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[Cancer Research 64, 1920-1923, March 15, 2004]
© 2004 American Association for Cancer Research

Advances in Brief

USP6 (Tre2) Fusion Oncogenes in Aneurysmal Bone Cyst

Andre M. Oliveira1,2, Bae-Li Hsi1, Stanislawa Weremowicz1, Andrew E. Rosenberg3, Paola Dal Cin1, Nora Joseph1, Julia A. Bridge4, Antonio R. Perez-Atayde5 and Jonathan A. Fletcher1,6

1 Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; 2 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; 3 Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; 4 Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska; 5 Department of Pathology, Children’s Hospital, Boston, Massachusetts; and 6 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Aneurysmal bone cyst (ABC) is a locally aggressive osseous lesion that typically occurs during the first two decades of life. ABC was regarded historically as a nonneoplastic process, but recent cytogenetic data have shown clonal rearrangements of chromosomal bands 16q22 and 17p13, indicating a neoplastic basis in at least some ABCs. Herein we show that a recurring ABC chromosomal translocation t(16;17)(q22;p13) creates a fusion gene in which the osteoblast cadherin 11 gene (CDH11) promoter region on 16q22 is juxtaposed to the entire ubiquitin-specific protease USP6 (Tre2) coding sequence on 17p13. CDH11-USP6 fusion transcripts were demonstrated only in ABC with t(16;17) but other ABCs had CDH11 or USP6 rearrangements resulting from alternate cytogenetic mechanisms. CDH11 is expressed strongly in bone, and our findings implicate a novel oncogenic mechanism in which deregulated USP6 transcription results from juxtaposition to the highly active CDH11 promoter.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Aneurysmal bone cyst (ABC) is a rapidly growing and locally aggressive osseous lesion that was first described in 1942 by Jaffe and Lichtenstein (1) . ABC affects all age groups but is more commonly found during the first two decades of life (2) . ABC can occur as a de novo lesion or be associated with other benign and malignant bone tumors. Until very recently, ABC was considered a nonneoplastic process of unknown etiology, and this view was supported by several reports of ABCs exhibiting normal karyotypes (3) . However, Panoutsakopoulos et al. (4) reported chromosomal translocation t(16;17)(q22;p13) as a recurrent cytogenetic abnormality in ABC, providing strong evidence for a clonal neoplastic basis in these lesions. Subsequently, Dal Cin et al. (5) demonstrated similar cytogenetic aberrations in solid and extraosseous variants of ABC. Herein we show that the chromosomal translocation t(16;17)(q22;p13) fuses the promoter region of the osteoblast cadherin 11 gene (CDH11) on chromosome 16q22 to the entire coding sequence of the ubiquitin protease (UBP) USP6 gene (also known as Tre2 oncogene) on chromosome 17p13. We also show that CDH11-USP6 might be specific for ABC in that it was not demonstrated in other osseous and nonosseous tumors. CDH11 is highly expressed in bone, indicating that USP6 tumorigenic activity can result from transcriptional up-regulation.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Tumor Samples, Bacterial Artificial Chromosome (BAC) Clone Identification, and DNA Extraction.
Eight cases of primary (de novo) ABC were studied. The samples were obtained from surgical excisions and were histologically characterized according to established criteria (6) .

BAC clones were obtained from Children’s Hospital Oakland Research Institute (Oakland, CA) and Research Genetics (Huntsville, AL). DNA isolation was performed according to a previously reported protocol (7) . After overnight bacterial growth, cell pellets were digested (25 mM Tris-HCL, 50 mM glucose, 10 mM EDTA, 5 mg/ml lysozyme, and 200 µg/ml RNase), and the DNA was precipitated with 5 M potassium acetate and 100% ethanol. BAC DNA was labeled by random priming with either digoxigenin- or biotin-modified nucleotides using the BioPrime DNA Labeling System (Invitrogen, Carlsbad, CA), purified by chromatography using S-200HR MicroSpin columns (Amersham Biosciences, Piscataway, NJ), coprecipitated with 0.3 µg/ml glycogen, 2.5 M ammonium acetate, and 2 volumes of 100% ethanol, and resuspended with hybridization buffer (50% formamide, 10% dextrose sulfate, and 2x SSC) and Cot-1 DNA (Invitrogen).

Fluorescence in Situ Hybridization (FISH) Mapping.
Metaphase harvesting, slide preparation, and trypsin-Giemsa staining for cytogenetic analyses were performed as described previously (8) . Dual color FISH and probe detection were performed, as described, using FITC-antidigoxigenin and Alexa Fluor 594-streptavidin (Molecular Probe, Eugene, OR; Ref. 9 ). Images were captured using a liquid cooled CCD camera (Photometrics, Tucson, AZ).

