USP6

Gene Summary

Gene:USP6; ubiquitin specific peptidase 6
Aliases: HRP1, TRE2, TRE17, Tre-2, TRESMCR, USP6-short
Location:17p13.2
Summary:-
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:ubiquitin carboxyl-terminal hydrolase 6
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
Show (15)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Wnt Signaling Pathway
  • Oncogene Proteins
  • Oncogenes
  • Mutation
  • Antibodies, Monoclonal, Humanized
  • Transcription
  • Young Adult
  • Uterine Cancer
  • RHOA
  • Oncogene Fusion Proteins
  • RTPCR
  • Bone Cysts, Aneurysmal
  • Ubiquitin Thiolesterase
  • Up-Regulation
  • Karyotyping
  • Proto-Oncogene Proteins
  • Ubiquitin-Specific Proteases
  • Collagen Type I
  • Cadherins
  • Adolescents
  • Endopeptidases
  • Breast Cancer
  • Cancer Gene Expression Regulation
  • Promoter Regions
  • Protein Transport
  • FISH
  • Chromosome 17
  • Neoplastic Cell Transformation
  • Molecular Sequence Data
  • Amino Acid Sequence
  • Translocation
  • Carcinoma
  • Gene Rearrangement
  • DNA-Binding Proteins
  • Childhood Cancer
  • Signal Transduction
  • Sequence Homology
  • HeLa Cells
  • Bone Cancer
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: USP6 (cancer-related)

Panagopoulos I, Gorunova L, Viset T, Heim S
Gene fusions AHRR-NCOA2, NCOA2-ETV4, ETV4-AHRR, P4HA2-TBCK, and TBCK-P4HA2 resulting from the translocations t(5;8;17)(p15;q13;q21) and t(4;5)(q24;q31) in a soft tissue angiofibroma.
Oncol Rep. 2016; 36(5):2455-2462 [PubMed] Free Access to Full Article Related Publications
We present an angiofibroma of soft tissue with the karyotype 46,XY,t(4;5)(q24;q31),t(5;8;17)(p15;q13;q21)[8]/46,XY,t(1;14)(p31;q32)[2]/46,XY[3]. RNA‑sequencing showed that the t(4;5)(q24;q31) resulted in recombination of the genes TBCK on 4q24 and P4HA2 on 5q31.1 with generation of an in‑frame TBCK‑P4HA2 and the reciprocal but out‑of‑frame P4HA2‑TBCK fusion transcripts. The putative TBCK‑P4HA2 protein would contain the kinase, the rhodanese‑like domain, and the Tre‑2/Bub2/Cdc16 (TBC) domains of TBCK together with the P4HA2 protein which is a component of the prolyl 4‑hydroxylase. The t(5;8;17)(p15;q13;q21) three‑way chromosomal translocation targeted AHRR (on 5p15), NCOA2 (on 8q13), and ETV4 (on 17q21) generating the in‑frame fusions AHRR‑NCOA2 and NCOA2‑ETV4 as well as an out‑of‑frame ETV4‑AHRR transcript. In the AHRR‑NCOA2 protein, the C‑terminal part of AHRR is replaced by the C‑terminal part of NCOA2 which contains two activation domains. The NCOA2‑ETV4 protein would contain the helix‑loop‑helix, PAS_9 and PAS_11, CITED domains, the SRC‑1 domain of NCOA2 and the ETS DNA‑binding domain of ETV4. No fusion gene corresponding to t(1;14)(p31;q32) was found. Our findings indicate that, in spite of the recurrence of AHRR‑NCOA2 in angiofibroma of soft tissue, additional genetic events (or fusion genes) might be required for the development of this tumor.

Willis BC, Archer SR, Shahid R, et al.
Two Case Reports of Nodular Fasciitis: A Newly Recognized Placental Lesion.
Fetal Pediatr Pathol. 2016; 35(2):93-7 [PubMed] Related Publications
We describe two occurrences of nontrophoblastic mesenchymal tumors of the placenta. The first placental tumor was found along the placental margin, and the second was identified close to the insertion of the fetal membranes along the placental disc. Microscopically both lesions demonstrated bland fibroblastic cells with intricate vasculature and inflammatory cells. Both lesions were negative for estrogen receptor (ER), progesterone receptor (PR), beta-HCG, PLAP, CD34, desmin, h-caldesmin, and smooth muscle actin by immunohistochemistry. Some cells were weakly positive for CD10, a nonspecific finding. The morphologic and immunohistochemical characteristics of these lesions were most consistent with nodular fasciitis, a tumor most commonly found in the soft tissues. FISH positive for USP6 gene rearrangement in our two patients confirmed the molecular similarity of these lesions to nodular fasciitis of soft tissue. Such lesions can be easily dismissed on gross placental examination as infarcts or thrombi, thus these rare entities are likely underreported.

