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Bone: Aneurysmal bone cysts

Written2011-12Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
This article is an update of :
2004-06Paola Dal Cin
Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
2002-01Paola Dal Cin
Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA

(Note : for Links provided by Atlas : click)


ICD-Topo C400-C403,C408-C414,C418-C419 BONES & JOINTS
Atlas_Id 5133
Phylum Bones::Aneurysmal bone cyst
WHO/OMS Classification Bones

Clinics and Pathology

Etiology The most widely accepted pathogenetic mechanism of aneurysmal bone cysts has long involved a local circulatory disturbance leading to markedly increased venous pressure and the development of a dilated and enlarged vascular bed within the affected bone area. However, the recent identification of recurrent chromosome abnormalities has challenged this historical perception. May involve the arrest of maturation of the osteoblasts caused by USP6 overexpression and dysregulation of autocrine BMP (bone morphology protein) signaling (Lau et al., 2010).
Clinics Aneurysmal bone cysts (ABC) are benign lesions, but locally aggressive, that occur more frequently in the metaphyses of long bones, especially distal femur, the proximal tibia and vertebral posterior bodies. Multiple involvement is frequent. It can occur at any age but most patients are diagnosed in the first 2 decades of life. It can exist as primary bone lesion or as secondary lesions arising in association with other osseous conditions, namely giant cell tumor, chondroblastoma, chondromyxoid fibroma and fibrous dysplasia. Pain and swelling are the most common complaints.
Pathology As the name implies, the lesion is histopathologically characterized by hemorrhagic cystic and cavernous spaces surrounded by fibrous septa composed of mildly to moderately mitotically active spindle cells intermixed with scattered osteoclast-like multinucleated giant cells. Approximately 95% of ABC have typical histology whereas the remaining 5% are solid variants in which the usual cavernous channels and spaces may not be identified. An extraosseous couterpart of ABC has been described, sometimes referred to as ABC of soft tissues, and is histologically identical to ABC but diagnosed much less frequently.
Treatment ABC is most frequently treated by curettage, but local recurrences can still occur in about one fourth of cases.


Chromosome bands 16q22 and/or 17p13 are non randomly rearranged in ABC, regardless of tumor type (classic, solid) and or location (osseous and extraosseous). A recurrent t(16;17)(q22;p13), with CDH11 and USP6 involvements, has been identified in at least eleven cases to date, but other chromosomal segments as translocation partner for each chromosome have been described:
A t(1;17)(p34;p13) THRAP3/USP6 was found in one case.
A t(3;17)(q21;p13) CNBP/USP6 was found in one case.
A t(9;17)(q22;p13) OMD/USP6 was found in one case.
A t(17;17)(p13;q21) COL1A1/USP6 was found in two cases.

Other translocations of note:
one case of t(2;17)(p23;p13) (Sciot et al., 2000),
two cases of t(6;17)(p21;p13) (Winnepenninckx et al., 2001; Althof et al., 2004),
two cases of t(11;16)(q13;q22-23), one with a classical bone tumor, the other with a tumor of the soft tissues (Dal Cin et al., 2000; Oliveira et al., 2004),
one case of del(16)(q22) (Panagopoulos et al., 2001),
three cases with a t(17;17)(p13;q12) or an inv(17)(p13q11-12) (Dal Cin et al., 2000; Nielsen et al., 2002; Althof et al., 2004).
Although additional cases should be studied, it appears that in combined giant cell tumor and secondary aneurysmal bone cyst, both lesions can retain their characteristic chromosomal aberrations.

