USP6 genetic rearrangements in cellular fibroma of tendon sheath

Carter, Jodi M.; Wang, Xiaoke; Dong, Jie; Westendorf, Jennifer J.; Chou, Margaret M.; Oliveira, André M.

doi:10.1038/modpathol.2016.83

Cited by 58 publications

(45 citation statements)

References 29 publications

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“…A break-apart FISH assay is especially useful when there is a single gene fused with a variety of partner genes, as in the case of aneurysmal bone cyst or, now, nodular fasciitis. USP6 rearrangement has also been identified in a variety of other tumors, including cellular fibroma of tendon sheath 31 and giant cell reparative granulomas of the hands and feet (a subset of aneurysmal bone cyst), 32 allowing for the implementation of a single assay across these diseases. Occasionally, unusual patterns may be identified and it can be difficult to determine the clinical significance.…”

Section: Discussionmentioning

confidence: 99%

USP6 activation in nodular fasciitis by promoter-swapping gene fusions

et al. 2017

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Nodular fasciitis is a self-limited myofibroblastic lesion that can be misdiagnosed as a sarcoma as a result of its rapid growth, cellularity, and sometimes prominent mitotic activity. A recurrent translocation t(17;22) has been identified in nodular fasciitis, fusing the coding region of USP6 to the promoter region of MYH9, and resulting in increased USP6 expression. A subset of cases show USP6 rearrangement without the typical fusion variants by RT-PCR, or any MYH9 rearrangement by FISH. We sought to further characterize such tumors using molecular diagnostic assays. A novel RT-PCR assay was designed to detect the two known MYH9-USP6 fusion types in formalin-fixed paraffin-embedded and frozen tissue, and a break-apart FISH assay was designed to detect USP6 rearrangement. Twenty-six cases of nodular fasciitis diagnosed between 2002 and 2013 were retrieved from the pathology files of our institutions and were confirmed to be positive by FISH and/or RT-PCR. Seven samples showed USP6 rearrangement by FISH but were negative for MYH9-USP6 fusion by RT-PCR; these cases were subjected to a next-generation sequencing assay utilizing anchored multiplex PCR technology. This assay targets a single partner gene associated with fusions in bone and soft tissue tumors for agnostic detection of gene fusion partners. Novel fusion partners were identified in all seven cases and confirmed by RT-PCR. Structurally, all fusions consisted of the juxtaposition of the entire coding region of USP6 with the promoter of the partner gene, driving increased USP6 expression. This study confirms the neoplastic nature of nodular fasciitis, defines additional pathogenic fusion partners, and adds to the growing body of literature on USP6-associated neoplasia. Given the diagnostic challenges of these tumors, molecular assays can be useful ancillary tools; however, the prevalence of promoter swapping must be recognized when interpreting results.

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Section: Discussionmentioning

confidence: 99%

USP6 activation in nodular fasciitis by promoter-swapping gene fusions

et al. 2017

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“…Break‐apart fluorescence in situ hybridization (FISH) was performed on interphase nuclei for detection of USP6 rearrangement as previously described . Formalin‐fixed, paraffin‐embedded tissues are cut at 5 μm and mounted on glass slides.…”

Section: Methodsmentioning

confidence: 99%

“…Break-apart fluorescence in situ hybridization (FISH) was performed on interphase nuclei for detection of USP6 rearrangement as previously described. 12,13 Formalin-fixed, paraffin-embedded tissues are cut at 5 μm and mounted on glass slides. The probe set made up of commercially available bacterial artificial chromosome clones was hybridized to the appropriate target areas and two technologists each analyzed 50 interphase nuclei (100 total).…”

Section: Usp6 Fluorescence In Situ Hybridizationmentioning

confidence: 99%

“…USP6 is usually not expressed in non‐neoplastic mesenchymal tissue, but is aberrantly expressed at high levels in osteoblastoma, myofibroma, and Ewing sarcoma . 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 .…”

Section: Introductionmentioning

confidence: 99%

“…11 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. [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%

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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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Utility of an anchored multiplex polymerase chain reaction‐based fusion assay for diagnosis of soft tissue tumors in cytology

Helland,

Fisch,

Chebib

2024

Cancer Cytopathology

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BackgroundFine‐needle aspiration specimens from soft tissue tumors are complicated by lack of tissue architecture and limited material for ancillary testing. There are little data on the feasibility of next‐generation sequencing techniques for fusion detection on soft tissue cytology specimens. This study explored the role of an anchored multiplex polymerase chain reaction (PCR)‐based gene fusion assay in aiding the diagnosis of mesenchymal neoplasms on cytology samples.MethodsThe laboratory information system was queried for cytology specimens that had undergone testing by anchored multiplex PCR. After exclusion of epithelial and hematolymphoid neoplasms, clinical and pathologic information was collected on the remaining cases.ResultsThere were 1609 cytology specimens tested with anchored multiplex PCR. Of these, 48 (3%) were cytology specimens from mesenchymal tumors. Anchored multiplex PCR was positive for a reportable fusion transcript in 14 of 48 cases (29%); there was no fusion detected in 32 cases (67%), and there was insufficient tissue for analysis in two cases (4%). The detectable fusion partners included ALK (n = 4), STAT6 (n = 4), EWSR1 (n = 3), and one each of SS18, YAP1, and PHF1. Of the cases in which a fusion partner was detected, eight of 14 were disease‐defining on cytology preparation, and six of 14 provided molecular confirmation of a metastatic focus of a previously diagnosed tumor.ConclusionsThe anchored, multiplex PCR‐based gene fusion assay is a powerful orthogonal tool in helping diagnose mesenchymal neoplasms on cytology specimens. The material obtained for cytologic analysis yields sufficient quality/quantity of tissue in the majority of cases tested.

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USP6 genetic rearrangements in cellular fibroma of tendon sheath

Cited by 58 publications

References 29 publications

USP6 activation in nodular fasciitis by promoter-swapping gene fusions

USP6 activation in nodular fasciitis by promoter-swapping gene fusions

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

Utility of an anchored multiplex polymerase chain reaction‐based fusion assay for diagnosis of soft tissue tumors in cytology

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