Kang A, Kumar JB, Thomas A, Bourke AG
A spontaneously resolving breast lesion: imaging and cytological findings of nodular fasciitis of the breast with FISH showing USP6 gene rearrangement.
BMJ Case Rep. 2015; 2015 [PubMed] Related Publications
We report a case of nodular fasciitis of the breast in a 48-year-old woman who presented with a tender rapidly growing right breast lump. Ultrasound guided fine needle aspiration (FNA) of the solid mass was performed. Cytology was reported as atypical spindle cell neoplasm and the patient was referred to a breast surgeon at a tertiary institution for a definitive diagnosis and further management. Follow-up ultrasound showed partial regression and MRI, mammogram after 2-3 weeks confirmed spontaneous and total resolution of the lesion. Nodular fasciitis of the breast is rarely diagnosed on cytology alone and a histological diagnosis is usually required for a definitive diagnosis. However, in this case, the lesion spontaneously resolved prior to core biopsy or diagnostic open biopsy. The cytological features in conjunction with immunohistochemistry and the clinical history strongly suggest nodular fasciitis, which is further supported by a USP6 FISH positive result.

Agaram NP, LeLoarer FV, Zhang L, et al.
USP6 gene rearrangements occur preferentially in giant cell reparative granulomas of the hands and feet but not in gnathic location.
Hum Pathol. 2014; 45(6):1147-52 [PubMed] Free Access to Full Article Related Publications
Giant cell reparative granulomas (GCRGs) are lytic lesions that occur predominantly in the gnathic bones and occasionally in the small bones of the hands and feet. They are morphologically indistinguishable from, and are regarded as synonymous with, solid variant of aneurysmal bone cysts (ABC) in extragnathic sites. Identification of USP6 gene rearrangements in primary ABC has made possible investigating potential pathogenetic relationships with other morphologic mimics. USP6 gene alterations in giant cell-rich lesions (GCRG/ABC) of small bones of the hands and feet have not been previously studied. We investigated USP6 gene alterations in a group of 9 giant cell-rich lesions of the hands and feet and compared the findings with morphologically similar lesions including 8 gnathic GCRGs, 22 primary ABCs, 8 giant cell tumors of bone, and 2 brown tumors of hyperparathyroidism. Overall, there were 49 samples from 48 patients including 26 females and 22 males. Of the 9 lesions of the hands and feet, 8 (89%) showed USP6 gene rearrangements, whereas no abnormalities were identified in the 8 gnathic GCRGs, 2 brown tumors, or 8 giant cell tumors of bone. Of the 22 primary ABCs, 13 (59%) showed USP6 gene rearrangements. In conclusion, most GCRGs of the hands and feet represent true ABCs and should be classified as such. The terminology of GCRG should be limited to lesions from gnathic location. Fluorescence in situ hybridization for USP6 break-apart is a useful ancillary tool in the diagnosis of primary ABCs and distinguishing them from GCRGs and other morphologically similar lesions.

Pauli C, Fuchs B, Pfirrmann C, et al.
Response of an aggressive periosteal aneurysmal bone cyst (ABC) of the radius to denosumab therapy.
World J Surg Oncol. 2014; 12:17 [PubMed] Free Access to Full Article Related Publications
Aneurysmal bone cyst (ABC), once considered a reactive lesion, has been proven to be a neoplasia characterized by rearrangements of the USP6-gene. Aggressive local growth and recurrences are common and therapeutic options may be limited due to the vicinity of crucial structures. We describe a case of a locally aggressive, multinucleated giant cell-containing lesion of the forearm of a 21-year old woman, treated with denosumab for recurrent, surgically uncontrollable disease. Under the influence of this RANKL inhibitor, the tumor showed a marked reduction of the content of the osteoclastic giant cells and an extensive metaplastic osteoid production leading to the bony containment, mostly located intracortically in the proximal radius. The diagnosis of a periosteal ABC was confirmed by FISH demonstrating USP6 gene rearrangement on the initial biopsy. Function conserving surgery could be performed, enabling reconstruction of the affected bone. Inhibition of RANKL with denosumab may offer therapeutic option for patients not only with giant cell tumors but also with ABCs.

Oliveira AM, Chou MM
USP6-induced neoplasms: the biologic spectrum of aneurysmal bone cyst and nodular fasciitis.
Hum Pathol. 2014; 45(1):1-11 [PubMed] Related Publications
USP6 (also known as TRE17) is a ubiquitin-specific protease that was identified as an oncogene in transfection experiments with Ewing sarcoma DNA 2 decades ago. Until recently, little was known about USP6 function and mechanisms of oncogenic activation. The identification of USP6 fusion genes in aneurysmal bone cyst (ABC) and, more recently, in nodular fasciitis led to a better understanding of the pathogenesis of these lesions. Furthermore, the detection of USP6 genomic rearrangements or USP6 fusion genes may be used as a diagnostic tool for these lesions. In this review, we discuss the clinicopathologic features, molecular pathology, and pathogenesis of ABC and nodular fasciitis. We also discuss the possible line of differentiation of ABC and its relationship to nodular fasciitis and other lesions.

