BRAF and KRAS Mutations in Sporadic Glomus Tumors

Chakrapani, Andrea; Warrick, Andrea; Nelson, Dylan; Beadling, Carol; Corless, Christopher L.

doi:10.1097/dad.0b013e31823931b4

Cited by 41 publications

(31 citation statements)

References 9 publications

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“…Furthermore, an association between digital glomus tumor and neurofibromatosis has been reported, with a biallelic inactivation of NF1 proposed as the mechanism of glomus tumor formation in this setting (Brems et al, 2009). A small rate of BRAF and KRAS mutations have been detected in sporadic soft tissue GT, which appears to be within the expected range of mutations described in other tumor types (Chakrapani et al, 2012).…”

Section: Discussionmentioning

confidence: 92%

Novel MIR143‐NOTCH fusions in benign and malignant glomus tumors

Mosquera

Sboner

Zhang

et al. 2013

Genes Chromosomes & Cancer

158

118

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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.

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Section: Discussionmentioning

confidence: 92%

Novel MIR143‐NOTCH fusions in benign and malignant glomus tumors

Mosquera

Sboner

Zhang

et al. 2013

Genes Chromosomes & Cancer

158

118

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“…Previous studies on glomus tumor, by contrast, showed a lack of b-catenin nuclear expression and CTNNB1 activating mutations. 19,28 Therefore, nuclear b-catenin expression and the presence of CTNNB1 mutations can be useful in distinguishing glomangiopericytoma and glomus tumor.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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Glomangiopericytoma (sinonasal-type hemangiopericytoma) is a rare mesenchymal neoplasm with myoid phenotype (smooth muscle actin-positive), which distinguishes this tumor from soft tissue hemangiopericytoma/solitary fibrous tumor. Molecular genetic changes underlying the pathogenesis of glomangiopericytoma are not known. In this study, 13 well-characterized glomangiopericytomas were immunohistochemically evaluated for b-catenin expression. All analyzed tumors showed strong expression and nuclear accumulation of b-catenin. Following this observation, b-catenin glycogen serine kinase-3 beta phosphorylation region, encoded by exon 3, was PCR amplified in all cases and evaluated for mutations using Sanger sequencing. Heterozygous mutations were identified in 12 of 13 tumors. All mutations consisted of single-nucleotide substitutions: three in codon 32 (c.94G4C (n ¼ 2) and c.95A4T), four in codon 33 (two each c.98C4G and c.98C4T), two in codon 37 (c.109T4G), one in codon 41 (c.121A4G), and two in codon 45 (c.133T4C). At the protein level, these substitutions would lead to p.D32H, p.D32V, p.S33C, p.S33F, p.S37A, p.T41A, and p.S45L mutations, respectively. Previously, similar mutations have been reported in different types of cancers and shown to trigger activation of b-catenin signaling. All analyzed glomangiopericytomas showed prominent nuclear expression of cyclin D1, as previously shown for tumors with nuclear expression of b-catenin as a sign of oncogenic activation. These results demonstrate that mutational activation of b-catenin and associated cyclin D1 overexpression may be central events in the pathogenesis of glomangiopericytoma. In additon, nuclear accumulation of b-catenin is a diagnostic marker for glomangiopericytoma. Modern Pathology (2015) 28, 715-720; doi:10.1038/modpathol.2014.161; published online 28 November 2014Glomangiopericytoma (sinonasal-type hemangiopericytoma) is a rare mesenchymal neoplasm of the nasal cavity and sinuses of low biologic potential. [1][2][3][4] It shows a myoid phenotype with consistent expression of smooth muscle actin. 3 b-Catenin, a cadherin-associated membrane protein, participates in the regulation of cell-to-cell adhesion and in some circumstances, also gene transcription as a nuclear protein, a terminal component of the canonical Wnt-signaling pathway. Aberrant expression of b-catenin encoded by CTNNB1 gene is a well-known event in tumorigenesis and tumor progression. 5,6 Among soft tissue tumors, somatic mutations in CTNNB1 are well known in the pathogenesis of sporadic desmoid-type fibromatosis. 7,8 These mutations cluster in CTNNB1 glycogen serine kinase-3 beta (GSK3b) phosphorylation region and constitutionally activate b-catenin signal by upholding cellular b-catenin levels. This happens via interference of ubiquitin-mediated proteolytic degradation by elimination of the phosphorylation sites necessary for ubiquitin action. 7,8 Accumulation of b-catenin in turn results in nuclear translocation, which is a telltale sign of a mutation, typically seen in sporadic de...

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“…Glomus tumours may be associated with neurofibromatosis-1, 41,42 and a subset of sporadic cases have been associated with BRAF (V600E) or KRAS (G12A) mutations. 43 After publication of the WHO classification, NOTCH mutations (of either NOTCH2 or NOTCH3) have also been demonstrated to be present in some glomus tumours. 44 …”

Section: Pericytic (Perivascular) Tumoursmentioning

confidence: 97%