USP6 (Tre2) Fusion Oncogenes in Aneurysmal Bone Cyst


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USP6 (Tre2) Fusion Oncogenes in Aneurysmal Bone Cyst
  2004;64:1920-1923. Cancer Res Andre M. Oliveira, Bae-Li Hsi, Stanislawa Weremowicz, et al. Fusion Oncogenes in Aneurysmal Bone Cyst USP6 (Tre2)    Updated version the most recent version of this article at:   Cited Articles article cites by 18 articles, 5 of which you can access for free at:   Citing articles article has been cited by 7 HighWire-hosted articles. Access the articles at:   E-mail alerts  related to this article or journal.Sign up to receive free email-alerts   SubscriptionsReprints and .pubs@aacr.orgDepartment atTo order reprints of this article or to subscribe to the journal, contact the AACR Publications   Permissions  .permissions@aacr.orgDepartment atTo request permission to re-use all or part of this article, contact the AACR Publications Research. on March 2, 2014. © 2004 American Association for Downloaded from  Research. on March 2, 2014. © 2004 American Association for Downloaded from   [CANCER RESEARCH 64, 1920–1923, March 15, 2004]  Advances in Brief  USP6 (Tre2)  Fusion Oncogenes in Aneurysmal Bone Cyst Andre M. Oliveira, 1,2 Bae-Li Hsi, 1 Stanislawa Weremowicz, 1 Andrew E. Rosenberg, 3 Paola Dal Cin, 1 Nora Joseph, 1 Julia A. Bridge, 4 Antonio R. Perez-Atayde, 5 and Jonathan A. Fletcher 1,6 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 Aneurysmal bone cyst (ABC) is a locally aggressive osseous lesion thattypically occurs during the first two decades of life. ABC was regardedhistorically as a nonneoplastic process, but recent cytogenetic data haveshown clonal rearrangements of chromosomal bands 16q22 and 17p13,indicating a neoplastic basis in at least some ABCs. Herein we show thata recurring ABC chromosomal translocation t(16;17)(q22;p13) creates afusion gene in which the osteoblast cadherin 11 gene ( CDH11 ) promoterregion on 16q22 is juxtaposed to the entire ubiquitin-specific protease USP6   ( Tre2 ) coding sequence on 17p13.  CDH11-USP6   fusion transcriptswere demonstrated only in ABC with t(16;17) but other ABCs had  CDH11 or  USP6   rearrangements resulting from alternate cytogenetic mecha-nisms.  CDH11  is expressed strongly in bone, and our findings implicate anovel oncogenic mechanism in which deregulated  USP6   transcriptionresults from juxtaposition to the highly active  CDH11  promoter. Introduction Aneurysmal bone cyst (ABC) is a rapidly growing and locallyaggressive osseous lesion that was first described in 1942 by Jaffe andLichtenstein (1). ABC affects all age groups but is more commonlyfound during the first two decades of life (2). ABC can occur as a  denovo  lesion or be associated with other benign and malignant bonetumors. Until very recently, ABC was considered a nonneoplasticprocess of unknown etiology, and this view was supported by severalreports of ABCs exhibiting normal karyotypes (3). However, Panout-sakopoulos  et al.  (4) reported chromosomal translocation t(16;17)(q22;p13) as a recurrent cytogenetic abnormality in ABC, provid-ing strong evidence for a clonal neoplastic basis in these lesions.Subsequently, Dal Cin  et al.  (5) demonstrated similar cytogeneticaberrations in solid and extraosseous variants of ABC. Herein weshow that the chromosomal translocation t(16;17)(q22;p13) fuses thepromoter region of the osteoblast cadherin 11 gene ( CDH11 ) onchromosome 16q22 to the entire coding sequence of the ubiquitinprotease (UBP)  USP6 gene  (also known as  Tre2  oncogene) on chro-mosome 17p13. We also show that  CDH11-USP6   might be specificfor ABC in that it was not demonstrated in other osseous and non-osseous tumors.  CDH11  is highly expressed in bone, indicating that USP6   tumsrcenic activity can result from transcriptional up-regulation. Materials and Methods Tumor Samples, Bacterial Artificial Chromosome (BAC) Clone Iden-tification, and DNA Extraction.  