Genes involved and Proteins

Note So far, USP6 is constantly involved : in the t(1;17)(p34;p13) THRAP3/USP6, the t(3;17)(q21;p13) CNBP/USP6, the t(9;17)(q22;p13) OMD/USP6, the t(16;17)(q22;p13) CDH11/USP6, and the t(17;17)(p13;q21) COL1A1/USP6. However, as mentioned above, the 16q22 breakpoint has also been found recurrently in the absence of an apparent 17p13 involvement, e.g. in the t(11;16)(q13;q22-23) or in the del(16)(q22).
Gene NameUSP6 (ubiquitin specific protease 6 (Tre-2 oncogene))
Location 17p13.2
Dna / Rna 7878 bp (major transcript).
Protein 1406 amino acids; USP6 is a hominoid-specific gene that was initially cloned from an Ewing sarcoma cell line. It 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. Sequence comparisons indicate that the first 14 exons of USP6 are derived from TBC1D3 (PRC17) whereas exons 15 to 30 are derived from USP32. 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. Because USP6 is absent in non-hominoid primates and is primarily expressed in testicular tissue, it has been suggested that USP6 contributed to hominoid speciation. Until recently USP6 function was poorly know but recent data suggest that USP6 is a component of a novel effector pathway for Rho GTPases Cdc42 and Rac1 and stimulates actin remodeling. USP6, also called TRE17/ubiquitin-specific protease 6 (USP6), is a deubiquitinase. It is the first de-ubiquitinating enzyme to activate NF-KB, and requires both catalytic subunits of IKK (IKKalpha and IKKbeta) (Pringle et al., 2011).

Gene NameTHRAP3 (thyroid hormone receptor associated protein 3)
Location 1p34.3
Protein THRAP3, also called TRAP150, is made of an arginine/serine-rich sequence in the N-terminal region and domains with similarity with BCLAF1 and with CASC3/MLN51 in the C-terminal region. It is part of the transcription regulatory complex TRAP/Mediator, and a component of the spliceosome. It both activates pre-mRNA splicing and induces mRNA degradation. The arginine/serine-rich N-term of THRAP3 is responsible for its splicing activity, and the C-term part for its mRNA degradation activity (Lee et al., 2010).

Gene NameCNBP (CCHC-type zinc finger nucleic acid binding protein)
Location 3q21.3
Protein CNBP, also called ZNF9, is made of 7 CCHC-type Zn fingers. Nucleic acid binding protein; binds single stranded DNA and RNA; act as a regulator of transcription and translation of many genes, including MYC. CNBP may regulate gene expression by catalyzing the formation of G4s (G-quadruplexes, formed by intramolecular four-stranded DNA structures).
Germinal mutation Myotonic dystrophy DM2 is caused by expansion of a (CCTG)(n) in CNBP. CNBP has also been implicated in sporadic inclusion body myositis (review in Calcaterra et al., 2010).

Gene NameOMD (osteomodulin)
Location 9q22.31
Protein OMD (osteomodulin), also called OSAD (osteoadherin), is a member of the small leucine rich-repeat proteoglycan (SLRP) family. It is an extracellular matrix keratan sulfate proteoglycan restricted to mineralized tissues. OMD is a marker for terminally differentiated matrix producing osteoblasts. OMD expression enhances the differentiation and maturation of osteoblasts. It is induced by osteoclast activity (Rehn et al., 2008).

Gene NameCDH11 (cadherin 11)
Location 16q21
Dna / Rna 3.6 and 3.8 kb mRNA (two major transcripts).
Protein 693 and 796 amino acids; membrane protein that mediate calcium-dependent cell-cell adhesion, member of the cadherin superfamily. CDH11 seems to be highly expressed during the development and differentiation of the osteoblastic lineage, indicating an important role in bone development. Two splice variants have been identified, one of which encodes an isoform with a shorter cytoplasmic domain. Its intracellular domain is anchored to the actin cytoskeleton through alpha and beta-catenin. Role in maintaining tissue architecture and cell polarity, limiting cell movement and proliferation. CDH11 antagonizes Wnt/beta-catenin signaling pathway, induces apoptosis, and regulates epithelial-mesenchymal transition (Li et al., 2011). CDH11 is involved in various cancers. Tumor suppressor function.

