SSX2 (Synovial Sarcoma, X breakpoint 2)

Identity

Other names	CT5.2
	HD21
	HOM-MEL-40
	MGC119055
	MGC15364
	MGC3884
	RP11-552J9.2
	SSX
	SSX2A
	SSX2B
HGNC	SSX2
Location	Xp11.22

DNA/RNA

	SSX2 Locus and mRNA Splice Variants. Note: Exons are drawn to scale.
Description	The SSX2 gene locus encompasses 9 exons and 10,304 bp (Xp11; 52,752,974-52,742,671).
Transcription	The SSX2 gene is transcribed on the minus strand. 7 SSX2 mRNA splice variants (SV1-SV7) have been detected in liver, testis, skin melanoma, endometrium, choriocarcinoma, placenta, spleen of Hodgkins lymphoma.

Protein

	SSX2 protein isoforms. mRNAs and protein composition of SSX2 isoforms a and b. open boxes are non-coding exons.

Description	So far, two SSX2 protein isoforms (a and b) are known to exist. Their mRNAs correspond to SV1 (1466 bases) and SV3 (1322 bases) splice variants, respectively. The start codon for both isoforms is located in Exon 2. SSX2 isoform a is 233 amino acids (26.5 kD) and SSX2 isoform b 188 amino acids (21.6 kD). Of both isoforms, SSX2 isoform b is the most commonly seen and so far the best studied.
Expression	SSX2 is a developmental nuclear protein normally expressed at high levels in testis (spermatogonia) and less abundantly in the thyroid gland. Its structural analysis revealed two functional domains; a 75 amino acids N-terminal region homologous to a Kruppel-associated box (KRAB) and a C-terminal 35 amino acids domain with a potent transcription repressor activity (SSXRD). KRAB boxes are usually present in zinc finger proteins and are implicated in transcription repression. SSX2 lacks DNA binding motifs and is thought to function in gene regulation through interaction with other transcription regulators. It contains a high density of charged amino acids (about 40%) and several consensus motifs for tyrosine phosphorylation and N-glycosylation.
Function	SSX2 is thought to function in development and germ line cells as a repressive gene regulator. Its control of gene expression is believed to be epigenetic in nature and to involve chromatin modification and remodeling. It is most likely mediated by the association of SSX2 with the Polycomb gene silencing complex at the SSXRD domain. Polycomb silencing involves chromatin compaction, DNA methylation, repressive histone modifications and inaccessibility of promoter regions to transcription machineries. Other SSX2-interacting partners include the LIM homeobox protein LHX4, a Ras-like GTPase Interactor, RAB3IP thought to be involved in vesicular transport, and SSX2IP, a putative cell cycle/circadian rhythm regulator. Further studies will illuminate the mechanism by which these associations contribute to SSX2 nuclear function.
Homology	Human SSX2 is a member of a nine-gene family (SSX1, SSX2, SSX3, SSX4, SSX5, SSX6, SSX7, SSX8 and SSX9) located on the X chromosome. The SSX proteins are highly homologous at the nucleotide (about 90%) and the protein level (80%-90%). They are encoded by six exons and their expression is normally confined to testis. Recently, a mouse SSX gene family with 13 members and conserved KRAB and SSXRD domains has been identified.

