Bone: Aneurysmal bone cysts

2011-12-01   Jean-Loup Huret 

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
2.Department of Pathology, Brigham, Womens Hospital, 75 Francis Street, Boston, MA 02115, USA

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.

Cytogenetics

Cytogenetics morphological

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 name

USP6 (ubiquitin specific protease 6 (Tre-2 oncogene))

Location

17p13.2

Dna rna description

7878 bp (major transcript).

Protein description

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 name

THRAP3 (thyroid hormone receptor associated protein 3)

Location

1p34.3

Protein description

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 name

CNBP (CCHC-type zinc finger nucleic acid binding protein)

Location

3q21.3

Protein description

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 mutations

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 name

OMD (osteomodulin)

Location

9q22.31

Protein description

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 name

CDH11 (cadherin 11)

Location

16q21

Dna rna description

3.6 and 3.8 kb mRNA (two major transcripts).

Protein description

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 name

COL1A1 (collagen, type I, alpha 1)

Location

17q21.33

Protein description

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 mutations

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

Description

5 partner - 3 USP6

Oncogenesis

Upregulation of USP6 mediated by the highly active CDH11 (or other) promoter.

Bibliography

Pubmed IDLast YearTitleAuthors
150449152004Cytogenetic and molecular cytogenetic findings in 43 aneurysmal bone cysts: aberrations of 17p mapped to 17p13.2 by fluorescence in situ hybridization.Althof PA et al
115663522001Aneurysmal bone cyst with chromosomal changes involving 7q and 16p.Baruffi MR et al
84318521993Solid variant of aneurysmal bone cyst.Bertoni F et al
209605302010CNBP: a multifunctional nucleic acid chaperone involved in cell death and proliferation control.Calcaterra NB et al
108250092000Variant translocations involving 16q22 and 17p13 in solid variant and extraosseous forms of aneurysmal bone cyst.Dal Cin P et al
114080732001Translocation (16;17)(q22;p13) is a recurrent anomaly of aneurysmal bone cysts.Herens C et al
208645342010TRE17/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 et al
201237362010TRAP150 activates pre-mRNA splicing and promotes nuclear mRNA degradation.Lee KM et al
221390842012The human cadherin 11 is a pro-apoptotic tumor suppressor modulating cell stemness through Wnt/β-catenin signaling and silenced in common carcinomas.Li L et al
117567702002Soft tissue aneurysmal bone cyst: a clinicopathologic study of five cases.Nielsen GP et al
157356892005Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes.Oliveira AM et al
17774121991Cytogenetic findings in aneurysmal bone cysts.Pfeifer FM et al
220810692012Atypical mechanism of NF-κB activation by TRE17/ubiquitin-specific protease 6 (USP6) oncogene and its requirement in tumorigenesis.Pringle LM et al
184967252008Osteoadherin is upregulated by mature osteoblasts and enhances their in vitro differentiation and mineralization.Rehn AP et al
81790781994Primary aneurysmal cyst of soft tissues (extraosseous aneurysmal cyst)Rodríguez-Peralto JL et al
111060782000Cytogenetic-morphologic correlations in aneurysmal bone cyst, giant cell tumor of bone and combined lesions. A report from the CHAMP study group.Sciot R et al
207243812011Comparative vertebrate evolutionary analyses of type I collagen: potential of COL1a1 gene structure and intron variation for common bone-related diseases.Stover DA et al
117643832001Aneurysmal bone cyst of the nose with 17p13 involvement.Winnepenninckx V et al
114413692001Primary aneurysmal bone cysts: 16q22 and/or 17p13 chromosome abnormalities.Wyatt-Ashmead J et al

External Links

Citation

Jean-Loup Huret

Bone: Aneurysmal bone cysts

Atlas Genet Cytogenet Oncol Haematol. 2011-12-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/5133/bone-aneurysmal-bone-cysts

Historical Card

2004-06-01 Bone: Aneurysmal bone cysts by  Paola Dal Cin 

Department of Pathology, Brigham, Womens Hospital, 75 Francis Street, Boston, MA 02115, USA

2002-01-01 Bone: Aneurysmal bone cysts by  Paola Dal Cin 

Department of Pathology, Brigham, Womens Hospital, 75 Francis Street, Boston, MA 02115, USA