Gene NameCOL1A1 (collagen, type I, alpha 1)
Location 17q21.33
Protein Two pro a1(I) chain associate in trimers with one pro a2(I) chain to form the type I collagen fibrils after proteolysis. Constituent of the extra cellular matrix in connective tissue of bone, skin, tendon, ligament, teeth.
Germinal mutation COL1A1 has been found mutated in osteoporosis, osteogenesis imperfecta types I-IV, Ehlers-Danlos types I and VIIA, and Caffey disease (Stover and Verrelli, 2011).

Result of the chromosomal anomaly

Hybrid Gene
Description 5' partner - 3' USP6
Fusion Protein
Description Fusion of the promoter region of CDH11 (noncoding exons 1 and 2) to the entire coding region of USP6, which starts on exon 2 in the (16;17)(q22;p13). Therefore, there is only a fusion gene but not a fusion protein. This type of gene fusion is known as promoter swapping and has been described in other solid tumors, including pleomorphic adenoma and lipoblastoma. The same model applies to translocations of USP6 with other partners.
Oncogenesis Upregulation of USP6 mediated by the highly active CDH11 (or other) promoter.


Cytogenetic and molecular cytogenetic findings in 43 aneurysmal bone cysts: aberrations of 17p mapped to 17p13.2 by fluorescence in situ hybridization.
Althof PA, Ohmori K, Zhou M, Bailey JM, Bridge RS, Nelson M, Neff JR, Bridge JA.
Mod Pathol. 2004 May;17(5):518-25.
PMID 15044915
Aneurysmal bone cyst with chromosomal changes involving 7q and 16p.
Baruffi MR, Neto JB, Barbieri CH, Casartelli C.
Cancer Genet Cytogenet. 2001 Sep;129(2):177-80.
PMID 11566352
Solid variant of aneurysmal bone cyst.
Bertoni F, Bacchini P, Capanna R, Ruggieri P, Biagini R, Ferruzzi A, Bettelli G, Picci P, Campanacci M.
Cancer. 1993 Feb 1;71(3):729-34.
PMID 8431852
CNBP: a multifunctional nucleic acid chaperone involved in cell death and proliferation control.
Calcaterra NB, Armas P, Weiner AM, Borgognone M.
IUBMB Life. 2010 Oct;62(10):707-14.
PMID 20960530
Variant translocations involving 16q22 and 17p13 in solid variant and extraosseous forms of aneurysmal bone cyst.
Dal Cin P, Kozakewich HP, Goumnerova L, Mankin HJ, Rosenberg AE, Fletcher JA.
Genes Chromosomes Cancer. 2000 Jun;28(2):233-4.
PMID 10825009
World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of Soft Tissue Tumor and Bone. Aneurysmal bone cyst.
Fletcher CDM, Unni KK, Mertens F.
IARC Press: Lyon 2002: 338-339.
Translocation (16;17)(q22;p13) is a recurrent anomaly of aneurysmal bone cysts.
Herens C, Thiry A, Dresse MF, Born J, Flagothier C, Vanstraelen G, Allington N, Bex V.
Cancer Genet Cytogenet. 2001 May;127(1):83-4.
PMID 11408073
TRE17/ubiquitin-specific protease 6 (USP6) oncogene translocated in aneurysmal bone cyst blocks osteoblastic maturation via an autocrine mechanism involving bone morphogenetic protein dysregulation.
Lau AW, Pringle LM, Quick L, Riquelme DN, Ye Y, Oliveira AM, Chou MM.
J Biol Chem. 2010 Nov 19;285(47):37111-20. Epub 2010 Sep 23.
PMID 20864534
TRAP150 activates pre-mRNA splicing and promotes nuclear mRNA degradation.
Lee KM, Hsu IaW, Tarn WY.