Implicated in

Entity	Synovial sarcoma
Note	Synovial sarcoma (SS) is an aggressive soft tissue tumor that inflicts young adults between 15 and 40 years of age. Though its cell of origin is still unknown, it is thought to be a mesenchymal stem cell. Synovial sarcomas most frequently arise in the para-articular areas, but are also known to appear in other tissues such as the lung, heart, kidney, stomach, intestine, the abdomen, and the nervous system. Synovial sarcoma is characterized by a unique chromosomal translocation event, t(X;18)(p11.2;q11.2) that involves a break in the SYT gene on chromosome 18 and another in a SSX gene on the X chromosome. When fusion occurs at the breakpoints, it generates a hybrid gene, SYT-SSX, which encodes a potent oncogene. SYT-SSX is thought to initiate tumorigenesis and contribute to the development of synovial sarcoma. The t(X;18) tanslocation is the hallmark of synovial sarcomas. SYT-SSX is present in over 95% of SS cases. Its presence in human tumors is therefore of considerable diagnostic value and is usually detected using FISH, RT-PCR, qPCR or real time PCR. Of the nine members of the SSX family, the SSX1 and SSX2 gene loci are the most frequent sites of breakage in SS, and occasionally SSX4. The break in SSX occurs at the beginning of exon 6. According to cDNA sequence data, the SSX2 component contained in the SYT-SSX2 oncogene consists of exons 6 and 8. They represent the last 78 amino acids of SSX2 isoform b. This region lacks the KRAB repressive domain but retains the SSXRD region. SS presents in two distinct morphologies, monophasic, populated by spindle tumor cells, and biphasic with an additional glandular epithelial component. Several studies have demonstrated a strong correlation between the translocation subtype, tumor morphology and the clinical course of the disease. While the majority of SYT-SSX2-containing tumors were found to be monophasic, SYT-SSX1 was mostly detected in the biphasic tumors and was associated with a shorter metastasis-free period and a worse prognosis. However, the notion of the SYT-SSX subtype as a prognostic parameter influencing disease progression is still controversial due to contradictory data from later studies. The molecular function of SYT-SSX is key to cancer development. The fusion of SSX to SYT results in the disruption of SYT and its associated chromatin-remodeling/coactivator complexes (SWI/SNF, p300) normal function in gene expression. This deregulation is caused by SSX aberrant epigenetic control that likely leads to untimely activation of oncogenic pathways such as IGF2, Wnt and ephrin, and reactivation of the anti-apoptotic oncogene, bcl-2.
	The t(X;18)(p11;q11) translocation in synovial sarcoma: Formation of SYT-SSX2 fusion gene during the t(X;18) translocation in synovial sarcoma.
Hybrid/Mutated Gene	SYT-SSX2 Note: SYT-SSX2 variants are rare. One was described by Fligman et al. It contains an additional 126 bp segment proximal to Exon 6, where the break occurred in Exon 5 while maintaining the frame.
Entity	Cancer / testis antigen reactivated in several cancers.
Note	SSX2 is the prototype of CT antigens (MAGE, GAGE, NY-Eso-1), a group of proteins normally expressed in testis, whose genes are located on the X chromosome and are, for reasons unknown, aberrantly reactivated in several cancers. NAME: CT antigen-SSX2, HOM-MEL40, CT5.2 THERAPY/TARGET/VACCINE: CT antigens are immunogenic and are expressed exclusively in tumor tissues. They are therefore considered optimal targets for tumor immunotherapy and vaccine development. Attempts at generating CD4+ and CD8+ T cells reactive to SSX2-specific peptides are underway.
Disease	SSX2 is expressed as a CT antigen in several Cancers: Skin melanoma, Breast cancer, Endometrial Cancer, Lung Cancer, Bladder Cancer, Head-Neck cancer, Synovial sarcoma, Multiple myeloma, Colorectal carcinoma, Hepatocellular carcinoma, Prostate Cancer, Glioma, Stomach Cancer, Thyroid Cancer, Lymphoma, and Leukemia.
Prognosis	Expression of SSX2 and other CT antigens is associated with advanced metastatic cancer.

