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

Patrick R. Blackburn, Jaime I. Davila, Rory A. Jackson, Numrah Fadra, Mazen A. Atiq, Beth A. Pitel, Asha A. Nair, Todd J. VanDeWalker, Mark G. Hessler, Sara K. Hovel, Rebecca N. Wehrs, Karen J. Fritchie, Robert Brian Jenkins, Kevin C. Halling, Katherine B. Geiersbach

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalGenes Chromosomes and Cancer
DOIs
StatePublished - Jan 1 2019

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Ubiquitin-Specific Proteases
Aneurysmal Bone Cysts
RNA Sequence Analysis
Gene Fusion
Exons
Bone and Bones
Neoplasms
Gene Rearrangement
Giant Cells
Fluorescence In Situ Hybridization
Oncogenes
Osteogenesis
Femur
Reverse Transcription
Up-Regulation
Chromosomes
Polymerase Chain Reaction
Enzymes
Genes

Keywords

  • aneurysmal bone cyst
  • gene fusion
  • RNA sequencing
  • USP9X-USP6

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

Cite this

Blackburn, P. R., Davila, J. I., Jackson, R. A., Fadra, N., Atiq, M. A., Pitel, B. A., ... Geiersbach, K. B. (2019). RNA sequencing identifies a novel USP9X-USP6 promoter swap gene fusion in a primary aneurysmal bone cyst. Genes Chromosomes and Cancer. https://doi.org/10.1002/gcc.22742

RNA sequencing identifies a novel USP9X-USP6 promoter swap gene fusion in a primary aneurysmal bone cyst. / Blackburn, Patrick R.; Davila, Jaime I.; Jackson, Rory A.; Fadra, Numrah; Atiq, Mazen A.; Pitel, Beth A.; Nair, Asha A.; VanDeWalker, Todd J.; Hessler, Mark G.; Hovel, Sara K.; Wehrs, Rebecca N.; Fritchie, Karen J.; Jenkins, Robert Brian; Halling, Kevin C.; Geiersbach, Katherine B.

In: Genes Chromosomes and Cancer, 01.01.2019.

Research output: Contribution to journalArticle

Blackburn, PR, Davila, JI, Jackson, RA, Fadra, N, Atiq, MA, Pitel, BA, Nair, AA, VanDeWalker, TJ, Hessler, MG, Hovel, SK, Wehrs, RN, Fritchie, KJ, Jenkins, RB, Halling, KC & Geiersbach, KB 2019, 'RNA sequencing identifies a novel USP9X-USP6 promoter swap gene fusion in a primary aneurysmal bone cyst', Genes Chromosomes and Cancer. https://doi.org/10.1002/gcc.22742
Blackburn, Patrick R. ; Davila, Jaime I. ; Jackson, Rory A. ; Fadra, Numrah ; Atiq, Mazen A. ; Pitel, Beth A. ; Nair, Asha A. ; VanDeWalker, Todd J. ; Hessler, Mark G. ; Hovel, Sara K. ; Wehrs, Rebecca N. ; Fritchie, Karen J. ; Jenkins, Robert Brian ; Halling, Kevin C. ; Geiersbach, Katherine B. / RNA sequencing identifies a novel USP9X-USP6 promoter swap gene fusion in a primary aneurysmal bone cyst. In: Genes Chromosomes and Cancer. 2019.
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abstract = "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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AU - Davila, Jaime I.

AU - Jackson, Rory A.

AU - Fadra, Numrah

AU - Atiq, Mazen A.

AU - Pitel, Beth A.

AU - Nair, Asha A.

AU - VanDeWalker, Todd J.

AU - Hessler, Mark G.

AU - Hovel, Sara K.

AU - Wehrs, Rebecca N.

AU - Fritchie, Karen J.

AU - Jenkins, Robert Brian

AU - Halling, Kevin C.

AU - Geiersbach, Katherine B.

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N2 - 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.

AB - 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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