SSX2 (synovial sarcoma, X breakpoint 2)

2013-05-01   Josiane Eid , Christina Garcia , Andrea Frump 

Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA





SSX2 is a member of a family of at least nine genes (SSX1, SSX2, SSX3, SSX4, SSX5, SSX6, SSX7, SSX8 and SSX9) and ten pseudogenes (ψSSX1-10), all arranged in two clusters on the X chromosome, except ψSSX10 (Gure et al., 2002).
Atlas Image
SSX2 locus and mRNA splice variants. Note: Exons are drawn to scale.


The SSX2 gene locus encompasses 9 exons and 10304 bp (Xp11; 52725946-52736249).


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.



SSX2 is gaining importance as a developmental factor involved in the pathogenesis of synovial sarcoma, and as an immunotherapeutic target for several human cancers.
Atlas Image
SSX2 protein isoforms. mRNAs and protein composition of SSX2 isoforms a and b. Open boxes are non-coding exons.


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.


SSX2 is a nuclear protein normally expressed at high levels in the developing and normal adult testis (Apale and B spermatogonia) (Chen et al., 2011; Lim et al., 2011), and less abundantly in the thyroid gland (Crew et al., 1995). Its structural analysis (Lim et al., 1998) revealed two functional domains; an N-terminal region (amino acids 20-83) homologous to a Kruppel-associated box (KRAB) and a C-terminal 33 amino acids domain (amino acids 155-188) 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.


SSX2 is usually localized in the nucleus (dos Santos et al., 2000). However, cytoplasmic SSX2 was detected in pluripotent mesenchymal stem cells before differentiation (Cronwright et al., 2005).


SSX2 is thought to function in germ line cell development (Chen et al., 2011) as a repressive gene regulator. Its control of gene expression is believed to be epigenetic in nature and to involve chromatin modification and remodeling. This is likely mediated by SSX2 association with the Polycomb gene-silencing complex at the SSXRD domain (Soulez et al., 1999; Barco et al., 2009; Przybyl et al., 2012), and with histones (Kato et al., 2002). 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 (de Bruijn et al., 2008), a Ras-like GTPase Interactor, RAB3IP (de Bruijn et al., 2002) thought to be involved in vesicular transport, and SSX2IP, a putative cell cycle/circadian rhythm regulator. SSX2IP expression on the surface of myeloid leukemia cells (AML) marks it as an appropriate target for AML immunotherapy (Breslin et al., 2007). Recent evidence demonstrated a role for SSX2IP in promoting hepatocellular tumor metastasis and resistance to chemotherapy (Li et al., 2013).
Active studies are beginning to yield insights into SSX2 biological functions. Recent evidence demonstrated a regulatory role for SSX2 in nuclear receptor signaling and cancer cell invasion (Chen et al., 2012). A similar SSX2 effect on stem cell migration was reported previously (Cronwright et al., 2005).


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 (Gure et al., 1997; Gure et al., 2002). Recently, a mouse SSX gene family with 13 members and conserved KRAB and SSXRD domains has been identified (Chen et al., 2003).