Gao C, Devarajan K, Zhou Y, et al.
Identifying breast cancer risk loci by global differential allele-specific expression (DASE) analysis in mammary epithelial transcriptome.
BMC Genomics. 2012; 13:570 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The significant mortality associated with breast cancer (BCa) suggests a need to improve current research strategies to identify new genes that predispose women to breast cancer. Differential allele-specific expression (DASE) has been shown to contribute to phenotypic variables in humans and recently to the pathogenesis of cancer. We previously reported that nonsense-mediated mRNA decay (NMD) could lead to DASE of BRCA1/2, which is associated with elevated susceptibility to breast cancer. In addition to truncation mutations, multiple genetic and epigenetic factors can contribute to DASE, and we propose that DASE is a functional index for cis-acting regulatory variants and pathogenic mutations, and that global analysis of DASE in breast cancer precursor tissues can be used to identify novel causative alleles for breast cancer susceptibility.
RESULTS: To test our hypothesis, we employed the Illumina(®) Omni1-Quad BeadChip in paired genomic DNA (gDNA) and double-stranded cDNA (ds-cDNA) samples prepared from eight BCa patient-derived normal mammary epithelial lines (HMEC). We filtered original array data according to heterozygous genotype calls and calculated DASE values using the Log ratio of cDNA allele intensity, which was normalized to the corresponding gDNA. We developed two statistical methods, SNP- and gene-based approaches, which allowed us to identify a list of 60 candidate DASE loci (DASE ≥ 2.00, P ≤ 0.01, FDR ≤ 0.05) by both methods. Ingenuity Pathway Analysis of DASE loci revealed one major breast cancer-relevant interaction network, which includes two known cancer causative genes, ZNF331 (DASE = 2.31, P = 0.0018, FDR = 0.040) and USP6 (DASE = 4.80, P = 0.0013, FDR = 0.013), and a breast cancer causative gene, DMBT1 (DASE=2.03, P = 0.0017, FDR = 0.014). Sequence analysis of a 5' RACE product of DMBT1 demonstrated that rs2981745, a putative breast cancer risk locus, appears to be one of the causal variants leading to DASE in DMBT1.
CONCLUSIONS: Our study demonstrated for the first time that global DASE analysis is a powerful new approach to identify breast cancer risk allele(s).

Oliveira AM, Chou MM
The TRE17/USP6 oncogene: a riddle wrapped in a mystery inside an enigma.
Front Biosci (Schol Ed). 2012; 4:321-34 [PubMed] Related Publications
De-ubiquitinating enzymes (DUBs) play critical roles in diverse cellular processes, including intracellular trafficking, protein turnover, inflammatory signaling, and cell transformation. The first DUB to be identified as an oncogene was TRE17/Ubiquitin-specific protease 6 (USP6)/Tre-2. In addition to encoding a USP, TRE17 also contains a TBC (Tre-2/Bub2/Cdc16) domain implicated in GTPase regulation and trafficking. Though first described almost two decades ago, remarkably little has been elucidated regarding TRE17's molecular and cellular functions. However, recent work has implicated TRE17 as a key etiological factor in aneurysmal bone cyst (ABC), a locally recurrent pediatric bone tumor, and identified potential pathways through which it acts. In this review, we discuss the most up-to-date findings on the molecular functions of TRE17, the role of its USP and TBC domains, and potential models for how it contributes to transformation and ABC pathogenesis.

Fehér LZ, Pocsay G, Krenács L, et al.
Amplification of thymosin beta 10 and AKAP13 genes in metastatic and aggressive papillary thyroid carcinomas.
Pathol Oncol Res. 2012; 18(2):449-58 [PubMed] Related Publications
Papillary thyroid carcinoma (PTC) is the most common well-differentiated thyroid cancer. Although the great majority of the cases exhibit an indolent clinical course, some of them develop local invasion with distant metastasis, and a few cases transform into undifferentiated/anaplastic thyroid carcinoma with a rapidly lethal course. To identify gene copy number alterations predictive of metastatic potential or aggressive transformation, array-based comparative genomic hybridization (CGH-array) was performed in 43 PTC cases. Formalin-fixed and paraffin-embedded samples from primary tumours of 16 cases without metastasis, 14 cases with only regional lymph node metastasis, and 13 cases with distant metastasis, recurrence or extrathyroid extension were analysed. The CGH-array and confirmatory quantitative real-time PCR results identified the deletion of the EIF4EBP3 and TRAK2 gene loci, while amplification of thymosin beta 10 (TB10) and Tre-2 oncogene regions were observed as general markers for PTC. Although there have been several studies implicating TB10 as a specific marker based on gene expression data, our study is the first to report on genomic amplification. Although no significant difference could be detected between the good and bad prognosis cases in the A-kinase anchor protein 13 (AKAP13) gene region, it was discriminative markers for metastasis. Amplification in the AKAP13 region was demonstrated in 42.9% and 15.4% of the cases with local or with distant metastasis, respectively, while no amplification was detected in non-metastatic cases. AKAP13 and TB10 regions may represent potential new genomic markers for PTC and cancer progression.

