A novel <i>GTF2I/NCOA2</i> fusion gene emphasizes the role of <i>NCOA2</i> in soft tissue angiofibroma development

Arbajian, Elsa; Magnusson, Linda; Mertens, Fredrik; Domanski, Henryk A.; Steyern, Fredrik Vult von; Nord, Karolin Hansén

doi:10.1002/gcc.22033

Cited by 51 publications

(49 citation statements)

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“…7 Translocations involving NCOA2 have been observed in mesenchymal chondrosarcoma, spindle cell rhabdomyosarcoma, prostate cancer, colon cancer, acute leukemia, and soft tissue angiofibroma, whereas ETV3 abnormalities have been For [6][7][8][9] Neoplastic associations of ICH are limited to case reports that include patients with mast cell leukemia, acute myeloid leukemia, and B-cell lymphoma.…”

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confidence: 99%

ETV3-NCOA2 in indeterminate cell histiocytosis: clonal translocation supports sui generis

Brown

Kwong

McCalmont

et al. 2015

Blood

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Indeterminate cell histiocytosis (ICH) is a rare and controversial disorder first described by Wood et al 1 in 1985. ICH is characterized by a nonepidermotropic histiocytic infiltrate with immunohistochemical features that overlap with Langerhans cells (LCs) and nonLCs of monocyte-macrophage-dendritic cell lineage.1 It is unclear whether ICH is distinct from Langerhans cell histiocytosis (LCH) or instead represents a variant form of LCH. The gold standard for distinguishing ICH from LCH is demonstration of the absence of Birbeck granules by electron microscopy or, more practically, through use of langerin (CD207) immunohistochemistry (IHC), which is positive in LCH and non-reactive in ICH.2 Although LCH is understood to be a clonal proliferation, there has not been sufficient support for a common molecular pathway in ICH in the literature to date, leading some authors to consider ICH a reactive condition. Herein, we present 3 cases of ICH with a recurrent ETV3-NCOA2 translocation. This molecular finding provides evidence that ICH is a true clonal entity deserving of separate classification.Patient 1 was a 62-year-old woman who presented with a 30-year history of innumerable dome-shaped smooth red and brown papules and nodules scattered diffusely over her face, chest, back, and extremities. Skin biopsy demonstrated a dermal infiltrate of mononuclear histiocytes highlighted by CD1a and CD68 without langerin reactivity. Scattered mature lymphocytes and rare eosinophils were intermixed. S100 was positive in 5% of the histiocytic infiltrate. Electron microscopy confirmed the absence of Birbeck granules. Targeted next-generation sequencing was performed by Foundation Medicine (Cambridge, MA) using the previously described FoundationOne assay, 3 and it revealed an ETV3-NCOA2 gene fusion characterized as 59-ETV3(x1-4)1 NCOA2(x14-23)-39 resulting in an aberrant NCOA2. Other aberrant mutations, including those involving the RAS-RAF-MEK pathway, were not found. BRAF V600E IHC was negative. Fluorescence in situ hybridization (FISH) for the ETV3-NCOA2 translocation was positive (Figure 1, inset).Patient 2 was a 51-year-old woman who presented with a severalweek history of diffuse nonpruritic papules involving her arms, legs, neck, scalp, face, chest, and back. Histopathologic examination of a skin biopsy demonstrated a dermal infiltrate composed of mononuclear histiocytes with eosinophilic cytoplasm and admixed mature-appearing lymphocytes. The histiocytes were positive for S100, CD68, and CD1a, whereas langerin and BRAF V600E IHC were negative. FISH testing for the ETV3-NCOA2 translocation was positive (Figure 1).Patient 3 was an 81-year-old man who presented with a solitary lesion on the upper arm which had been present for approximately 6 months. Biopsy showed a multinodular dermal infiltrate of large, oval cells with abundant pale eosinophilic cytoplasm and reniform nuclei. The lesional cells were positive for S100, CD68, and CD1a, whereas langerin and BRAF V600E IHC were negative. FISH testing for the ETV3-NCOA2 translo...