External links

	Nomenclature
HGNC	SSX2   11336
Entrez_Gene	SSX2  6757  synovial sarcoma, X breakpoint 2
	Cards
Atlas	SSX2ID42406chXp11
GeneCards	SSX2
Ensembl	SSX2 [Search_View]   ENSG00000187754 [Gene_View]
Genatlas	SSX2
GeneLynx	SSX2
eGenome	SSX2
euGene	6757
	Genomic and cartography
GoldenPath	SSX2  -  Xp11.22   chrX:52797033-52807342 +  Xp11.22   [Description]    (hg18-Mar_2006)
Ensembl	SSX2 - Xp11.22 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	SSX2
	Gene and transcription
Genbank	AF190791 [ ENTREZ ]
Genbank	AM393802 [ ENTREZ ]
Genbank	BC002818 [ ENTREZ ]
Genbank	BC007343 [ ENTREZ ]
Genbank	BC016957 [ ENTREZ ]
RefSeq	NM_003147 [ SRS ]    NM_003147 [ ENTREZ ]
RefSeq	NM_175698 [ SRS ]    NM_175698 [ ENTREZ ]
RefSeq	AC_000155 [ SRS ]    AC_000155 [ ENTREZ ]
RefSeq	NC_000023 [ SRS ]    NC_000023 [ ENTREZ ]
RefSeq	NT_011630 [ SRS ]    NT_011630 [ ENTREZ ]
RefSeq	NW_001842368 [ SRS ]    NW_001842368 [ ENTREZ ]
AceView	SSX2 AceView - NCBI
Unigene	Hs.661107 [ SRS ]    Hs.661107 [ NCBI ]     HS661107 [ spliceNest ]
	Protein : pattern, domain, 3D structure
SwissProt	O75101 [ SRS]    O75101 [ EXPASY ]     O75101 [ INTERPRO ]     O75101 [ UNIPROT ]
Interpro	IPR007726 SSXT [ SRS ]    IPR007726 SSXT [ EBI ]
CluSTr	O75101
Blocks	O75101
HPRD	02180
	Protein Interaction databases
DIP	O75101
IntAct	O75101
	Polymorphism : SNP, mutations, diseases
OMIM	300192    [ map ]
GENECLINICS	300192
SNP	SSX2 [dbSNP-NCBI]
SNP	NM_003147 [SNP-NCI]
SNP	NM_175698 [SNP-NCI]
SNP	SSX2 [GeneSNPs - Utah]  SSX2] [HGBASE - SRS]
HAPMAP	SSX2 [HAPMAP]
TICdb	SSX2 [Translocation breakpoints In Cancer]
HGMD	SSX2
	General knowledge
Family Browser	SSX2 [UCSC Family Browser]
SOURCE	NM_003147
SOURCE	NM_175698
SMD	Hs.661107
SAGE	Hs.661107
GO	nucleic acid binding [Amigo]  nucleic acid binding
GO	protein binding [Amigo]  protein binding
GO	cellular_component [Amigo]  cellular_component
GO	intracellular [Amigo]  intracellular
GO	nucleus [Amigo]  nucleus
GO	transcription [Amigo]  transcription
GO	regulation of transcription, DNA-dependent [Amigo]  regulation of transcription, DNA-dependent
PubGene	SSX2
TreeFam	SSX2
CTD	6757 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	SSX2 Related clones (RZPD - Berlin)
	PubMed
PubMed	24 Pubmed reference(s) in LocusLink

Bibliography

Fusion of SYT to two genes, SSX1 and SSX2, encoding proteins with homology to the Kruppel-associated box in human synovial sarcoma.

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PMID 7539744

Molecular diagnosis of synovial sarcoma and characterization of a variant SYT-SSX2 fusion transcript.

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PMID 7495284

The SSX-2 gene, which is involved in the t(X;18) translocation of synovial sarcomas, codes for the human tumor antigen HOM-MEL-40.

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PMID 8840996

SSX: a multigene family with several members transcribed in normal testis and human cancer.

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Int J Cancer 1997; 72: 965-971.

PMID 9378559

SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma.

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N Engl J Med 1998;338: 153-160.

PMID 9428816

A KRAB-related domain and a novel transcription repression domain in proteins encoded by SSX genes that are disrupted in human sarcomas.

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Oncogene 1998; 17: 2013-2018.

PMID 9788446

A survey of the humoral immune response of cancer patients to a panel of human tumor antigens.

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J Exp Med 1998; 187:1349-1354.

PMID 9547346

Expression of SSX genes in human tumors.

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Int J Cancer 1998; 77: 19-23.

PMID 9639388

SSX and the synovial-sarcoma-specific chimaeric protein SYT-SSX co-localize with the human Polycomb group complex.

Soulez M, Saurin AJ, Freemont PS, Knight JC.

Oncogene 1999; 18: 2739-2746.

PMID 10348348

Strong association of SYT-SSX fusion type and morphologic epithelial differentiation in synovial sarcoma.

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PMID 10718206

Analysis of SYT-SSX fusion transcripts and bcl-2 expression and phosphorylation status in synovial sarcoma.

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Lab Invest 2000; 80: 805-813.

PMID 10879732

Molecular mechanisms underlying human synovial sarcoma development.

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Genes Chromosomes Cancer 2001; 30: 1-14.

PMID 11107170

Fusions of the SYT and SSX genes in synovial sarcoma.

Ladanyi M.

Oncogene 2001; 20: 5755-5762.