Erickson-Johnson MR, Chou MM, Evers BR, et al.
Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6 gene fusion.
Lab Invest. 2011; 91(10):1427-33 [PubMed] Related Publications
Nodular fasciitis (NF) is a relatively common mass-forming and self-limited subcutaneous pseudosarcomatous myofibroblastic proliferation of unknown pathogenesis. Due to its rapid growth and high mitotic activity, NF is often misdiagnosed as a sarcoma. While studying the USP6 biology in aneurysmal bone cyst and other mesenchymal tumors, we identified high expression levels of USP6 mRNA in two examples of NF. This finding led us to further examine the mechanisms underlying USP6 overexpression in these lesions. Upon subsequent investigation, genomic rearrangements of the USP6 locus were found in 92% (44 of 48) of NF. Rapid amplification of 5'-cDNA ends identified MYH9 as the translocation partner. RT-PCR and direct sequencing revealed the fusion of the MYH9 promoter region to the entire coding region of USP6. Control tumors and tissues were negative for this fusion. Xenografts of cells overexpressing USP6 in nude mice exhibited clinical and histological features similar to human NF. The identification of a sensitive and specific abnormality in NF holds the potential to be used diagnostically. Considering the self-limited nature of the lesion, NF may represent a model of 'transient neoplasia', as it is, to our knowledge, the first example of a self-limited human disease characterized by a recurrent somatic gene fusion event.

Geiersbach K, Rector LS, Sederberg M, et al.
Unknown partner for USP6 and unusual SS18 rearrangement detected by fluorescence in situ hybridization in a solid aneurysmal bone cyst.
Cancer Genet. 2011; 204(4):195-202 [PubMed] Related Publications
USP6 rearrangement is the most common genetic abnormality in primary aneurysmal bone cyst, and SS18 rearrangement has not been previously described in any type of tumor where synovial sarcoma was excluded from the differential diagnosis. We report a case of solid aneurysmal bone cyst in which fluorescence in situ hybridization (FISH) analysis indicated rearrangements of both USP6 and SS18, but histologic features were consistent with aneurysmal bone cyst throughout the lesion. Reverse-transcription polymerase chain reaction (RT-PCR) for the SS18-SSX1 and SS18-SSX2 translocations, identity testing, and SS18 FISH were performed on cytogenetic monolayer cultures and formalin-fixed paraffin-embedded (FFPE) tissue. Genomic microarray, FISH, and immunohistochemistry were performed on follow-up studies of the FFPE specimen. The karyotype was 45,X,add(X)(p11.2),add(4)(q13),add(8)(p21),-13,add(17)(p11.2),add(18)(q11.2) in all 20 cells analyzed from monolayer cultures. The karyotype showed no cytogenetically visible alterations of chromosomal regions harboring known partners for USP6. Metaphase FISH with a commercial SS18 break-apart probe showed translocation of the 5' portion of the SS18 probe to the short arm of the derivative X, as is observed in synovial sarcoma. RT-PCR showed no evidence of a SS18-SSX fusion, and immunohistochemistry was negative for TLE1, EMA, and cytokeratin AE1/3 expression. FISH on FFPE sections with a custom break-apart probe flanking USP6 showed evidence for a USP6 rearrangement throughout the tumor (25-50%). FISH on FFPE sections with a commercial SS18 break-apart FISH probe showed more variable results (0-50% split signals). There was no evidence of a SS18-USP6 fusion by FISH or RT-PCR. A molecular inversion probe array revealed a deletion encompassing the entire SS18 gene and its promoter, as well as portions of the region targeted by the commercial SS18 FISH probe. In conclusion, results obtained from commercially available FISH probes may occasionally yield misleading results. In this case, the SS18 rearrangement by FISH resulted from a complex rearrangement of 18q11.2 with a deletion of the SS18 gene. The translocation partner for USP6 remains unknown in this case.