Implicated in

Entity name
Synovial sarcoma (SS) is an aggressive soft tissue tumor that afflicts 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 (Haldar et al., 2007; Naka et al., 2010). 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, head and neck, and the nervous system (Ferrari et al., 2008).
Synovial sarcoma is characterized by a unique chromosomal translocation event, t(X;18)(p11.2;q11.2) that involves a break in the SS18 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, SS18-SSX, which encodes a potent oncogene. SS18-SSX is thought to initiate tumorigenesis and contribute to the development of synovial sarcoma (Ladanyi, 2001; Przybyl et al., 2012).
The t(X;18) tanslocation is the hallmark of synovial sarcomas. SS18-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 (Amary et al., 2007; Ten Heuvel et al., 2008).
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 SS18-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 (Crew et al., 1995; de Leeuw et al., 1995; Wei et al., 2003).
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 SS18-SSX2 containing tumors were found to be monophasic, SS18-SSX1 was mostly detected in the biphasic tumors and was associated with a shorter metastasis-free period and a worse prognosis (Kawai et al., 1998; Antonescu et al., 2000; Ladanyi et al., 2002; Fernebro et al., 2006). However, the notion of the SS18-SSX subtype as a prognostic parameter influencing disease progression is still controversial due to contradictory data from later studies (Guillou et al., 2004; Ladanyi, 2005).
The molecular function of SS18-SSX is key to cancer development (dos Santos et al., 2001; de Bruijn et al., 2007; Przybyl et al., 2012). Fusion of SSX1/2 to SS18 results in the disruption of SS18 and its associated chromatin-remodeling/coactivator complexes (SWI/SNF, p300) normal function in gene expression (de Bruijn et al., 2006). SSX affinity for developmental genes controlled by Polycomb leads to the deregulation of such genes by SS18-SSX1/2 (Barco et al., 2009; Su et al., 2012). Deregulation of expression programs by SS18-SSX1/2 results in a series of biological events implicated in synovial sarcoma pathogenesis. These events likely include reprogramming of stem cell differentiation (Garcia et al., 2012), and untimely activation of oncogenic pathways such as IGF2 (Sun et al., 2006), Wnt (Horvai et al., 2006; Pretto et al., 2006; Bozzi et al., 2008), FGF (Ishibe et al., 2005; Garcia et al., 2012), and ephrin (Barco et al., 2007), as well as reactivation of the anti-apoptotic pathway and the bcl-2 oncogene (Mancuso et al., 2000, Jones et al., 2013).
SS18-SSX2 variants are rare. One was described by Fligman et al (1995). It contains an additional 126 bp segment proximal to SSX2 Exon 6, where the break occurred in Exon 5 while maintaining the frame. Another SS18-SSX2 variant includes 50 additional base pairs of SSX2 Exon 5 (Otsuka et al., 2006).
Hybrid gene
Atlas Image
SS18-SSX fusion protein generated by the t(X;18)(p11.2;q11.2) chromosomal translocation. (X) represents cross-over. Arrowheads indicate breakpoints on SS18 and SSX.
Entity name
Cancer / testis antigen reactivated in several cancers (CT antigen-SSX2, HOM-MEL40, CT5.2)
SSX2 is a major prototype of CT antigens (e.g. MAGE, GAGE, NY-Eso-1), a group of proteins whose expression is restricted to testis and human cancers. A large subset of CT antigen genes (over 30), including the SSX family, are located on the X chromosome, and are, for reasons unknown, aberrantly reactivated in several major cancers. The complete absence of CT antigen expression in normal tissues renders them ideal targets for cancer immunotherapy (Gure et al., 1997; Simpson et al., 2005; Smith and McNeel, 2010; Lim et al., 2012).
Immunogenic response to reactivated SSX2 was first discovered in the sera of patients with malignant melanoma (Tureci et al., 1996). Since then aberrant expression of SSX2 has been detected in a large array of human cancers: skin melanoma (Tureci et al., 1998), breast cancer (Tureci et al., 1998; Mashino et al., 2001), endometrial cancer (Tureci et al., 1998), lung cancer (Gure et al., 2005), bladder cancer (Tureci et al., 1998), head-neck cancer (Tureci et al., 1998; Atanackovic et al., 2006), synovial sarcoma (Tureci et al., 1998), multiple myeloma (Taylor et al., 2005), colorectal carcinoma (Tureci et al., 1998; Scanlan et al., 2002), hepatocellular carcinoma (Chen et al., 2001; Bricard et al., 2005; Wu et al., 2006), prostate cancer (Dubovsky and McNeel, 2007; Smith and McNeel, 2011), glioma (Tureci et al., 1996, Tureci et al., 1998), stomach cancer (Mashino et al., 2001), thyroid cancer (Tureci et al., 1996), lymphoma (Tureci et al., 1998; Colleoni et al., 2002), leukemia (Niemeyer et al., 2003), neuroblastoma (Chi et al., 2002), osteosarcoma (Naka et al., 2002), ovarian cancer (Tureci et al., 1998; Valmori et al., 2006), and kidney cancer (Du et al., 2005).
In several cancers, SSX2 and other CT antigens are considered diagnostic and prognostic markers of advanced malignancy. In multiple myeloma, non-small cell lung cancer, prostate cancer, and colorectal cancer, their coordinate expression is correlated with markedly reduced survival (Dubovsky and McNeel, 2007; Gure et al., 2005; Taylor et al., 2005) and metastasis (Choi and Chang, 2012).

