Xp11.22

CT5.2,HD21,HOM-MEL-40,MGC119055,MGC15364,MGC3884,SSX,SSX2A,SSX2B

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).

SS18-SSX2.

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).

Immunotherapy:
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.