Lau AW, Pringle LM, Quick L, et al.
TRE17/ubiquitin-specific protease 6 (USP6) oncogene translocated in aneurysmal bone cyst blocks osteoblastic maturation via an autocrine mechanism involving bone morphogenetic protein dysregulation.
J Biol Chem. 2010; 285(47):37111-20 [PubMed] Free Access to Full Article Related Publications
Aneurysmal bone cyst (ABC) is a pediatric osseous tumor characterized by extensive destruction of the surrounding bone. The molecular mechanisms underlying its pathogenesis are completely unknown. Recent work showed that translocation of the TRE17/USP6 locus occurs in over 60% of ABC cases resulting in TRE17 overexpression. Immature osteoblasts are presumed to be the cell type harboring translocation of TRE17 in at least a subset of ABCs. However, the effects of TRE17 overexpression on transformation and osteoblast function are unknown. TRE17 encodes a ubiquitin-specific protease (USP) and a TBC (TRE2-Bub2-Cdc16) domain that promotes activation of the Arf6 GTPase. Here we report that TRE17 potently inhibits the maturation of MC3T3 pre-osteoblasts in a USP-dependent and Arf6-independent manner. Notably, we find that TRE17 function is mediated through an autocrine mechanism. Transcriptome analysis of TRE17-expressing cells reveals dysregulation of several pathways with established roles in osteoblast maturation. In particular, signaling through the bone morphogenetic protein (BMP) pathway, a key regulator of osteogenesis, is profoundly altered. TRE17 simultaneously inhibits the expression of BMP-4 while augmenting the BMP antagonist, Gremlin-1. Osteoblastic maturation is restored in TRE17-expressing cells by the addition of exogenous BMP-4, thus establishing a functional role for BMP-4 during TRE17-induced transformation. Because bone homeostasis involves a precise balance between the activities of osteoblasts and osteoclasts, our studies raise the possibility that attenuated osteoblast maturation caused by TRE17 overexpression may contribute to the bone loss/destruction observed in ABC.

Akhavantabasi S, Akman HB, Sapmaz A, et al.
USP32 is an active, membrane-bound ubiquitin protease overexpressed in breast cancers.
Mamm Genome. 2010; 21(7-8):388-97 [PubMed] Related Publications
USP32, on chromosomal band 17q23.1-17q23.2, is a highly conserved but uncharacterized gene that gave rise during evolution to a well-known hominoid-specific proto-oncogene, USP6. We investigated the expression profile of USP32 in human tissues and examined its functions to gain insight into this novel member of the well-conserved ubiquitination system. We detected ubiquitous USP32 expression across tissues and confirmed the predicted deubiquitination function owing to the presence of conserved peptidase signature aspargine, cysteine, histidine, and aspartic acid domains of ubiquitin-specific proteases. A Golgi localization of GFP-fused USP32 was detected by fluorescent protection assay and BODIPY-TR staining. In addition, stable silencing of USP32 caused a significant decrease in the proliferation and migration rate of cells. Based on these and the fact that USP32 maps to 17q23, which is commonly amplified in breast cancers, we analyzed USP32 expression in breast cancer cells. We detected high expression of USP32 in 50% (9 of 18) of breast cancer cell lines and 22% (9 of 41) of primary breast tumors compared to mammary epithelial cells. In summary, we report the preliminary characterization of this novel deubiquitinating enzyme on 17q23 and demonstrate its functional role in the ubiquitin system and its potential involvement in tumorigenesis.

Ye Y, Pringle LM, Lau AW, et al.
TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NF-kappaB.
Oncogene. 2010; 29(25):3619-29 [PubMed] Free Access to Full Article Related Publications
Aneurysmal bone cyst (ABC) is an aggressive, pediatric bone tumor characterized by extensive destruction of the surrounding bone. Although first described over 60 years ago, its molecular etiology remains poorly understood. Recent work revealed that ABCs harbor translocation of TRE17/USP6, leading to its transcriptional upregulation. TRE17 encodes a ubiquitin-specific protease (USP), and a TBC domain that mediates binding to the Arf6 GTPase. However, the mechanisms by which TRE17 overexpression contributes to tumor pathogenesis, and the role of its USP and TBC domains, are unknown. ABCs are characterized by osteolysis, inflammatory recruitment and extensive vascularization, the processes in which matrix proteases have a prominent role. This led us to explore whether TRE17 regulates the production of matrix metalloproteinases (MMPs). In this study we show that TRE17 is sufficient to induce expression of MMP-9 and MMP-10, in a manner requiring its USP activity, but not its ability to bind Arf6. TRE17 induces transcription of MMP-9 through activation of nuclear factor-kappaB (NF-kappaB), mediated in part by the GTPase RhoA and its effector kinase, ROCK. Furthermore, xenograft studies show that TRE17 induces formation of tumors that reproduce multiple features of ABC, including a high degree of vascularization, with an essential role for the USP domain. In sum, these studies reveal that TRE17 is sufficient to initiate tumorigenesis, identify MMPs as novel TRE17 effectors that likely contribute to ABC pathogenesis and define the underlying signaling mechanism of their induction.