RNA Isolation, Reverse Transcription-PCR (RT-PCR), and cDNA Sequencing.
RNA was isolated from frozen tissue material after mechanical homogenization and overnight incubation in Trizol (Invitrogen) at 4°C. RNA reverse transcription into cDNA was performed using the GeneAmp RNA PCR kit (Applied Biosystems, Foster City, CA) for 2 h at 42°C using random hexamers. All PCR reactions were performed using the Takara Ex Taq kit with the following parameters for 35 cycles: denaturation at 94°C for 30 s; annealing at 65°C for 30 s; and extension at 72°C for 1 min. The PCR primers included CDH11+83F (5'-GTGAATGGGACCGGGACT-3') and USP6+1781R (5'-CTCGGTGTCCCTTGTCATACTT-3'). The PCR products were gel purified using the QIAquick Gel Extraction kit (Qiagen, Valencia, CA) and sequenced using an ABI PRISM 3100 Genetic Analyzer (Applied Biosystems).


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Identification of ABC Chromosome 17p13 and 16q22 Breakpoints.
Metaphase cell FISH mapping of the chromosome band 17p13 region revealed that BAC RP11-46I8 spanned the 17p13 genomic breakpoint in ABC cases 1 and 2 (Table 1)Citation .;T1 AQ:A> Approximately 40% of the RP11-46I8 FISH signal was retained on the derivative chromosome 17, implicating the ZNF232 and USP6 genes as the most likely targets of the 17p13 rearrangement. Additional FISH analyses with BACs CTD-2006B23, CTD-3231H2, and RP11-124C16 refined the genomic breakpoint to an 8-kb region comprised of USP6 exons 1–3 and sequences upstream of USP6 (Fig. 1, A and C)Citation . The USP6 coding sequence spans from exons 2 to 30, suggesting that the genomic breakpoints might be upstream of the start of the coding sequence.


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  		Table 1 Clinical and cytogenetic features of ABC in this study

 


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  		Fig. 1. Schematic of bacterial artificial chromosome (BAC) clones in relationship to USP6 and ZNF232 at chromosome band 17p13 (A) and in relationship to CDH11 at chromosome band 16q22 (B). Dashed vertical lines indicate the consensus genomic breakpoint regions, as determined by fluorescence in situ hybridization. Representative fluorescence in situ hybridization images in an aneurysmal bone cyst with translocation t(16;17) show USP6 rearrangement, seen as separation of BACs RP11-124C16 and CTD-2367F23 (C); CDH11 rearrangement, seen as splitting of BAC CTD-2326E5 (D); and CDH11-USP6 fusion, seen as juxtaposition of BACs RP11-137A18 and CTD-2367F23 (E).

 
Metaphase FISH mapping of the chromosome band 16q22 region initially localized the genomic breakpoint to a 20-kb region containing the 3'-end of intron 1, exon 2, and intron 2 of the CDH11 cadherin gene (Fig. 1, B and D)Citation . This breakpoint region was then additionally localized to a 10-kb region at the start of CDH11 intron 2 in cases 1, 2, and 3 (Table 1)Citation , using BACs RP11-76J1 and RP11-138B22 (data not shown). The intron 2 breakpoint region is upstream of the CDH11 coding sequence, which begins in CDH11 exon 3. Juxtaposition of CDH11 and USP6 by the t(16;17)(q22;p13) was corroborated by dual-color FISH with BAC RP11-137A18 flanking the 5'-end of CDH11 and BAC CTD-2367F23 flanking the 3'-end of USP6 (Fig. 1E)Citation .

Identification of CDH11-USP6 Fusion Transcript Breakpoints.
CDH11 is expressed strongly in mesenchymal cells, particularly those of osteoblastic differentiation, whereas USP6 expression is expressed predominantly in germ cells (10 , 11) . These known expression profiles, together with the genomic FISH localizations, were most consistent with fusion oncogenes composed of the CDH11 5' untranslated region and the entire USP6 coding sequence. The possibility of CDH11-USP6 fusion transcripts was evaluated in eight ABCs—four of which had t(16;17)—by RT-PCR with a CDH11 exon 1 forward primer (CDH11+83F) and a USP6 exon 2/3 reverse primer (USP6+1781R). CDH11-USP6 fusion products were identified only in the ABC with t(16;17). RT-PCR gel electrophoresis and sequence analyses revealed alternative splicing at the CDH11-USP6 breakpoint region in the ABC with t(16;17), and we refer to the different splicing products as CDH11-USP6 types 1–5 (Fig. 2, A and B)Citation . In type 1, the CDH11 noncoding exon 1 was fused to part of the USP6 noncoding exon 1; in type 2, CDH11 exon 1 was fused to USP6 coding exon 2; in type 3, the CDH11 noncoding exon 2 was fused to the same part of the USP6 non-coding exon 1, as described for type 1; in type 4, CDH11 exon 2 was fused to USP6 exon 2; and in type 5, CDH11 exon 2 was fused to a 58-bp alternate exon upstream of USP6 exon 1 (GenBank accession nos. AY380226, AY38025, AY380223, AY380224, and AY380222, respectively). The fusion breakpoints in all five splicing variants were before the start of the CDH11 coding sequence (CDH11 exon 3) and preserved the USP6 ATG initiation codon, which begins at the second nucleotide of USP6 exon 2. RT-PCR for the reciprocal fusion product (USP6-CDH11) was repeatedly negative in all ABC with cytogenetic t(16;17), suggesting that the CDH11 coding sequences are not essential to the ABC transforming mechanism.