Eight cases of primary ( de novo ) ABC werestudied. The samples were obtained from surgical excisions and were histo-logically characterized according to established criteria (6).BAC clones were obtained from Children’s Hospital Oakland ResearchInstitute (Oakland, CA) and Research Genetics (Huntsville, AL). DNA isola-tion was performed according to a previously reported protocol (7). Afterovernight bacterial growth, cell pellets were digested (25 m M  Tris-HCL, 50m M  glucose, 10 m M  EDTA, 5 mg/ml lysozyme, and 200   g/ml RNase), andthe DNA was precipitated with 5  M  potassium acetate and 100% ethanol. BACDNA 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 col-umns (Amersham Biosciences, Piscataway, NJ), coprecipitated with 0.3  g/mlglycogen, 2.5  M  ammonium acetate, and 2 volumes of 100% ethanol, andresuspended with hybridization buffer (50% formamide, 10% dextrose sulfate,and 2  SSC) and Cot-1 DNA (Invitrogen). Fluorescence  in Situ  Hybridization (FISH) Mapping.  Metaphase har-vesting, slide preparation, and trypsin-Giemsa staining for cytogenetic analy-ses were performed as described previously (8). Dual color FISH and probedetection were performed, as described, using FITC-antidigoxigenin and AlexaFluor 594-streptavidin (Molecular Probe, Eugene, OR; Ref. 9). Images werecaptured using a liquid cooled CCD camera (Photometrics, Tucson, AZ). RNA Isolation, Reverse Transcription-PCR (RT-PCR), and cDNA Se-quencing.  RNA was isolated from frozen tissue material after mechanicalhomogenization and overnight incubation in Trizol (Invitrogen) at 4°C. RNAreverse transcription into cDNA was performed using the GeneAmp RNAPCR kit (Applied Biosystems, Foster City, CA) for 2 h at 42°C using randomhexamers. All PCR reactions were performed using the Takara Ex Taq kitwith 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 PCRprimers included  CDH11  83F (5  -GTGAATGGGACCGGGACT-3  ) and USP6   1781R (5  -CTCGGTGTCCCTTGTCATACTT-3  ). The PCR productswere gel purified using the QIAquick Gel Extraction kit (Qiagen, Valencia,CA) and sequenced using an ABI PRISM 3100 Genetic Analyzer (AppliedBiosystems). ResultsIdentification of ABC Chromosome 17p13 and 16q22 Break-points.  Metaphase cell FISH mapping of the chromosome band17p13 region revealed that BAC RP11-46I8 spanned the 17p13genomic breakpoint in ABC cases 1 and 2 (Table 1). Approximately40% of the RP11-46I8 FISH signal was retained on the derivativechromosome 17, implicating the  ZNF232  and  USP6   genes as the mostlikely targets of the 17p13 rearrangement. Additional FISH analyseswith BACs CTD-2006B23, CTD-3231H2, and RP11-124C16 refinedthe genomic breakpoint to an 8-kb region comprised of   USP6   exons1–3 and sequences upstream of   USP6   (Fig. 1,  A  and  C  ). The  USP6  coding sequence spans from exons 2 to 30, suggesting that thegenomic breakpoints might be upstream of the start of the codingsequence.Metaphase FISH mapping of the chromosome band 16q22 regioninitially localized the genomic breakpoint to a 20-kb region containingthe 3  -end of intron 1, exon 2, and intron 2 of the  CDH11  cadheringene (Fig. 1,  B  and  D ). This breakpoint region was then additionallylocalized to a 10-kb region at the start of   CDH11  intron 2 in cases 1,2, and 3 (Table 1), using BACs RP11-76J1 and RP11-138B22 (datanot shown). The intron 2 breakpoint region is upstream of the  CDH11 Received 9/8/03; revised 12/17/03; accepted 12/24/03. 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 pagecharges. This article must therefore be hereby marked  advertisement   in accordance with18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints:  Jonathan A. Fletcher, Department of Pathology, Brigham andWomen’sHospital,75FrancisStreet,Boston,MA02115.E-mail:amoliveira@partners.orgor 1920 Research. on March 2, 2014. © 2004 American Association for Downloaded from   coding sequence, which begins in  CDH11  exon 3. Juxtaposition of  CDH11  and  USP6   by the t(16;17)(q22;p13) was corroborated bydual-color FISH with BAC RP11-137A18 flanking the 5  -end of  CDH11  and BAC CTD-2367F23 flanking the 3  -end of   USP6  (Fig. 1  E  ). Identification of   CDH11-USP6   Fusion Transcript Breakpoints. CDH11  is expressed strongly in mesenchymal cells, particularly thoseof osteoblastic differentiation, whereas  USP6   expression is expressedpredominantly in germ cells (10, 11). These known expression pro-files, together with the genomic FISH localizations, were most con-sistent with fusion oncogenes composed of the  CDH11  5  untranslatedregion and the entire  USP6   coding sequence. The possibility of  CDH11-USP6   fusion transcripts was evaluated in eight ABCs — fourof which had t(16;17) — by RT-PCR with a  CDH11  exon 1 forwardprimer ( CDH11  83F) and a  USP6   exon 2/3 reverse primer( USP6   1781R).  