van de Luijtgaarden AC, Veth RP, Slootweg PJ, et al.
Metastatic potential of an aneurysmal bone cyst.
Virchows Arch. 2009; 455(5):455-9 [PubMed] Free Access to Full Article Related Publications
Aneurysmal bone cysts (ABCs) are benign bone tumors consisting of blood-filled cavities lined by connective tissue septa. Recently, the hypothesis that ABCs are lesions reactive to local hemodynamics has been challenged after the discovery of specific recurrent chromosomal abnormalities. Multiple cases of malignant transformation of ABC into (osteo)sarcoma have been described, as well as a number of cases of telangiectatic osteosarcoma which had been misdiagnosed as ABC. We herewith document a case of a pelvic ABC metastatic to the lung, liver, and kidneys. Diagnosis was confirmed by the presence of a break in the USP6 gene, which is pathognomonic for ABC, in a pulmonary metastasis of our patient. Sarcomatous transformation as an explanation for this behavior was ruled out by demonstrating diploid DNA content in both the pulmonary lesion and the primary tumor.

Sukov WR, Franco MF, Erickson-Johnson M, et al.
Frequency of USP6 rearrangements in myositis ossificans, brown tumor, and cherubism: molecular cytogenetic evidence that a subset of "myositis ossificans-like lesions" are the early phases in the formation of soft-tissue aneurysmal bone cyst.
Skeletal Radiol. 2008; 37(4):321-7 [PubMed] Related Publications
OBJECTIVE: USP6 rearrangements with several partner genes have been identified recently in primary but not in secondary aneurysmal bone cysts (ABCs). Several lesions show histologic features that may overlap with ABC, including myositis ossificans (MO), brown tumor, and cherubism. The objective of this study was to assess whether these lesions harbored USP6 rearrangements.
MATERIALS AND METHODS: Twelve patients with classic radiologic and histologic features of MO, 6 with brown tumors, and 5 with cherubism diagnosed at our institution were studied for the presence of USP6 rearrangements using fluorescence in situ hybridization with probes flanking the USP6 locus on chromosome 17p13. In addition, conventional cytogenetic analysis was performed in 2 patients with cherubism.
RESULTS: USP6 rearrangements were identified in 2 patients with radiologic and histologic features consistent with MO. None of the patients with brown tumor or cherubism demonstrated USP6 rearrangements. Cytogenetic analysis of the cherubism patients demonstrated normal karyotypes.
CONCLUSION: These findings indicate that a subset of cases with apparent classic histologic and imaging features of MO are rather better classified as being soft-tissue ABC with clonal USP6 rearrangements. In contrast, no USP6 rearrangements were found in patients with cherubism or brown tumor, supporting the prevailing view that these lesions are distinct biologic entities.

Panagopoulos I, Mertens F, Löfvenberg R, Mandahl N
Fusion of the COL1A1 and USP6 genes in a benign bone tumor.
Cancer Genet Cytogenet. 2008; 180(1):70-3 [PubMed] Related Publications
Aneurysmal bone cyst (ABC) is a benign intraskeletal cyst that often expands rapidly and shows a strong tendency to recur. Rearrangement of chromosome band 17p13 is a characteristic genetic feature of ABC, with t(16;17)(q22;p13) the most frequent chromosomal aberration. This translocation generates a CDH11-USP6 fusion gene in which the strong promoter of osteoblast cadherin 11 gene at 16q22 is fused to the entire ubiquitin-specific protease 6 coding sequence at 17p13. As a result, USP6 (alias Tre2) is transcriptionally upregulated. Fusion genes of several variant translocations have been reported in ABC, including a case with t(17;17) and COL1A1-USP6 fusion. In each translocation, the entire USP6 coding sequence is fused downstream to the promoter region of the partner gene. Here we report a second case of a bone tumor carrying a t(17;17) resulting in a COL1A1-USP6 chimeric gene. As in the previous case, exon 1 of COL1A1 was fused to exon 2 of USP6 in the chimeric transcript. A translation process of the hybrid transcript using the starting ATG codon of the COL1A1 gene results in a truncated, 38 amino acid residues variant of the COL1A1 peptide. Although a pathogenic effect of the small COL1A1 peptide cannot be ruled out, overexpression of USP6 through fusion with the COL1A1 promoter is a more reasonable hypothesis.