PMID 11607825

The cancer-related protein SSX2 interacts with the human homologue of a Ras-like GTPase interactor, RAB3IP, and a novel nuclear protein, SSX2IP.

de Bruijn DR, dos Santos NR, Kater-Baats E, Thiissen J, van den Berk L, Stap J, Balemans M, Schepens M, Merkx G, van Kessel AG.

Genes Chromosomes Cancer 2002: 285-298.

PMID 12007189

The SSX gene family: characterization of 9 complete genes.

Gure AO, Wei IJ, Old LJ, Chen YT.

Int J Cancer 2002; 101: 448-453.

PMID 12216073

SYT associates with human SNF/SWI complexes and the C-terminal region of its fusion partner SSX1 targets histones.

Kato H, Tiernberg A, Zhang W, Krutchinsky AN, An W, Takeuchi T, Obtsuki Y, Sugano S, de Bruijn DR, Chait BT, Roeder RG.

J Biol Chem 2002; 277: 5498-55505.

PMID 11734557

Impact of SYT-SSX Fusion Type on the Clinical Behavior of Synovial Sarcoma: A Multi-Institutional Retrospective Study of 243 Patients.

Ladanyi M, Antonescu CR, Leung DH, Woodruff JM, Kawai A, Healey JH, Brennan MF, Bridge JA, Neff JR, Barr FG, Goldsmith JD, Brooks JS, Goldblum JR, Ali SZ, Shipley J, Cooper CS, Fisher C, Skytting B, Larsson O.

Cancer Res 2002; 62: 135-140.

PMID 11782370

Identification and characterization of mouse SSX genes: a multigene family on the X chromosome with restricted cancer/testis expression.

Chen YT, Alpen B, Ono T, Gure AO, Scanlan MA, Biggs WH 3d, Arden K, Nakayama E, Old LJ.

Genomics 2003; 82: 628-636.

PMID 14611804

Identification of an HLA-A*02 restricted immunogenic peptide derived from the cancer testis antigen HOM-MEL-40/SSX2.

Wagner C, Neumann F, Kubuschok B, Regitz E, Mischo A, Stevanovic S, Friedrich M, Schmidt W, Rammensee HG, Pfreundschuh M.

Cancer Immun 2003; 3: 18.

PMID 14677925

Histologic Grade, But Not SYT-SSX Fusion Type, Is an Important Prognostic Factor in Patients With Synovial Sarcoma: A Multicenter, Retrospective Analysis.

Guillou L, Benhattar J, Bonichon F, Gallagher G, Terrier P, Stauffer E, de Saint Aubain Somerhausen N, Michels JJ, Jundt G, Ranchère Vince D, Taylor S, Genevay M, Collin F, Trassard M, Coindre JM

J Clin Oncol 2004; 22: 4040-4050.

PMID 15364967

Distinct but overlapping T helper epitopes in the 37-58 region of SSX-2.

Ayyoub M, Merlo A, Hesdorffer CS, Speiser D, Rimoldi D, Cerottini JC, Ritter G, Chen YT, Old LJ, Stevanovic S, Valmori D.

Clin Immunol 2005; 114: 70-78.

PMID 15596411

Naturally acquired MAGE-A10-and SSX-2-specific CD8+ T cell responses in patients with hepatocellular carcinoma.

Bricard G, Bouzourene H, Martinet O, Rimoldi D, Halkic N, Gillet M, Chaubert P, Macdonald HR, Romero P, Cerottini JC, Speiser DE.

J Immunol 2005; 174: 1709-1716.

PMID 15661935

Correlates of SYT-SSX fusion type in synovial sarcoma: getting more complex but also more interesting?

Ladanyi M.

J Clin Oncol 2005;23: 3638-3639.

PMID 15908683

Cancer/testis antigens, gametogenesis and cancer.

Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ.

Nature Rev Cancer 2005; 5: 615-625.

PMID 16034368

SSX cancer testis antigens are expressed in most multiple myeloma patients: co-expression of SSX1, 2, 4, and 5 correlates with adverse prognosis and high frequencies of SSX-positive PCs.

Taylor BJ, Reiman T, Pittman JA, Keats JJ, de Bruijn DR, Mant MJ, Belch AR, Pilarsky LM.

J Immunother 2005; 28: 564-575.

