcription factor. These finding was supported by high expression of genes targeted by NOTCH. The CARMN‐NOTCH2 translocation was detected in 14 out of 16 (88%) GTs of the upper digestive tract; but in only in two out of six cutaneous GTs (33%). Most digestive GT arose from the stomach (n = 13), and the others from duodenal (2) or oesophagous (1). Nuclear expression of NOTCH2 was detected in the 14 cases containing the fusion transcripts. The CARMN‐NOTCH2 fusion transcript may contribute to activation of the NOTCH2 pathway in GT and drive tumor development. The high frequency of this translocation in GT of the upper digestive track suggest that detection of nuclear NOTCH2 expression may be useful diagnostic biomarker of these tumors.

Gastroesophageal Glomus Tumors

“…CARMN is a long-noncoding RNA that is expressed in vascular smooth muscle cells, and it contains MIR143 and MIR145 which were previously implicated specifically in NOTCH gene fusions. NOTCH2 fusions are identified in both benign and malignant glomus tumors of the gastrointestinal tract,4 and a recent immunohistochemistry study showed that these fusions drove nuclear overexpression of NOTCH2 in 14 of 16 sequenced upper gastrointestinal glomus tumors (88%) 5. We identified NOTCH2 alterations in 80% of both benign and malignant glomus tumors, including frequent CARMN :: NOTCH2 fusions.…”

“…NOTCH2 fusions are identified in both benign and malignant glomus tumors of the gastrointestinal tract, 4 and a recent immunohistochemistry study showed that these fusions drove nuclear overexpression of NOTCH2 in 14 of 16 sequenced upper gastrointestinal glomus tumors (88%). 5 We identified NOTCH2 alterations in 80% of both benign and malignant glomus tumors, including frequent CARMN::NOTCH2 fusions. We possibly underestimated the number of NOTCH2 fusion events because the DNA sequencing panel that we used had somewhat limited sensitivity for gene fusions.…”

“…[3][4][5] CARMN::NOTCH2 fusions are more common in gastric glomus tumors than in glomus tumors at other sites, with a reported frequency of ∼80% to 90%. 5 These fusions are present in both indolent and aggressive gastroesophageal glomus tumors and thus do not predict clinical behavior.…”

PDGFRB and NOTCH3 Mutations are Detectable in a Wider Range of Pericytic Tumors, Including Myopericytomas, Angioleiomyomas, Glomus Tumors, and Their Combined Tumors

“…11 CARMN is also described as fusion partner of NOTCH2 in glomus tumors of the upper digestive tract. 13 Our FISH analysis did not reveal SRF rearrangement in the pericytic tumors examined, but identi ed MIR143/NOTCH2 gene fusion in two glomus tumors. None of the examined tumors were found to exhibit simultaneous gene mutations and rearrangements, supporting the notion that PDGFRB/NOTCH3 mutations and SRF or NOTCH rearrangements are mutually exclusive molecular genetic abnormalities.…”

“…There are no widely accepted criteria to classify combined pericytic tumors, and they are generally described based on their predominant histologic patterns. 2 Recent studies have revealed genetic abnormalities such as platelet-derived growth factor receptor-beta (PDGFRB) mutation, [3][4][5][6][7] NOTCH receptor 3 (NOTCH3) mutation, 4,8 serum response factor (SRF)-rearrangement, 9,10 and NOTCH-rearrangement [11][12][13] as associated with various pericytic tumors. Among these abnormalities, PDGFRB germline mutations have been identi ed in cases of familial infantile myo bromatoses, [3][4][5] whereas PDGFRB somatic mutations are associated with sporadic myo bromas, myopericytomas, and myopericytomatoses.…”