Yang S, Jeung HC, Jeong HJ, et al.
Identification of genes with correlated patterns of variations in DNA copy number and gene expression level in gastric cancer.
Genomics. 2007; 89(4):451-9 [PubMed] Related Publications
To identify DNA copy number changes that had a direct influence on mRNA expression in gastric cancer, cDNA microarray-based comparative genomic hybridization (aCGH) and gene expression profiling were performed using 17 K cDNA microarrays. A set of 158 genes showing Pearson correlation coefficients over 0.6 between DNA copy number changes and mRNA expression level variations was selected. In an independent gene expression profiling of 60 tissue samples, the 158 genes were able to distinguish most of the normal and tumor tissues in an unsupervised hierarchical clustering, suggesting that the differential expression patterns displayed by this specific group of genes are most likely based on the gene copy number changes. Furthermore, 43 statistically significant (P<0.01) genes were selected that correctly distinguished all of the tissue samples. The copy number changes detected by aCGH can be verified by fluorescence in situ hybridization and real-time polymerase chain reaction. The selected genes include those that were previously identified as being tumor suppressors or deleted in various tumors, including GATA binding protein 4 (GATA4), monoamine oxidase A (MAOA), cyclin C (CCNC), and oncogenes including malignant fibrous histiocytoma amplified sequence 1 (MFHAS1/MASL1), high mobility group AT-hook 2 (HMGA2), PPAR binding protein (PPARBP), growth factor receptor-bound protein 7 (GRB7), and TBC1 (tre-2, BUB2, cdc16) domain family, member 1 (TBC1D1).

Oliveira AM, Perez-Atayde AR, Dal Cin P, et al.
Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes.
Oncogene. 2005; 24(21):3419-26 [PubMed] Related Publications
Aneurysmal bone cysts (ABC) are locally aggressive bone tumors that often feature chromosome 17p13 rearrangements. One of the ABC 17p13 rearrangements--t(16;17)(q22;p13)--was recently shown to create a CDH11-USP6 fusion in which the USP6/TRE17 oncogene is overexpressed through juxtaposition with the CDH11 promoter. Herein, we characterize four different ABC translocations involving 17p13, and we show that each is associated with a novel USP6 fusion oncogene. Specifically, we demonstrate that t(1;17), t(3;17), t(9;17), and t(17;17) result in USP6 fusions with TRAP150 (thyroid receptor-associated protein 150), ZNF9 (ZiNc Finger 9), Osteomodulin, and COL1A1 (Collagen 1A1), respectively. The oncogenic mechanism in these fusion genes is akin to CDH11-USP6, with the USP6 coding sequences juxtaposed to the promoter regions in each of the four novel translocation partners. The novel fusion partners appear well suited to drive USP6 transcription in the bone/mesenchymal context: osteomodulin is expressed strongly in osteoblastic lineages, and the COL1A1 promoter has an oncogenic role in the mesenchymal cancer dermatofibrosarcoma protuberans. In summary, these studies show that USP6 oncogenic activation results from heterogeneous genomic mechanisms involving USP6 transcriptional upregulation by juxtaposition with ectopic promoters.

Oliveira AM, Perez-Atayde AR, Inwards CY, et al.
USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in so-called secondary aneurysmal bone cysts.
Am J Pathol. 2004; 165(5):1773-80 [PubMed] Free Access to Full Article Related Publications
Aneurysmal bone cyst (ABC) is a locally recurrent bone lesion that has been regarded as a reactive process. Recently, a neoplastic basis in primary ABC was evidenced by demonstration of clonal chromosome band 17p13 translocations that place the USP6 (TRE2 or TRE17) oncogene under the regulatory influence of the highly active CDH11 promoter. Herein, we report CDH11 and/or USP6 rearrangements in 36 of 52 primary ABCs (69%), of which 10 had CDH11-USP6 fusion, 23 had variant USP6 rearrangements without CDH11 rearrangement, and three had variant CDH11 rearrangements without USP6 rearrangement. USP6 and CDH11 rearrangements were restricted to spindle cells in the ABC and were not found in multinucleated giant cells, inflammatory cells, endothelial cells, or osteoblasts. CDH11 and USP6 rearrangements did not correlate with recurrence-free survival, or with other clinicopathological features. CDH11 and USP6 rearrangements were not found in any of 17 secondary ABC associated with giant cell tumor, chondroblastoma, osteoblastoma, and fibrous dysplasia. These findings demonstrate that primary ABC are mesenchymal neoplasms exhibiting USP6 and/or CDH11 oncogenic rearrangements. By contrast, secondary ABC lack CDH11 and USP6 rearrangements, and although morphological mimics of primary ABC, appear to represent a non-specific morphological pattern of a diverse group of non-ABC neoplasms.

Oliveira AM, Hsi BL, Weremowicz S, et al.
USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst.
Cancer Res. 2004; 64(6):1920-3 [PubMed] Related Publications
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.