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  		Fig. 2. A, top panel: reverse transcription-PCR demonstrating CDH11-USP6 fusion products only in aneurysmal bone cyst (ABC) with translocation t(16;17)(q22;p13). Lower panel: reverse transcription-PCR for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a control for RNA integrity. B, diagram showing the overall structure of CDH11, USP6, and the predicted CDH11-USP6 fusion transcripts. White areas indicate noncoding exons; gray areas indicate coding sequences. Protein domains are represented by light gray rectangles and include CH, cadherin domain; T, transmembrane domain; CYT, cadherin COOH-terminal cytoplasmic region; TBC, TBC/GAP GTPase domain; and UBP, ubiquitin protease domain. The numbers indicate exon numbers for CDH11 and USP6, and the small white rectangle in the type 5 fusion represents an alternative exon upstream to USP6 known exon 1. C, sequences of the splicing junctions in the CDH11-USP6 fusion genes. The USP6 ATG initiation codon is underlined.

 
CDH11 and USP6 Involvement in Aneurysmal Bone Cyst.
Genomic rearrangements of CDH11 and USP6 were evaluated in ABCs with 16q22 or 17p13 cytogenetic aberrations (Table 1Citation , cases 1–7), and in an ABC that lacked such aberrations (Table 1Citation , case 8), FISH was performed using BAC probes flanking both genes. All ABCs with cytogenetic t(16;17) showed genomic CDH11 and USP6 rearrangement by FISH (Table 1Citation , cases 1–4). By contrast, ABC with cytogenetic 17p13 rearrangements only (in the absence of apparent 16q22 rearrangement), showed rearrangement of the USP6 locus—but not the CDH11 locus—by FISH (Table 1Citation , cases 5 and 6). Similarly, an ABC with cytogenetic 16q22 rearrangement only (in the absence of apparent 17p13 rearrangement), showed rearrangement of the CDH11 locus—but not the USP6 locus—by FISH (Table 1Citation , case 7). As in the ABC with t(16;17), the genomic breakpoint in case 7 was within CDH11 intron 2 and therefore upstream of the CDH11 coding sequence, suggesting that the CDH11 promoter might drive transcriptional up-regulation of an alternative oncogene in this case.

The specificity of the CDH11-USP6 fusion transcript was evaluated by performing RT-PCR for CHD11-USP6 fusion, and dual-color split apart FISH for CDH11 and USP6 rearrangement in various osseous and nonosseous tumors (Fig. 2ACitation and Table 2Citation ). These studies showed no evidence of CDH11 or USP6 rearrangement in any of the non-ABC tumors.


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  		Table 2 RT-PCR results for CDH11-USP6 in non-ABC tumors

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
ABC is a locally aggressive and rapidly growing cystic bone lesion that occurs mainly during the first two decades of life. Although ABC can arise in any anatomical location, metaphyses of the long bones of the lower extremities are most often affected (2) . Histologically, ABC is characterized by multiple hemorrhagic cysts surrounded by fibrous septa composed of a highly mitotic spindle cell proliferation intermixed with osteoclast-type giant cells and reactive woven bone. Until recently, ABC was viewed as a nonneoplastic lesion, but cytogenetic studies have shown convincing evidence of a clonal, neoplastic basis for this disease.

In this study, we demonstrate that the recurrent chromosomal translocation t(16;17)(q22;p13) leads to fusion of the promoter region of the osteoblast cadherin gene CDH11 to the entire coding sequence of the ubiquitin-specific protease USP6 (also known as Tre2). CDH11 maps at the 16q21-q22.1 chromosome band interface and is a member of a large family of cell surface glycoproteins involved in Ca2+-dependent cell-cell adhesion (12) . CDH11 was cloned by Okazaki et al. (11) from mouse osteoblast and human osteosarcoma cell lines and is highly expressed in osteoblastic cell lines, osteoblast precursors, and primary osteoblastic cells. Data suggest a relationship between CDH11 expression and neoplastic aggressiveness (13, 14, 15) . As an example, Feltes et al. (13) have recently shown that coexpression of a CDH11 splicing variant and the wild-type CDH11 promotes breast cancer cell invasion. Notably, although those studies highlight potential oncogenic roles for CDH11, no CDH11 coding sequence is preserved in the CDH11-USP6 fusion transcripts in ABC. Rather, our findings indicate that the role of CDH11 in the CDH11-USP6 fusion transcript is to provide a highly active promoter, thereby contributing to USP6 transcriptional up-regulation. Our data also suggest that related oncogenic mechanisms apply in ABC cases 5–7, which lack t(16;17) but which have rearrangement of one region (16q22 or 17p13) or the other.