PMID 16224274

The synovial-sarcoma-associated SS18-SSX2 fusion protein induces epigenetic gene (de)regulation.

de Bruijn DR, Allander SV, van Dijk AH, Willemse MP, Thijssen J, van Groningen JJ, Meltzer PS, van Kessel AG.

Cancer Res 2006; 66: 9474-9482.

PMID 17018603

Gene expression profiles relate to SS18/SSX fusion type in synovial sarcoma.

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Int J Cancer 2006; 118: 1165-1172.

PMID 16152617

Expression of SSX2 tumor antigen in baculovirus expression system and its application for screening of blood serum of melanoma patients.

Kyyamova RG, Gryshkova VS, Zhyyoloup AM.

Exp Oncol 2006; 28: 110-113.

PMID 16837900

A variant of the SYT-SSX2 fusion gene in a case of synovial sarcoma.

Otsuka S, Nishijo K, Nakayama T, Aoyama T, Ishibe T, Shibata KR, Shima Y, Nakamura T, Otsuka T, Toguchida J.

Cancer Genet Cytogenet 2006; 167: 82-88.

PMID 16682293

The synovial sarcoma translocation protein SYT-SSX2 recruits β-catenin to the nucleus and associates with it in an active complex.

Pretto D, Barco R, Rivera J, Neel N, Gustavson MD, Eid JE.

Oncogene 2006; 25: 3661-3669.

PMID 16462762

IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein SYT-SSX1.

Sun Y, Gao D, Liu Y, Huang J, Lessnick S, Tanaka S.

Oncogene 2006; 25: 1042-1052.

PMID 16247461

Detection of SS18-SSX fusion transcripts in formalin-fixed paraffin-embedded neoplasms: analysis of conventional RT-PCR, qRT-PCR and dual color FISH as diagnostic tools for synovial sarcoma.

Amary MF, Berisha F, Bernardi Fdel C, Herbert A, James M, Reis-Filho JS, Fisher C, Nicholson AG, Tirabosco R, Diss TC, Flanagan AM.

Mod Pathol 2007; 20: 482-496.

PMID 17334349

The synovial sarcoma SYT-SSX2 oncogene remodels the cytoskeleton through activation of the ephrin pathway.

Barco R, Hunt LB, Frump AL, Garcia CB, Benesh A, Caldwell RL, Eid JE.

Mol Biol Cell 2007;18:4003-4012.

PMID 17686994

SSX2IP: an emerging role in cancer.

Breslin A, Denniss FA, Guinn BA.

Biochem Biophys Res Commun 2007; 363: 462-465. (REVIEW)

PMID 17904521

The (epi)genetics of human synovial sarcoma.

de Bruijn DR, Nap JP, van Kessel AG.

Genes Chromosomes Cancer 2007; 46: 107-117. (REVIEW)

PMID 17117414

Dubovsky JA, McNeel DG.

Prostate 2007; 67: 1781-1790.

PMID 17929270

A conditional mouse model of synovial sarcoma: insights into a myogenic origin.

Haldar M, Hancock JD, Coffin CM, Lessnick SL, Capecchi MR.

Cancer Cell 2007; 11: 375-388.

PMID 17418413

Expression and purification of the cancer antigen SSX2: a potential cancer vaccine.

Huang CJ, Chen RH, Vannelli T, Lee F, Ritter G, Olf LJ, Batt CA.

Protein Expr Purif 2007; 56: 212-219.

PMID 17931884

The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein LHX4.

de Bruijn DR, van Dijk AH, Willemse MP, van Kessel AG.

Oncogene 2008; 27: 653-662.

PMID 17667940

Diagnostic accuracy of FISH and RT-PCR in 50 routinely processed synovial sarcomas.

Ten Heuvel SE, Hoekstra HJ, Suurmeijer AJ.

Appl Immunohistochem Mol Morphol 2008;

PMID 18301245

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Contributor(s)

Written	04-2008	Josiane Eid, Christina Garcia, Andrea Frump
		Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA

Citation

This paper should be referenced as such :

Eid J, Garcia C, Frump A . SSX2 (Synovial Sarcoma, X breakpoint 2). Atlas Genet Cytogenet Oncol Haematol. April 2008 . URL : http://AtlasGeneticsOncology.org/Genes/SSX2ID42406chXp11.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:17:42 2008