The high immunogenicity of CT antigens and their tissue-restricted expression make them optimal targets for tumor immunotherapy and vaccine development. SSX2 is a major tumor antigen. Due to SSX2 wide expression in cancer, a single anti-SSX2 therapy will potentially benefit multiple diseases. Immunodominant SSX2-derived peptides that elicit adequate T-cell responses have been identified, and initial reports have described their successful use in vivo (Wagner et al., 2003; Ayyoub et al., 2004a; Ayyoub et al., 2004b; Neumann et al., 2004; Ayyoub et al., 2005; Kyyamova et al., 2006; Huang et al., 2007; Neumann et al., 2011; Smith and McNeel, 2011). Since the majority of tumors express more than one CT antigen, attempts at generating polyvalent T cells directed against multiple epitopes for simultaneous antigen recognition are ongoing (Gerdemann et al., 2011; Smith et al., 2011). Notably, CT antigen-specific cytotoxic T lymphocytes were able to recognize and destroy chemoresistant lymphoma cells expressing the cognate antigens (Shafer et al., 2010). Finally, CT antigen directed immunotherapy could potentially become a valuable addition to chemotherapy for effective treatment of cancer.


Pubmed IDLast YearTitleAuthors
173343492007Detection 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 et al
107182062000Strong association of SYT-SSX fusion type and morphologic epithelial differentiation in synovial sarcoma.Antonescu CR et al
169291652006Expression of cancer-testis antigens as possible targets for antigen-specific immunotherapy in head and neck squamous cell carcinoma.Atanackovic D et al
150852022004An immunodominant SSX-2-derived epitope recognized by CD4+ T cells in association with HLA-DR.Ayyoub M et al
155964112005Distinct but overlapping T helper epitopes in the 37-58 region of SSX-2.Ayyoub M et al
193373762009The synovial sarcoma-associated SYT-SSX2 oncogene antagonizes the polycomb complex protein Bmi1.Barco R et al
176869942007The synovial sarcoma SYT-SSX2 oncogene remodels the cytoskeleton through activation of the ephrin pathway.Barco R et al
186334592008Molecular characterization of synovial sarcoma in children and adolescents: evidence of akt activation.Bozzi F et al
179045212007SSX2IP: an emerging role in cancer.Breslin A et al
156619352005Naturally acquired MAGE-A10- and SSX-2-specific CD8+ T cell responses in patients with hepatocellular carcinoma.Bricard G et al
111798342001Expressions of cancer-testis antigens in human hepatocellular carcinomas.Chen CH et al
223446192012Cancer/testis antigen SSX2 enhances invasiveness in MCF-7 cells by repressing ERα signaling.Chen L et al
146118042003Identification and characterization of mouse SSX genes: a multigene family on the X chromosome with restricted cancer/testis expression.Chen YT et al
220164182011Chromosome X-encoded cancer/testis antigens show distinctive expression patterns in developing gonads and in testicular seminoma.Chen YT et al
125211242002Expression of SSX-2 and SSX-4 genes in neuroblastoma.Chi SN et al
222877452012The expression of MAGE and SSX, and correlation of COX2, VEGF, and survivin in colorectal cancer.Choi J et al
120943742002Expression of SSX genes in the neoplastic cells of Hodgkin's lymphoma.Colleoni GW et al
75397441995Fusion of SYT to two genes, SSX1 and SSX2, encoding proteins with homology to the Kruppel-associated box in human synovial sarcoma.Crew AJ et al
157816332005Cancer/testis antigen expression in human mesenchymal stem cells: down-regulation of SSX impairs cell migration and matrix metalloproteinase 2 expression.Cronwright G et al
158543472005[Expression of SSX2 gene in human urologic neoplasms].Du P et al
179292702007Inducible expression of a prostate cancer-testis antigen, SSX-2, following treatment with a DNA methylation inhibitor.Dubovsky JA et al
161526172006Gene expression profiles relate to SS18/SSX fusion type in synovial sarcoma.Fernebro J et al
184408002008Synovial sarcoma of children and adolescents: the prognostic role of axial sites.Ferrari A et al
74952841995Molecular diagnosis of synovial sarcoma and characterization of a variant SYT-SSX2 fusion transcript.Fligman I et al
219967282012Reprogramming of mesenchymal stem cells by the synovial sarcoma-associated oncogene SYT-SSX2.Garcia CB et al
219151032011Cytotoxic T lymphocytes simultaneously targeting multiple tumor-associated antigens to treat EBV negative lymphoma.Gerdemann U et al
153649672004Histologic grade, but not SYT-SSX fusion type, is an important prognostic factor in patients with synovial sarcoma: a multicenter, retrospective analysis.Guillou L et al
162992362005Cancer-testis genes are coordinately expressed and are markers of poor outcome in non-small cell lung cancer.Gure AO et al
93785591997SSX: a multigene family with several members transcribed in normal testis and human cancer.Gure AO et al
122160732002The SSX gene family: characterization of 9 complete genes.Güre AO et al
174184132007A conditional mouse model of synovial sarcoma: insights into a myogenic origin.Haldar M et al
167400292006Beta-catenin nuclear expression correlates with cyclin D1 expression in primary and metastatic synovial sarcoma: a tissue microarray study.Horvai AE et al