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confidence: 99%

ETV3-NCOA2 in indeterminate cell histiocytosis: clonal translocation supports sui generis

Brown

Kwong

McCalmont

et al. 2015

Blood

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“…Interestingly, GTF2I has also been shown to regulate nuclear translocation of ERK1/2 upon mitogenic signaling [31], and indicates an indirect role of GTF2I in activation of the MAPK pathway. Occurrence of additional GTF2I -fusions; GTF2I-BRAF 4–10 (primary melanoma) [29], GTF2I-NCOA2 (soft tissue angiofibroma development) [34] and GTF2I-RARA (acute promyelocytic leukemia) [35], further supports a oncogenic role. In the present study, the GTF2I promoter appears to be stronger than the KIAA1549 indicated by the elevated expression of both the GTF2I-BRAF fusion and the GTF2I transcript.…”

Section: Discussionmentioning

confidence: 99%

A new GTF2I-BRAF fusion mediating MAPK pathway activation in pilocytic astrocytoma

et al. 2017

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Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. A recurrent feature of PA is deregulation of the mitogen activated protein kinase (MAPK) pathway most often through KIAA1549-BRAF fusion, but also by other BRAF- or RAF1-gene fusions and point mutations (e.g. BRAFV600E). These features may serve as diagnostic and prognostic markers, and also facilitate development of targeted therapy. The aims of this study were to characterize the genetic alterations underlying the development of PA in six tumor cases, and evaluate methods for fusion oncogene detection. Using a combined analysis of RNA sequencing and copy number variation data we identified a new BRAF fusion involving the 5’ gene fusion partner GTF2I (7q11.23), not previously described in PA. The new GTF2I-BRAF 19–10 fusion was found in one case, while the other five cases harbored the frequent KIAA1549-BRAF 16–9 fusion gene. Similar to other BRAF fusions, the GTF2I-BRAF fusion retains an intact BRAF kinase domain while the inhibitory N-terminal domain is lost. Functional studies on GTF2I-BRAF showed elevated MAPK pathway activation compared to BRAFWT. Comparing fusion detection methods, we found Fluorescence in situ hybridization with BRAF break apart probe as the most sensitive method for detection of different BRAF rearrangements (GTF2I-BRAF and KIAA1549-BRAF). Our finding of a new BRAF fusion in PA further emphasis the important role of B-Raf in tumorigenesis of these tumor types. Moreover, the consistency and growing list of BRAF/RAF gene fusions suggests these rearrangements to be informative tumor markers in molecular diagnostics, which could guide future treatment strategies.

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“…NCOA2 is well known for its involvement in chimeric transcripts in hematologic malignancies and soft tissue tumors. It has been reported to be fused with different partners: KAT6A ‐ NCOA2 (also known as MOZ ‐ TIF2 ) was found in acute myeloid leukemia (AML),20, 21 ETV6 (TEL)‐NCOA2 was reported in childhood acute leukemia, PAX3‐NCOA2 in alveolar rhabdomyosarcoma,22 HEY1‐NCOA2 in mesenchymal chondrosarcomas,23, 24 SRF‐NCOA2 , TEAD1‐NCOA2 , and VGLL2‐NCOA2 in rhabdomyosarcomas,25, 26 and AHRR‐NCOA2 27 and GTF2‐NCOA2 28 in angiofibromas. In all the mentioned fusions, NCOA2 is the 3’‐partner gene, as it was in the present case.…”

Section: Discussionmentioning

confidence: 99%

RNA‐sequencing identifies novel GREB1‐NCOA2 fusion gene in a uterine sarcoma with the chromosomal translocation t(2;8)(p25;q13)

Brunetti

Panagopoulos

Gorunova

et al. 2017

Genes Chromosomes & Cancer

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Sarcomas account for 3% of all uterine malignancies and many of them are characterized by acquired, specific fusion genes whose detection has increased pathogenetic knowledge and diagnostic precision. We describe a novel fusion gene, GREB1‐NCOA2, detected by transcriptome sequencing and validated by reverse transcriptase polymerase chain reaction and Sanger sequencing in an undifferentiated uterine sarcoma. The chimeric transcript was an in‐frame fusion between exon 3 of GREB1 and exon 15 of NCOA2. The fusion is reported here for the first time, but it involves the GREB1 gene, an important promoter of tumor growth and progression, and NCOA2 which is known to be involved in transcriptional regulation. The alteration and recombination of these genes played a role in the tumorigenesis and/or progression of this sarcoma.

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A novel GTF2I/NCOA2 fusion gene emphasizes the role of NCOA2 in soft tissue angiofibroma development

Cited by 51 publications

References 7 publications

ETV3-NCOA2 in indeterminate cell histiocytosis: clonal translocation supports sui generis

ETV3-NCOA2 in indeterminate cell histiocytosis: clonal translocation supports sui generis

A new GTF2I-BRAF fusion mediating MAPK pathway activation in pilocytic astrocytoma

RNA‐sequencing identifies novel GREB1‐NCOA2 fusion gene in a uterine sarcoma with the chromosomal translocation t(2;8)(p25;q13)

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