Identification of two alternative fusion genes, SYT-SSX1 and SYT-SSX2, in t(X; 18)(p11.2;q11.2)-positive synoviaol sarcomas

Leeuw, H.C.G.M. de; Balemans, M.; Weghuis, D.E.M. Olde; Kessel, A.H.M. Geurts van

doi:10.1093/hmg/4.6.1097

Cited by 192 publications

(107 citation statements)

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“…These probes, in turn, were used to isolate a chim eric breakpoint fragm ent containing both chromosome X and chrom osom e 18-derived sequences [19,20], Further positional cloning studies led to the isolation of the genes that are disrupted in t(X ;18)(pll.2;qll.2)'positive synovial sarcomas. It was found that, in conformity with the previous findings, one of these genes (SYT; chromosome 18) becomes fused to one of tw o alternative X chromosomal genes [SSXl or SSX2) located in the OATL1 and OATL2 regions, respectively [21][22][23].…”

Section: Introductionsupporting

confidence: 76%

“…The SYT-SSX fusion RNAs are about 2.4 kb long (Figure 2) and, in the majority of cases, encode proteins in w h ich the last eight amino acids of SYT are substituted for the last 78 amino acids of SSX. Some rare variants have also been described which carry m ore N -term inally located breakpoints either in SYT or SSX [22,23]. It is notew orthy that all the reported fusion transcripts exclude the putative KRAB domain present in SSX and at least one of the putative SH2 binding domains present in SYT.…”

Section: Introductionmentioning

confidence: 96%

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Molecular cytogenetics of bone and soft tissue tumors

Kessel

Santos

Simons

et al. 1997

Cancer Genetics and Cytogenetics

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Section: Introductionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 96%

Molecular cytogenetics of bone and soft tissue tumors

Kessel

Santos

Simons

et al. 1997

Cancer Genetics and Cytogenetics

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“…SS is, regardless of histological subtype, genetically characterized by the chromosomal translocation t(X;18)(p11.2;q11.2) (2, 3), which is exclusively found in this malignancy (4 -8). The t(X;18) leads to the fusion of the SYT gene on chromosome 18, and an SSX gene on the X chromosome (9,10). The SYT gene is widely expressed in normal human tissues (9).…”

mentioning

confidence: 99%

A Novel Type of SYT/SSX Fusion: Methodological and Biological Implications

et al. 2002

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Synovial sarcoma (SS) is a rare soft-tissue tumor that affects children and young adults. It is characterized by the chromosomal translocation t(X; 18)(p11.2;q11.2), which results in the fusion of the SYT gene on chromosome 18 with a SSX gene on chromosome X. In the majority of cases, SYT is fused to exon 5 of SSX1 (64%), SSX2 (36%), or, rarely, SSX4. A novel fusion transcript variant deriving from the fusion of SYT to exon 6 of SSX4 gene (SYT/SSX4v) was found coexpressed in one of the previously reported SYT/SSX4 cases. In the present investigation, we describe a new SS case that was previously shown to be negative for SYT/SSX1 and SYT/SSX2 expression by conventional reverse transcription polymerase chain reaction (RT-PCR) methods. By redesigning and optimizing the RT-PCR protocol, we were able to detect SYT/SSX4v as the sole fusion transcript expressed in this tumor sample. This finding suggests that this novel fusion gene, which involves exon 6 of SSX only, is sufficient to keep the transforming function conferred by the SYT/SSX translocation of SS. In about 3% of morphologically, ultrastructurally, and immunohistochemically defined SS, the SYT/SSX fusion transcript is not detected using conventional RT-PCR. Here we demonstrate that optimization of the RT-PCR method is important for detecting different and unexpected SYT/SSX variants, which otherwise could be overlooked. Using nine cases of SS in which SYT/SSX fusion transcripts were not detected by conventional RT-PCR methods, we demonstrate the presence of SYT/SSX transcripts in two cases using the proposed RT-PCR approach. Applications of optimized RT-PCR can contribute to reduce falsenegative SYT/SSX SS cases reported in literature.

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“…Cytogenetically, it is characterized by a recurring chromosomal translocation, t(X;18)(p11;q11), which is found in more than 95% of all cases (dos Santos et al, 2001;Ladanyi et al, 2002). As a result of this translocation, the SS18 gene (previously called SYT) on chromosome 18 is fused to either one of the three closely related SSX genes on the X chromosome, SSX1, SSX2 or SSX4 (Clark et al, 1994;Crew et al, 1995;de Leeuw et al, 1995;Skytting et al, 1999). The occurrence of either SS18-SSX1 or SS18-SSX2 fusions was found to correlate to histologic (de Leeuw et al, 1994) and/or prognostic (Kawai et al, 1998;Ladanyi et al, 2002) parameters, although the latter observation could not be confirmed (Guillou et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…In the majority of SS18-SSX fusion proteins characterized to date, the C-terminal eight amino acids of the SS18 protein are replaced by the C-terminal 78 amino acids of one of the SSX proteins (Clark et al, 1994;Crew et al, 1995;de Leeuw et al, 1995). As a consequence, the SS18 QPGY domain is interrupted and the complete KRAB domain of SSX is lost.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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As a result of the synovial sarcoma-associated t(X;18) translocation, the SS18 gene on chromosome 18 is fused to either one of the three closely related SSX genes on the X chromosome. The SS18 protein is thought to act as a transcriptional co-activator, whereas the SSX proteins are thought to act as transcriptional corepressors. The main SSX-repression domain is located in its C terminus, a domain that is retained in the respective SS18-SSX fusion proteins. Both the SS18 and SSX proteins lack DNAbinding domains. Previously, we found that the SS18 and SS18-SSX fusion proteins may be tethered to DNA targets via the SS18-interacting protein AF10. Here, we set out to isolate proteins that interact with the SSX C-terminal repression domain using a yeast two-hybrid interaction trap. Of the positive clones isolated, two corresponded to the LIM homeobox protein LHX4, a DNA-binding protein that is involved in transcription regulation. An endogenous interaction was subsequently established in mammalian cells via colocalization and coimmunoprecipitation of the respective proteins. Interestingly, the LHX4 gene was previously found to be deregulated in various human leukemias. In addition, it was previously found that LIM homeobox proteins may bind to and activate the glycoprotein-a (CGA) promoter. Using LHX4 chromatin immunoprecipitation and CGApromoter assays, we found that endogenous LHX4 binds to the CGA promoter and that LHX4-mediated CGA activation is enhanced by the SS18-SSX protein, but not by the SSX protein. Taken together, we conclude that this novel protein -protein interaction may have direct consequences for the (de)regulation of SSX and/or SS18-SSX target genes and, thus, for the development of human synovial sarcomas.

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Identification of two alternative fusion genes, SYT-SSX1 and SYT-SSX2, in t(X; 18)(p11.2;q11.2)-positive synoviaol sarcomas

Cited by 192 publications

References 0 publications

Molecular cytogenetics of bone and soft tissue tumors

Molecular cytogenetics of bone and soft tissue tumors

A Novel Type of SYT/SSX Fusion: Methodological and Biological Implications

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

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