CDH11-USP6   fusion products were identified onlyin the ABC with t(16;17). RT-PCR gel electrophoresis and sequenceanalyses revealed alternative splicing at the  CDH11-USP6   breakpointregion in the ABC with t(16;17), and we refer to the different splicingproducts as  CDH11-USP6   types 1 – 5 (Fig. 2,  A  and  B ). In type 1, the CDH11  noncoding exon 1 was fused to part of the  USP6   noncodingexon 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  exon2 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 inall five splicing variants were before the start of the  CDH11  codingsequence ( CDH11  exon 3) and preserved the  USP6   ATG initiationcodon, which begins at the second nucleotide of   USP6   exon 2.RT-PCR for the reciprocal fusion product ( USP6-CDH11 ) was re-peatedly negative in all ABC with cytogenetic t(16;17), suggestingthat the  CDH11  coding sequences are not essential to the ABCtransforming mechanism. CDH11 and  USP6   Involvement in Aneurysmal Bone Cyst. Genomic rearrangements of   CDH11  and  USP6   were evaluated inABCs with 16q22 or 17p13 cytogenetic aberrations (Table 1, cases1 – 7), and in an ABC that lacked such aberrations (Table 1, case 8),FISH was performed using BAC probes flanking both genes. AllABCs with cytogenetic t(16;17) showed genomic  CDH11  and  USP6  rearrangement by FISH (Table 1, cases 1 – 4). By contrast, ABC withcytogenetic 17p13 rearrangements only (in the absence of apparent16q22 rearrangement), showed rearrangement of the  USP6   locus — but not the  CDH11  locus — by FISH (Table 1, cases 5 and 6). Simi-larly, an ABC with cytogenetic 16q22 rearrangement only (in theabsence of apparent 17p13 rearrangement), showed rearrangement of the  CDH11  locus — but not the  USP6   locus — by FISH (Table 1, case7). As in the ABC with t(16;17), the genomic breakpoint in case 7 waswithin  CDH11  intron 2 and therefore upstream of the  CDH11  coding Table 1  Clinical and cytogenetic features of ABC in this study Case A/G a Location KaryotypeReverse transcription-PCR  CDH11-USP6  Fluorescence  in situ  hybridization USP6   (17p13)  CDH11  (16q22)  CDH11-USP6  1 12M Calcaneum 46,XY,der(16)t(16;17)(q22;p13)      2 15F Pubis 46,XX,t(11;14)(p10;q10),t(16;17)(q13;p13)      3 13F Tibia 46,XX,t(16;17)(q12 – 22;p13)      4 14F Femur 46,XY,t(16;17)(q22;p13)      5 8M Humerous 46,XY,t(17;17)(p13;q12)      6 15F Clavicle 46,XX,del(3)(p22),add(4)(p16),add(5)(p15),?der(17)      7 10F Vertebra 46,XX,t(11;16)(q13;q22 – 23)      8 18F Radius 47,XX,  mar      a A, age in years; G, gender.Fig. 1. Schematic of bacterial artificial chromo-some (BAC) clones in relationship to  USP6   and  ZNF232  at chromosome band 17p13 (  A ) and inrelationship to  CDH11  at chromosome band 16q22(  B ).  Dashed vertical lines  indicate the consensusgenomic breakpoint regions, as determined by flu-orescence  in situ  hybridization. Representative flu-orescence  in situ  hybridization images in an aneu-rysmal bone cyst with translocation t(16;17) show USP6   rearrangement, seen as separation of BACsRP11-124C16 and CTD-2367F23 ( C  );  CDH11  re-arrangement, seen as splitting of BAC CTD-2326E5 (  D ); and  CDH11-USP6   fusion, seen as juxtaposition of BACs RP11-137A18 and CTD-2367F23 (  E  ). 