USP6 activation in nodular fasciitis by promoter-swapping gene fusions

Patel, Nimesh R.; Chrisinger, John S.A.; Demicco, Elizabeth G.; Sarabia, Stephen F.; Reuther, Jacquelyn; Kumar, Erica; Oliveira, André M.; Billings, Steven D.; Bovée, Judith V.M.G.; Roy, Angshumoy; López‐Terrada, Dolores; Wang, Wei Lien

doi:10.1038/modpathol.2017.78

Cited by 91 publications

(80 citation statements)

References 66 publications

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“…Interestingly, nodular fasciitis, cellular fibromas of tendon sheath, fibro‐osseous pseudotumor of digits, and myositis ossificans are also characterized by reciprocal translocations involving USP6 , suggesting a shared underlying pathobiology in these disorders . In nodular fasciitis, a soft tissue neoplasm characterized by a loose arrangement of fibroblasts and myofibroblasts, the most common rearrangement leads to a MYH9‐USP6 promoter swap fusion . Some fusion partners appear to be shared across neoplasms; for instance, CTNNB1‐USP6 and SPARC‐USP6 fusions have been identified in both nodular fasciitis and ABCs …”

Section: Introductionmentioning

confidence: 99%

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RNA sequencing identifies a novel USP9X‐USP6 promoter swap gene fusion in a primary aneurysmal bone cyst

Blackburn

Davila

Jackson

et al. 2019

Genes Chromosomes & Cancer

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Primary aneurysmal bone cyst (ABC) is a benign multiloculated cystic lesion of bone that is defined cytogenetically by USP6 gene rearrangements. Rearrangements involving USP6 are promoter swaps, usually generated by fusion of the noncoding upstream exons of different partner genes with exon 1 or 2 of USP6, thus leading to transcriptional upregulation of full‐length USP6 coding sequence. Testing for USP6 rearrangements is used diagnostically to distinguish it from secondary ABC and other giant cell‐rich primary bone tumors. In this report, we present a case of a 16‐year‐old male with a primary ABC of the left distal femur. USP6 break apart fluorescence in situ hybridization was positive for a rearrangement and conventional chromosome analysis identified a reciprocal X;17 translocation. In order to identify the putative USP6 fusion partner, we performed RNA sequencing and uncovered a novel USP9X‐USP6 promoter swap fusion. This result was confirmed by reverse transcription‐polymerase chain reaction (RT‐PCR) and by mate pair sequencing thus showing the utility of these alternative methodologies in identifying novel fusion candidates. Ubiquitin‐specific protease 9X (USP9X), like USP6, encodes a highly conserved substrate‐specific deubiquitylating enzyme. USP9X is highly expressed in a number of tissue types and acts as both an oncogene and tumor suppressor in several human cancers. We conclude that oncogenic activation of USP6 via USP9X promoter exchange represents a novel driver of primary ABC formation.

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Section: Introductionmentioning

confidence: 99%

“…[12][13][14][15] In nodular fasciitis, a soft tissue neoplasm characterized by a loose arrangement of fibroblasts and myofibroblasts, the most common rearrangement leads to a MYH9-USP6 promoter swap fusion. 16 Some fusion partners appear to be shared across neoplasms;…”

Section: Introductionmentioning

confidence: 99%

RNA sequencing identifies a novel USP9X‐USP6 promoter swap gene fusion in a primary aneurysmal bone cyst

Blackburn

Davila

Jackson

et al. 2019

Genes Chromosomes & Cancer

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“…Furthermore, it offers the opportunity to discover novel fusion partners, as was shown by several studies. 7,8 In this study, the applicability of AMP-based targeted NGS for the detection of genetic translocations in bone and soft tissue tumors was investigated during routine diagnostics in a tertiary referral practice, and results were compared with conventional FISH, reverse transcriptase-PCR and immunohistochemistry when available. In discordant cases, further analysis was performed with additional FISH probes and reverse transcriptase-PCR primers.…”

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confidence: 99%

Molecular Analysis of Gene Fusions in Bone and Soft Tissue Tumors by Anchored Multiplex PCR–Based Targeted Next-Generation Sequencing

Lam

Cleton‐Jansen

Cleven

et al. 2018

The Journal of Molecular Diagnostics

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Molecular assays for translocation detection in bone and soft tissue tumors have gradually been incorporated into routine diagnostics. However, conventional methods such as fluorescence in situ hybridization (FISH) and reverse transcriptase-PCR come with several drawbacks. In this study, the applicability of a novel technique termed anchored multiplex PCR (AMP) for next-generation sequencing (NGS), using the Archer FusionPlex Sarcoma kit, aimed at 26 genes, was evaluated and compared with FISH and reverse transcriptase-PCR. In case of discrepant results, further analysis occurred with a third independent technique. Eighty-one samples were subjected to AMP-based targeted NGS, and 86% (n = 70) were successfully conducted and were either fusion positive (n = 48) or fusion negative, but met all criteria for good quality (n = 22). A concordance of 90% was found between NGS and conventional techniques. AMP-based targeted NGS showed superior results, as in four cases reverse transcriptase-PCR and FISH were false negative. Moreover, because the assay targets one partner of a gene fusion, novel or rare fusion partners can be identified. Indeed, it revealed COL1A1 and SEC31A as novel fusion partners for USP6 in nodular fasciitis. Despite the fact that fusions involving genes outside the selectively captured region cannot be detected and false-negative results due to poor quality samples can be encountered, this method has demonstrated excellent diagnostic utility for translocation detection in sarcomas.

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“…In addition, nodular fasciitis shows uniform growth with circumscription and the presence of plump fibroblasts in a myxoid matrix, resembling tissue culture . Nodular fasciitis represents a self‐limiting neoplastic proliferation harboring USP6 gene rearrangement, with the most common fusion partner being the MYH9 gene …”

Section: Discussionmentioning

confidence: 99%

Cutaneous aneurysmal bone cyst—First report of a case and literature review

Chung¹,

Petelin

Pižem

et al. 2019

J Cutan Pathol

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Aneurysmal bone cyst (ABC) is a benign, expansile, multiloculated and blood-filled cystic lesion most commonly involving bones. We report herein the case of a 78-year-old woman with a dermal ABC located in the skin of the right foot. Histologically, the lesion displayed characteristic features of ABC, including blood-filled cystic spaces lined by loose connective tissue, admixed with solid areas composed of spindle cells and osteoclast-like giant cells, associated with foci of woven bone formation and matrix calcification ("blue bone" formation). Fewer than 30 cases of extraosseous ABCs have been described in soft tissues and, to the best of our knowledge, ABC primarily occurring in the skin, not associated with an underlying lesion in the bone, has not so far been reported in the literature. K E Y W O R D Saneurysmal bone cyst, cutaneous, dermal, USP6 gene translocation

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USP6 activation in nodular fasciitis by promoter-swapping gene fusions

Cited by 91 publications

References 66 publications

RNA sequencing identifies a novel USP9X‐USP6 promoter swap gene fusion in a primary aneurysmal bone cyst

RNA sequencing identifies a novel USP9X‐USP6 promoter swap gene fusion in a primary aneurysmal bone cyst

Molecular Analysis of Gene Fusions in Bone and Soft Tissue Tumors by Anchored Multiplex PCR–Based Targeted Next-Generation Sequencing

Cutaneous aneurysmal bone cyst—First report of a case and literature review

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