Osada H, Tatematsu Y, Masuda A, et al.
Heterogeneous transforming growth factor (TGF)-beta unresponsiveness and loss of TGF-beta receptor type II expression caused by histone deacetylation in lung cancer cell lines.
Cancer Res. 2001; 61(22):8331-9 [PubMed] Related Publications
Transforming growth factor (TGF)-beta strongly inhibits epithelial cell proliferation. Alterations of TGF-beta signaling are thought to play a role in tumorigenesis. We show in the present study that most lung cancer cell lines have lost the growth-inhibitory response to TGF-beta signal, and that those with TGF-beta unresponsiveness can be divided into two major groups, TGF-beta type II receptor (TGFbetaRII)(+)/Smad7(+) and TGFbetaRII(-)/Smad7(-), suggesting the heterogeneous mechanisms underlying the TGF-beta responsiveness. The mechanism of the loss of TGFbetaRII expression of the latter group was further studied, identifying aberrant DNA methylation of the promoter region in a limited fraction of cell lines. Interestingly, we found that the alteration of chromatin structure because of histone deacetylation may also be involved, showing a good correlation with loss of TGFbetaRII expression. This notion was supported by the findings of a restriction enzyme accessibility assay, of a chromatin immunoprecipitation assay with anti-acetyl histone antibodies, and of an in vivo induction of TGFbetaRII expression by histone deacetylase inhibitors including trichostatin A (TSA) and sodium butyrate. In vitro induction of TGFbetaRII promoter reporter activity by TSA was also detected and found to require the CCAAT box within the -127/-75 region. A positive regulatory mechanism for TGFbetaRII expression in a TGF-beta-expressing cell line was also investigated, and a TPA-responsive element (TRE)-like motif, TRE2, was detected in addition to the previously reported TRE-like motif Y element in the positive regulatory region. Alterations in two discrete proteins interacting with these two TRE-like motifs were also suspected of being involved in the loss of TGFbetaRII expression. This is the first study to demonstrate that, in addition to the TSA-responsive region and TRE2 motif in the TGFbetaRII promoter, the alteration of histone deacetylation may be involved in the loss of TGFbetaRII expression in lung cancer cell lines.

Onno M, Nakamura T, Hillova J, Hill M
Identification of novel sequences in the repertoire of hypervariable TRE17 genes from immortalized nonmalignant and malignant human keratinocytes.
Gene. 1993; 131(2):209-15 [PubMed] Related Publications
The TRE17 oncogene, originally cloned from transfected DNA of Ewing's sarcoma cells, maps to chromosome 17q and is expressed in a wide variety of human cancer cells. We recently detected the variants of this gene by using the polymerase chain reaction (PCR) and sequencing from the first exon to the third intron. Based on sequence homology scores, the variants could be grouped into three families, denoted alpha, beta, and gamma. Here, we used human keratinocytes from healthy skin which had been spontaneously immortalized and then rendered malignant by serum privation in vitro. Both immortalized and malignant cells expressed TRE17 sequences to the same extent, and, according to the restriction site analysis of cloned PCR products, both contained common and rare TRE17 variants in similar proportions. These variants, one of each from both cell types, were then sequenced and compared with those from the previous study. In the phylogenetic tree, they clustered with alpha and gamma at the most distant tree positions. The overall fraction of conserved sites in the whole TRE17 repertoire was 80%. An unexpected feature of the observed variability was that intronic sites were significantly better conserved than exonic sites. Members of TRE17 gamma detected in immortalized and malignant keratinocytes differed one from another, and both differed from the TRE17 gamma already identified in Ewing's sarcoma. No TRE17 gamma has been found so far in healthy tissues, thus leaving open the possibility of its origin from TRE17 beta by somatic changes during tumor progression.

Onno M, Nakamura T, Mariage-Samson R, et al.
Human TRE17 oncogene is generated from a family of homologous polymorphic sequences by single-base changes.
DNA Cell Biol. 1993; 12(2):107-18 [PubMed] Related Publications
The tre oncogenic locus was identified in transformants receiving human DNA from Ewing's sarcoma cells EW1. Genetic elements of tre originate from chromosomes 5, 18, and 17. The TRE17 oncogene is consistently transcribed in various human cancer cells and proves oncogenic (onc) in expression vector-based assays. Here, the nucleotide sequence of TRE17 with defined noncoding and two coding exons (4,426 nucleotides) was compared with sequences cloned from placental DNA library or generated by polymerase chain reaction (PCR) from EW1 and independent healthy individuals. Cloned sequences displayed restriction site polymorphism, with different patterns for EW1 and normal tissues. Sequence analysis revealed that they originate from a family of homologous sequences alpha, beta, and gamma. TRE17 alpha and less frequent TRE17 beta (similarity score approximately equal to 88%) were found in both normal and EW1 cells. oncTRE17, classified as TRE17 beta, differed from the wild-type TRE17 beta, besides a few intronic changes, by a single-base frameshift insertion in one of the coding exons. TRE17 gamma, so far identified in EW1 but not in normal somatic cells, diverged from oncTRE17 by 6% nucleotide substitutions and by stop codons in each reading frame. The results are consistent with the possibility that TRE17 sequences other than oncTRE17 are translated if alternatively spliced. Expression of TRE17 in normal somatic cells was, however, not yet reported.

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