USP6 is a ubiquitin-specific protease that was cloned from NIH3T3 transformants after transfection with cDNA from human Ewing sarcoma (16 , 17) . Although originally mapped to the pericentromeric region of the chromosome 17 long arm, more recent studies have localized USP6 to the short arm at chromosome band 17p13. Interestingly, USP6 is a hominoid-specific gene that arose from an evolutionary chimeric gene fusion between the TBC1D3 (also known as PRC17) and USP32 (NY-REN-60) genes, which are both located on the long arm of chromosome 17 (10) . Because USP6 is absent in nonhominoid primates and is primarily expressed in testicular tissue, Paulding et al. (10) have suggested that USP6 contributed to hominoid speciation.

USP6 has an extremely high degree of sequence conservation with the two component genes (TBC1D3 and USP32) from which it arose. Sequence comparisons indicate that the first 14 exons of USP6 are derived from TBC1D3(PRC17), whereas exons 15–30 are derived from USP32 (10) . TBC1D3(PRC17) is located at chromosome band 17q12 and encodes a protein with a TBC/GAP domain involved in Rab/Ypt GTPase signaling. USP32 is located at chromosome band 17q23 and encodes a protein composed of two EF-hand calcium-binding motifs, a myristoylation site, and a UBP domain. USP6 protein retains the TBC domain of TBC1D3(PRC17) and the UBP domain of USP32.

In ABC with t(16;17), the genomic breakpoint at chromosome band 16q22 occurs in intron 2 of CDH11, therefore upstream to its coding sequence, which starts within CDH11 exon 3. Similarly, the genomic breakpoint on chromosome 17p13 occurs upstream of the USP6 coding sequence, which starts at the second nucleotide of USP6 exon 2. Although our studies demonstrate several splicing variants for the CDH11-USP6 fusion region, each of these preserves the known USP6 open reading frame. In addition, CDH11-USP6 fusion transcripts, but not reciprocal USP6-CDH11 transcripts, were demonstrated consistently in ABC with t(16;17). These findings indicate that USP6 overexpression results from juxtaposition to the highly active CDH11 promoter in ABC with t(16;17). This oncogenic mechanism, sometimes referred to as promoter-swapping, has precedent in several other tumors, including salivary gland adenomas and lipoblastoma (9 , 18) .

Notably, USP6 overexpression has been shown to transform mesenchymal cells. Nakamura et al. (16) demonstrated that NIH3T3 fibroblast-lineage cells were transformed by a natural USP6 transcript with only a partial UBP domain. By contrast, USP6 transcripts with the entire UBP domain did not exhibit transforming activity in this assay (10) . These findings suggest that the TBC domain in USP6 might have oncogenic function, whereas the more COOH-terminal UBP domain might have tumor suppressor properties. A recent study by Pei et al. (19) is consistent with this hypothesis. These authors showed that TBC1D3(PRC17) is amplified in prostate cancer and—as with the shorter splicing variant of USP6—capable of transforming NIH3T3 cells. In addition, point mutations that modified conserved amino acids in the TBC domain inhibited TBC1D3(PRC17) transforming activity (19) . These observations suggest that overexpression of the TBC1D3 or USP6 TBC domains can transform mesenchymal cells.

In summary, our studies demonstrate fusion of the promoter region of the osteoblast cadherin gene CDH11 to the entire coding sequence of the ubiquitin-specific protease gene USP6, resulting from the recurrent ABC translocation t(16;17)(q22;p13). Furthermore, some ABCs have translocations targeting either CDH11 or USP6 in the absence of CDH11-USP6, indicating the presence of variant fusion oncogenes. The fusion transcript CDH11-USP6 appears to be specific for ABC, and the oncogenic mechanism likely involves transcriptional up-regulation of USP6.


   ACKNOWLEDGMENTS
 
We thank Jeffrey L. Myers, Lawrence J. Burgart, Ricardo V. Lloyd and the Department of Pathology and Laboratory Medicine at Mayo Clinic for support and advice, and Christopher A. French and Sheng Xiao for mentoring and invaluable discussions.


   FOOTNOTES
 
Grant support: Mayo Clinic and Mayo Clinic Foundation (A. M. Oliveira).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Jonathan A. Fletcher, Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail: amoliveira{at}partners.org or jfletcher{at}partners.org

Received 9/ 8/03. Revised 12/17/03. Accepted 12/24/03.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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