Nucleic Acids Res. 2010 Jun;38(10):3340-50. Epub 2010 Jan 31.
PMID 20123736
The human cadherin 11 is a pro-apoptotic tumor suppressor modulating cell stemness through Wnt/b-catenin signaling and silenced in common carcinomas.
Li L, Ying J, Li H, Zhang Y, Shu X, Fan Y, Tan J, Cao Y, Tsao SW, Srivastava G, Chan AT, Tao Q.
Oncogene. 2011 Dec 5. doi: 10.1038/onc.2011.541. [Epub ahead of print]
PMID 22139084
Soft tissue aneurysmal bone cyst: a clinicopathologic study of five cases.
Nielsen GP, Fletcher CD, Smith MA, Rybak L, Rosenberg AE.
Am J Surg Pathol. 2002 Jan;26(1):64-9.
PMID 11756770
Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes.
Oliveira AM, Perez-Atayde AR, Dal Cin P, Gebhardt MC, Chen CJ, Neff JR, Demetri GD, Rosenberg AE, Bridge JA, Fletcher JA.
Oncogene. 2005 May 12;24(21):3419-26.
PMID 15735689
Cytogenetic findings in aneurysmal bone cysts.
Pfeifer FM, Bridge JA, Neff JR, Mouron BJ.
Genes Chromosomes Cancer. 1991 Nov;3(6):416-9.
PMID 1777412
Atypical mechanism of NF-kB activation by TRE17/ubiquitin-specific protease 6 (USP6) oncogene and its requirement in tumorigenesis.
Pringle LM, Young R, Quick L, Riquelme DN, Oliveira AM, May MJ, Chou MM.
Oncogene. 2011 Nov 14. doi: 10.1038/onc.2011.520. [Epub ahead of print]
PMID 22081069
Osteoadherin is upregulated by mature osteoblasts and enhances their in vitro differentiation and mineralization.
Rehn AP, Cerny R, Sugars RV, Kaukua N, Wendel M.
Calcif Tissue Int. 2008 Jun;82(6):454-64.
PMID 18496725
Primary aneurysmal cyst of soft tissues (extraosseous aneurysmal cyst).
Rodriguez-Peralto J L, Lopez-Barea F, Sanchez-Herrera S, Atienza M.
Am J Surg Pathol. 1994 Jun;18(6):632-6.
PMID 8179078
Cytogenetic-morphologic correlations in aneurysmal bone cyst, giant cell tumor of bone and combined lesions. A report from the CHAMP study group.
Sciot R, Dorfman H, Brys P, Dal Cin P, De Wever I, Fletcher CD, Jonson K, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Samson I, Tallini G, Van den Berghe H, Vanni R, Willen H.
Mod Pathol. 2000 Nov;13(11):1206-10.
PMID 11106078
Comparative vertebrate evolutionary analyses of type I collagen: potential of COL1a1 gene structure and intron variation for common bone-related diseases.
Stover DA, Verrelli BC.
Mol Biol Evol. 2011 Jan;28(1):533-42. Epub 2010 Aug 19.
PMID 20724381
Aneurysmal bone cyst of the nose with 17p13 involvement.
Winnepenninckx V, Debiec-Rychter M, Jorissen M, Bogaerts S, Sciot R.
Virchows Arch. 2001 Nov;439(5):636-9.
PMID 11764383
Primary aneurysmal bone cysts: 16q22 and/or 17p13 chromosome abnormalities.
Wyatt-Ashmead J, Bao L, Eilert RE, Gibbs P, Glancy G, McGavran L.
Pediatr Dev Pathol. 2001 Jul-Aug;4(4):418-9.
PMID 11441369


This paper should be referenced as such :
Huret, JL
Bone: Aneurysmal bone cysts
Atlas Genet Cytogenet Oncol Haematol. 2012;16(5):368-371.
Free journal version : [ pdf ]   [ DOI ]
On line version :
History of this paper:
Dal, Cin P. Bone: Aneurysmal bone cysts. Atlas Genet Cytogenet Oncol Haematol. 2002;6(2):136-137.
Dal, Cin P. Bone: Aneurysmal bone cysts. Atlas Genet Cytogenet Oncol Haematol. 2004;8(3):254-256.

Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes USP6

Translocations implicated (Data extracted from papers in the Atlas)

 t(1;17)(p34;p13) THRAP3/USP6
 t(16;17)(q22;p13) CDH11/USP6
 t(17;17)(p13;q21) COL1A1/USP6
 t(3;17)(q21;p13) CNBP/USP6
 t(9;17)(q22;p13) OMD/USP6

External links

Mitelman database t(1;17)(p34;p13) [CaseList]     t(1;17)(p34;p13) [Transloc - MCList]   THRAP3/USP6 Fusion - MCList]
Mitelman database t(16;17)(q22;p13) [CaseList]     t(16;17)(q22;p13) [Transloc - MCList]   CDH11/USP6 Fusion - MCList]
COSMIC[ CDH11 ]   [ USP6 ]
Mitelman database t(17;17)(p13;q21) [CaseList]     t(17;17)(p13;q21) [Transloc - MCList]   COL1A1/USP6 Fusion - MCList]
COSMIC[ COL1A1 ]   [ USP6 ]
Mitelman database t(3;17)(q21;p13) [CaseList]     t(3;17)(q21;p13) [Transloc - MCList]   CNBP/USP6 Fusion - MCList]
Mitelman database t(9;17)(q22;p13) [CaseList]     t(9;17)(q22;p13) [Transloc - MCList]   OMD/USP6 Fusion - MCList]
COSMIC[ OMD ]   [ USP6 ]
arrayMap Topo ( C40,C41) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
COSMIC_fusionCDH11 (16q21) USP6 (17p13.2)    [fusion1399] [fusion1400] [fusion1401] [fusion1402] [fusion1403] [fusion1404] [fusion1405] [fusion1406] [fusion1408] [fusion1409]
Mitelman databaseCDH11/USP6[MCList]    CDH11 (16q21) USP6 (17p13.2)   
Mitelman databaseCDH11/USP6[MCList]    CDH11 (16q21) USP6 (17p13.2)   t(16;17)(q21;p13)
COSMIC_fusionCNBP (3q21.3) USP6 (17p13.2)    [fusion1416] [fusion1417] [fusion1418]
Mitelman databaseCNBP/USP6[MCList]    CNBP (3q21.3) USP6 (17p13.2)   t(3;7)(q21;p13)
TICdbCNBP/USP6    CNBP (3q21.3) USP6 (17p13.2)
COSMIC_fusionCOL1A1 (17q21.33) USP6 (17p13.2)    [fusion1397] [fusion1398] [fusion1414] [fusion1415]
Mitelman databaseCOL1A1/USP6[MCList]    COL1A1 (17q21.33) USP6 (17p13.2)   t(17;17)(p13;q21)
TICdbCOL1A1/USP6    COL1A1 (17q21.33) USP6 (17p13.2)
COSMIC_fusionOMD (9q22.31) USP6 (17p13.2)    [fusion1412] [fusion1413]
Mitelman databaseOMD/USP6[MCList]    OMD (9q22.31) USP6 (17p13.2)   
Mitelman databaseOMD/USP6[MCList]    OMD (9q22.31) USP6 (17p13.2)   t(9;17)(q22;p13)
COSMIC_fusionTHRAP3 (1p34.3) USP6 (17p13.2)    [fusion1410] [fusion1411]
Mitelman databaseTHRAP3/USP6[MCList]    THRAP3 (1p34.3) USP6 (17p13.2)   t(1;17)(p34;p13)
TICdbTHRAP3/USP6    THRAP3 (1p34.3) USP6 (17p13.2)
Disease databaseBone: Aneurysmal bone cysts
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed

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