Affiliations of authors: B. Brodin, M. Törnkvist, K. Haslam, Y. Xie, O. Larsson Department of Oncology and Pathology, CCK R8:04, Karolinska Hospital, Stockholm, Sweden; A. Bartolazzi, Department of Pathology, Regina Elena Cancer Institute, Rome, Italy.
Correspondence to: Olle Larsson, M.D., Ph.D., CCK R8:04, Karolinska Hospital, SE-171 76 Stockholm, Sweden (e-mail: olle.larsson{at}onkpat.ki.se).
The SYT-SSX4 variant demonstrated by Agus et al. is novel and differs from hitherto known SYT-SSX transcripts in the sense that SYT is fused to exon 2 of SSX4 instead of to exon 5. Consequently, parts of the Krüppel associated box (KRAB) domain (located in exons 1 and 2) are present in this fusion transcript, which could have a functional impact since KRAB acts as a repressor.
Recently, we found a synovial sarcoma tumor exclusively expressing SYT-SSX4, in which SYT is fused to exon 6 of the SSX4 gene (unpublished results). Nevertheless, this tumor exhibited a highly malignant phenotype with early onset of metastatic disease. This finding is surprising, since exon 5, which is expressed in all SYT-SSX-positive synovial sarcomas reported so far, has been proposed to be important for the transforming ability of SYT-SSX. The major base-pair (bp) differences between SYT-SSX1, SYT-SSX2, and SYT-SSX4, which otherwise are very homologous, are found in the so-called divergent domain (DD) within this exon (1). (Our investigations on synovial sarcoma patients, including this patient, have been approved by a National Ethical Committee, and we received written informed consent from the patient.) It has been suggested that this region may underlie the biologic differences between SYT-SSX1 and SYT-SSX2. The absence of exon 5 in the present tumor suggests that the transforming potential of the SYT-SSX fusion protein cannot be restricted to this part of the molecule. The SSX repressor domain (SSXRD), which is responsible for the repression of transcription (2), is located in exon 6. This region has also been shown to be responsible for the distribution of the SSX protein in the cell nucleus (1). Therefore, this part of SYT-SSX has also been proposed to play a crucial role in the development of synovial sarcomas. However, this contradicts the finding of Sonobe et al. (3), who identified a synovial sarcoma tumor carrying an exon 6-truncated variant of SYT-SSX1, which lacks the 240 bp of the 3' portion of SSX including SSXRD. All results taken together, therefore, indicate that SSX is not per se involved in the transforming process of SYT-SSX. Instead, the SYT portion, which in fact contains transcription-activating regions (3), might be critical in this respect, and perhaps the transactivating ability of SYT is augmented because of conformational changes following fusion with the SSX gene. The recent finding that SYT-SSX is linked functionally to the transcriptional regulatory machinery involving hBRM/ hSNF2a (4) discloses a complex scenario in which protein-protein interactions, suppression, and activation of target genes may play an integrated role in the development of synovial sarcoma.
In agreement with the finding of Agus et al., we stress the fact that several unexpected SYT-SSX variants can be demonstrated in otherwise reverse transcription-polymerase chain reaction (RT-PCR)-negative cases by use of an optimized RT-PCR approach. For example, it should be noted that the use of consensus primers for SYT-SSX with SSX primers specific for the 3' end of exon 6 could miss fusion gene variants. This is illustrated by the exon 6-truncated SYT-SSX variant described by Sonobe et al. (3). Using optimized RT- PCR, we believe that several novel and unexpected SYT-SSX variants will be discovered in the future. Probably, tumors expressing SYT-SSX4 transcripts are much more represented than the few reported so far (Fig. 1).
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NOTES
Supported by grants from the Swedish Cancer Society, the Stockholm Cancer Society, the Swedish Children Cancer Society, the Swedish Foundation for Strategic Research, and the Karolinska Institute.
REFERENCES
1 dos Santos NR, de Bruijn DR, van Kessel AG. Molecular mechanisms underlying human synovial sarcoma development. Genes Chromosomes Cancer 2001;30:1-14.[Medline]
2 Lim FL, Soulez M, Koczan D, Thiesen HJ, Knight JC. A KRAB-related domain and a novel transcription repression domain in proteins encoded by SSX genes that are disrupted in human sarcomas. Oncogene 1998; 17:2013-8.[Medline]
3 Sonobe H, Takeuchi T, Liag SB, Taguchi T, Yuri K, Shimizu K, et al. A new human synovial sarcoma cell line, HS-SY-3, with a truncated form of hybrid SYT/SSX1 gene. Int J Cancer 1999; 82: 459-64. [Medline]
4
Nagai M, Tanaka S, Tsuda M, Endo S, Kato H, Sonobe H, et al. Analysis of transforming activity of human synovial sarcoma-associated chimeric protein SYT-SSX1 bound to chromatin remodeling factor hBRM/hSNF2 alpha. Proc Natl Acad Sci U S A 2001;98:3843-8.
5
Skytting B, Nilsson G, Brodin B, Xie Y, Lundeberg J, Uhlen M, et al. A novel fusion gene, SYT-SSX4, in synovial sarcoma [letter]. J Natl Cancer Inst 1999;91:974-5.
6 Brodin B, Haslam K, Yang K, Bartolazzi A, Xie Y, Starborg M, et al. Cloning and characterization of spliced fusion transcript variants of synovial sarcoma: SYT/SSX4, SYT/SSX4v, and SYT/SSX2v. Possible regulatory role of the fusion gene product in wild type SYT expression. Gene 2001;268:173-82.[Medline]
7 Mancuso T, Mezzelani A, Riva C, Fabbri A, Dal Bo L, Sampietro G, et al. Analysis of SYT-SSX fusion transcripts and bcl-2 expression and phosphorylation status in synovial sarcoma. Lab Invest 2000;80:805-13.[Medline]
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