1921 USP6 (Tre2) FUSION ONCOGENES IN ANEURYSMAL BONE CYST Research. on March 2, 2014. © 2004 American Association for Downloaded from   sequence, suggesting that the  CDH11  promoter might drive transcrip-tional up-regulation of an alternative oncogene in this case.The specificity of the  CDH11-USP6   fusion transcript was evaluatedby performing RT-PCR for  CHD11-USP6   fusion, and dual-color splitapart FISH for  CDH11  and  USP6   rearrangement in various osseousand nonosseous tumors (Fig. 2  A  and Table 2). These studies showedno evidence of   CDH11  or  USP6   rearrangement in any of the non-ABC tumors. Discussion ABC is a locally aggressive and rapidly growing cystic bone lesionthat occurs mainly during the first two decades of life. Although ABCcan arise in any anatomical location, metaphyses of the long bones of the lower extremities are most often affected (2). Histologically, ABCis characterized by multiple hemorrhagic cysts surrounded by fibroussepta composed of a highly mitotic spindle cell proliferation inter-mixed with osteoclast-type giant cells and reactive woven bone. Untilrecently, ABC was viewed as a nonneoplastic lesion, but cytogeneticstudies have shown convincing evidence of a clonal, neoplastic basisfor this disease.In this study, we demonstrate that the recurrent chromosomaltranslocation t(16;17)(q22;p13) leads to fusion of the promoter regionof the osteoblast cadherin gene  CDH11  to the entire coding sequenceof the ubiquitin-specific protease  USP6   (also known as  Tre2 ).  CDH11 maps at the 16q21-q22.1 chromosome band interface and is a memberof a large family of cell surface glycoproteins involved in Ca 2  -dependent cell-cell adhesion (12).  CDH11  was cloned by Okazaki  et al.  (11) from mouse osteoblast and human osteosarcoma cell lines andis highly expressed in osteoblastic cell lines, osteoblast precursors,and primary osteoblastic cells. Data suggest a relationship betweenCDH11 expression and neoplastic aggressiveness (13 – 15). As anexample, Feltes  et al.  (13) have recently shown that coexpression of a  CDH11  splicing variant and the wild-type  CDH11  promotes breastcancer cell invasion. Notably, although those studies highlight poten-tial oncogenic roles for CDH11, no  CDH11  coding sequence ispreserved in the  CDH11-USP6   fusion transcripts in ABC. Rather, ourfindings indicate that the role of   CDH11  in the  CDH11-USP6   fusiontranscript is to provide a highly active promoter, thereby contributingto  USP6   transcriptional up-regulation. Our data also suggest thatrelated oncogenic mechanisms apply in ABC cases 5 – 7, which lack t(16;17) but which have rearrangement of one region (16q22 or17p13) or the other. USP6   is a ubiquitin-specific protease that was cloned from NIH3T3transformants after transfection with cDNA from human Ewing sar-coma (16, 17). Although srcinally mapped to the pericentromericregion of the chromosome 17 long arm, more recent studies havelocalized  USP6   to the short arm at chromosome band 17p13. Inter-estingly,  USP6   is a hominoid-specific gene that arose from an evo-lutionary chimeric gene fusion between the  TBC1D3  (also known as PRC17  ) and  USP32  (  NY-REN-60 ) genes, which are both located onthe long arm of chromosome 17 (10). Because  USP6   is absent innonhominoid primates and is primarily expressed in testicular tissue,Paulding  et al.  (10) have suggested that  USP6   contributed to hominoidspeciation.USP6 has an extremely high degree of sequence conservation withthe two component genes ( TBC1D3  and  USP32 ) from which it arose.Sequence comparisons indicate that the first 14 exons of   USP6   arederived from  TBC1D3(PRC17  ), whereas exons 15 – 30 are derivedfrom  USP32  (10).  TBC1D3(PRC17  ) is located at chromosome band17q12 and encodes a protein with a TBC/GAP domain involved in Fig. 2.  A ,  top panel:  reverse transcription-PCR dem-onstrating  CDH11-USP6   fusion products only in aneu-rysmal bone cyst (ABC) with translocation t(16;17)(q22;p13).  Lower panel:  reverse transcription-PCR forglyceraldehyde-3-phosphate dehydrogenase ( GAPDH  )as a control for RNA integrity.  B , diagram showing theoverall structure of   CDH11 ,  USP6  , and the predicted CDH11-USP6   fusion transcripts.  