179318842007Expression and purification of the cancer antigen SSX2: a potential cancer vaccine.Huang CJ et al
158146522005Disruption of fibroblast growth factor signal pathway inhibits the growth of synovial sarcomas: potential application of signal inhibitors to molecular target therapy.Ishibe T et al
227970742013SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas.Jones KB et al
117345572002SYT associates with human SNF/SWI complexes and the C-terminal region of its fusion partner SSX1 targets histones.Kato H et al
94288161998SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma.Kawai A et al
168379002006Expression of SSX2 tumor antigen in baculovirus expression system and its application for screening of blood serum of melanoma patients.Kyyamova RG et al
117823702002Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: a multi-institutional retrospective study of 243 patients.Ladanyi M et al
159086832005Correlates of SYT-SSX fusion type in synovial sarcoma: getting more complex but also more interesting?Ladanyi M et al
234523952013SSX2IP promotes metastasis and chemotherapeutic resistance of hepatocellular carcinoma.Li P et al
97884461998A KRAB-related domain and a novel transcription repression domain in proteins encoded by SSX genes that are disrupted in human sarcomas.Lim FL et al
217064742011OCT2, SSX and SAGE1 reveal the phenotypic heterogeneity of spermatocytic seminoma reflecting distinct subpopulations of spermatogonia.Lim J et al
224320852012Cancer-testis antigens: the current status on antigen regulation and potential clinical use.Lim SH et al
108797322000Analysis of SYT-SSX fusion transcripts and bcl-2 expression and phosphorylation status in synovial sarcoma.Mancuso T et al
115312572001Expression of multiple cancer-testis antigen genes in gastrointestinal and breast carcinomas.Mashino K et al
119206292002Expression of SSX genes in human osteosarcomas.Naka N et al
205180202010Synovial sarcoma is a stem cell malignancy.Naka N et al
216301072011A peptide epitope derived from the cancer testis antigen HOM-MEL-40/SSX2 capable of inducing CD4⁺ and CD8⁺ T-cell as well as B-cell responses.Neumann F et al
153820482004Identification of an HLA-DR-restricted peptide epitope with a promiscuous binding pattern derived from the cancer testis antigen HOM-MEL-40/SSX2.Neumann F et al
126813662003Expression of serologically identified tumor antigens in acute leukemias.Niemeyer P et al
166822932006A variant of the SYT-SSX2 fusion gene in a case of synovial sarcoma.Otsuka S et al
164627622006The synovial sarcoma translocation protein SYT-SSX2 recruits beta-catenin to the nucleus and associates with it in an active complex.Pretto D et al
225504152012Downstream and intermediate interactions of synovial sarcoma-associated fusion oncoproteins and their implication for targeted therapy.Przybyl J et al
121243392002Cancer-related serological recognition of human colon cancer: identification of potential diagnostic and immunotherapeutic targets.Scanlan MJ et al
203675722010Antigen-specific cytotoxic T lymphocytes can target chemoresistant side-population tumor cells in Hodgkin lymphoma.Shafer JA et al
160343682005Cancer/testis antigens, gametogenesis and cancer.Simpson AJ et al
218805882011Expression and immunotherapeutic targeting of the SSX family of cancer-testis antigens in prostate cancer.Smith HA et al
219042192011Vaccines targeting the cancer-testis antigen SSX-2 elicit HLA-A2 epitope-specific cytolytic T cells.Smith HA et al
103483481999SSX and the synovial-sarcoma-specific chimaeric protein SYT-SSX co-localize with the human Polycomb group complex.Soulez M et al
224399312012Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics.Su L et al
162474612006IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein SYT-SSX1.Sun Y et al
162242742005SSX 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 et al
183012452008Diagnostic accuracy of FISH and RT-PCR in 50 routinely processed synovial sarcomas.Ten Heuvel SE et al
96393881998Expression of SSX genes in human tumors.Türeci O et al
88409961996The SSX-2 gene, which is involved in the t(X;18) translocation of synovial sarcomas, codes for the human tumor antigen HOM-MEL-40.Türeci O et al
164284782006Expression of synovial sarcoma X (SSX) antigens in epithelial ovarian cancer and identification of SSX-4 epitopes recognized by CD4+ T cells.Valmori D et al
146779252003Identification of an HLA-A*02 restricted immunogenic peptide derived from the cancer testis antigen HOM-MEL-40/SSX2.Wagner C et al
126870232003Characteristic sequence motifs located at the genomic breakpoints of the translocation t(X;18) in synovial sarcomas.Wei Y et al
165462222006Expression of cancer-testis antigen (CTA) in tumor tissues and peripheral blood of Chinese patients with hepatocellular carcinoma.Wu LQ et al
176679402008The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein Bruijn DR et al
76554671995Identification of two alternative fusion genes, SYT-SSX1 and SYT-SSX2, in t(X;18)(p11.2;q11.2)-positive synovial Leeuw B et al
111071702001Molecular mechanisms underlying human synovial sarcoma development.dos Santos NR et al