White areas  indicatenoncoding exons;  gray areas  indicate coding se-quences. Protein domains are represented by  light grayrectangles  and include CH, cadherin domain; T, trans-membrane domain; CYT, cadherin COOH-terminalcytoplasmic region; TBC, TBC/GAP GTPase domain;and UBP, ubiquitin protease domain. The numbersindicate exon numbers for  CDH11  and  USP6  , and thesmall  white rectangle  in the type 5 fusion represents analternative 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  .Table 2  RT-PCR results for CDH11-USP6 in non-ABC tumors Tumor n  CDH11-USP6  Ewing sarcoma 4  — Osteosarcoma 4  — Osteoblastoma 2  — Giant cell tumor 1  — Chondrosarcoma 1  — Synovial sarcoma 1  — Rhabdomyosarcoma 1  — Nodular fasciitis 1  — Leiomyosarcoma 4  — Malignant peripheral nerve sheath tumor 1  — Endometrial stromal sarcoma 1  — Gastrointestinal stromal tumor 2  — Mesothelioma 2  — Chronic myelogenous leukemia 1  — T-cell leukemia 3  — B-cell lymphoma 1  — Breast adenocarcinoma 5  — Prostate adenocarcinoma 1  — Total 36  — 1922 USP6 (Tre2) FUSION ONCOGENES IN ANEURYSMAL BONE CYST Research. on March 2, 2014. © 2004 American Association for Downloaded from   Rab/Ypt GTPase signaling.  USP32  is located at chromosome band17q23 and encodes a protein composed of two EF-hand calcium-binding motifs, a myristoylation site, and a UBP domain. USP6protein retains the TBC domain of TBC1D3(PRC17) and the UBPdomain of USP32.In ABC with t(16;17), the genomic breakpoint at chromosome band16q22 occurs in intron 2 of   CDH11 , therefore upstream to its codingsequence, which starts within  CDH11  exon 3. Similarly, the genomicbreakpoint on chromosome 17p13 occurs upstream of the  USP6  coding sequence, which starts at the second nucleotide of   USP6   exon2. 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, butnot reciprocal  USP6-CDH11  transcripts, were demonstrated consis-tently 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, some-times referred to as promoter-swapping, has precedent in several othertumors, including salivary gland adenomas and lipoblastoma (9, 18).Notably, USP6 overexpression has been shown to transform mes-enchymal cells. Nakamura  et al.  (16) demonstrated that NIH3T3fibroblast-lineage cells were transformed by a natural  USP6   transcriptwith only a partial UBP domain. By contrast,  USP6   transcripts withthe entire UBP domain did not exhibit transforming activity in thisassay (10). These findings suggest that the TBC domain in USP6might have oncogenic function, whereas the more COOH-terminalUBP domain might have tumor suppressor properties. A recent studyby Pei  et al.  (19) is consistent with this hypothesis. These authorsshowed that  TBC1D3(PRC17  ) is amplified in prostate cancer and — aswith the shorter splicing variant of   USP6  — capable of transformingNIH3T3 cells. In addition, point mutations that modified conservedamino acids in the TBC domain inhibited  TBC1D3(PRC17  ) trans-forming activity (19). These observations suggest that overexpressionof the  TBC1D3  or  USP6   TBC domains can transform mesenchymalcells.In summary, our studies demonstrate fusion of the promoter regionof the osteoblast cadherin gene  CDH11  to the entire coding sequenceof the ubiquitin-specific protease gene  USP6  , resulting from therecurrent ABC translocation t(16;17)(q22;p13). Furthermore, someABCs have translocations targeting either  CDH11  or  USP6   in theabsence of   CDH11-USP6  , indicating the presence of variant fusiononcogenes. The fusion transcript  CDH11-USP6   appears to be specificfor ABC, and the oncogenic mechanism likely involves transcriptionalup-regulation of   USP6  . Acknowledgments We thank Jeffrey L. Myers, Lawrence J. Burgart, Ricardo V. Lloyd and theDepartment of Pathology and Laboratory Medicine at Mayo Clinic for supportand advice, and Christopher A. French and Sheng Xiao for mentoring andinvaluable discussions. References 1. Jaffe H, Lichtenstein L. Solitary unicameral bone cyst: with emphasis on the roentgenpicture, the pathologic appearance and the pathogenesis. Arch Surg 1942;44:1004 – 25.2. Vergel De Dios AM, Bond JR, Shives TC, McLeod RA, Unni KK. Aneurysmal bonecyst. A clinicopathologic study of 238 cases. Cancer (Phila.) 1992;69:2921 – 31.3. Pfeifer FM, Bridge JA, Neff JR, Mouron BJ. Cytogenetic findings in aneurysmal bonecysts. Genes Chromosomes Cancer 1991;3:416 – 9.4. Panoutsakopoulos G, Pandis N, Kyriazoglou I, Gustafson P, Mertens F, Mandahl N.Recurrent t(16;17)(q22;p13) in aneurysmal bone cysts. Genes Chromosomes Cancer1999;26:265 – 6.5. 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