Other Information

Locus ID:

NCBI: 6757
MIM: 300192
HGNC: 11336
Ensembl: ENSG00000241476


dbSNP: 6757
ClinVar: 6757
TCGA: ENSG00000241476


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
241664952014SS18-SSX fusion protein-induced Wnt/β-catenin signaling is a therapeutic target in synovial sarcoma.28
120071892002The cancer-related protein SSX2 interacts with the human homologue of a Ras-like GTPase interactor, RAB3IP, and a novel nuclear protein, SSX2IP.22
219967282012Reprogramming of mesenchymal stem cells by the synovial sarcoma-associated oncogene SYT-SSX2.21
161526172006Gene expression profiles relate to SS18/SSX fusion type in synovial sarcoma.18
253636562015Ectopic expression of cancer/testis antigen SSX2 induces DNA damage and promotes genomic instability.15
269470172016The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis.10
246456452014SSX2-4 expression in early-stage non-small cell lung cancer.9
246818462014Development of a T cell receptor targeting an HLA-A*0201 restricted epitope from the cancer-testis antigen SSX2 for adoptive immunotherapy of cancer.9
155964112005Distinct but overlapping T helper epitopes in the 37-58 region of SSX-2.7
157355742005Molecular diagnosis of synovial sarcoma: RT-PCR detection of SYT-SSX1/2 fusion transcripts in paraffin-embedded tissue.7


Josiane Eid ; Christina Garcia ; Andrea Frump

SSX2 (synovial sarcoma, X breakpoint 2)

Atlas Genet Cytogenet Oncol Haematol. 2013-05-01

Online version:

Historical Card

2008-04-01 SSX2 (synovial sarcoma, X breakpoint 2) by  Josiane Eid,Christina Garcia,Andrea Frump 

Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA