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

BACKGROUND Synovial sarcomas account for up to 10 percent of soft-tissue sarcomas and include two major histologic subtypes, biphasic and monophasic, defined respectively by the presence and absence of glandular epithelial differentiation in a background of spindle tumor cells. A characteristic SYT-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is detectable in almost all synovial sarcomas. The translocation fuses the SYT gene from chromosome 18 to either of two highly homologous genes at Xp11, SSX1 or SSX2. SYT-SSX1 and SYT-SSX2 are thought to tunction as aberrant transcriptional regulators. We attempted to determine the influence of the two alternative forms of the SYT-SSX fusion gene on tumor morphology and clinical outcome in patients with this sarcoma. METHODS We analyzed SYT-SSX fusion transcripts in 45 synovial sarcomas (33 monophasic and 12 biphasic) by the reverse-transcriptase polymerase chain reaction and compared the results with relevant clinical and pathological data. RESULTS The SYT-SSX1 and SYT-SSX2 fusion transcripts were detected in 29 (64 percent) and 16 (36 percent) of the tumors, respectively. There was a significant relation (P=0.003) between histologic subtype (monophasic vs. biphasic) and SSX1 or SSX2 involvement in the fusion transcript: all 12 biphasic synovial sarcomas had a SYT-SSX1 fusion transcript, and all 16 tumors that were positive for SYT-SSX2 were monophasic. Kaplan-Meier analysis of 39 patients with localized tumors showed that the 15 patients with SYT-SSX2 had significantly better metastasis-free survival than the 24 patients with SYT-SSX1 (P=0.03 by multivariate analysis; relative risk, 3.0). There were no significant correlations between the type of SYT-SSX transcript and age, sex, tumor location and size, whether there were metastases at diagnosis, or whether patients underwent chemotherapy. Histologic subtype alone was not prognostically important. CONCLUSIONS The type of SYT-SSX fusion transcript correlates with both the histologic subtype and the clinical behavior of synovial sarcoma. SYT-SSX fusion transcripts are a defining diagnostic marker of synovial sarcomas and may also yield important independent prognostic information.

[1]  D. Brett,et al.  The SYT protein involved in the t(X;18) synovial sarcoma translocation is a transcriptional activator localised in nuclear bodies. , 1997, Human molecular genetics.

[2]  J. Lopes,et al.  Nuclear localization of SYT, SSX and the synovial sarcoma-associated SYT-SSX fusion proteins. , 1997, Human molecular genetics.

[3]  P. Sorensen,et al.  Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  J. Melo,et al.  The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. , 1996, Blood.

[5]  G. Budd,et al.  Ifosfamide in the treatment of soft tissue sarcomas. , 1996, Seminars in oncology.

[6]  D H Leung,et al.  Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  J. Fletcher,et al.  Synovial sarcoma: prognostic significance of tumor size, margin of resection, and mitotic activity for survival. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  O. Delattre,et al.  Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients? , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  C. Cooper,et al.  Interphase fluorescence in situ hybridization and reverse transcription polymerase chain reaction as a diagnostic aid for synovial sarcoma. , 1996, The American journal of pathology.

[10]  P. Sorensen,et al.  Gene fusions encoding chimaeric transcription factors in solid tumours. , 1996, Seminars in cancer biology.

[11]  B. de Leeuw,et al.  A novel Krüppel-associated box containing the SSX gene (SSX3) on the human X chromosome is not implicated in t(X;18)-positive synovial sarcomas. , 1996, Cytogenetics and cell genetics.

[12]  C. Cooper,et al.  Long-range organization of reiterated sequences, including the SSX1 cDNA at the OATL1 cluster in Xp11.23. , 1995, Genomics.

[13]  W. Gerald,et al.  Molecular diagnosis of synovial sarcoma and characterization of a variant SYT-SSX2 fusion transcript. , 1995, The American journal of pathology.

[14]  M. Ladanyi.  The emerging molecular genetics of sarcoma translocations. , 1995, Diagnostic molecular pathology : the American journal of surgical pathology, part B.

[15]  B. de Leeuw,et al.  Identification of two alternative fusion genes, SYT-SSX1 and SYT-SSX2, in t(X;18)(p11.2;q11.2)-positive synovial sarcomas. , 1995, Human molecular genetics.

[16]  B. Gusterson,et al.  Fusion of SYT to two genes, SSX1 and SSX2, encoding proteins with homology to the Kruppel‐associated box in human synovial sarcoma. , 1995, The EMBO journal.

[17]  R. Hipskind,et al.  Interphase cytogenetic analysis of distinct X‐chromosomal translocation breakpoints in synovial sarcoma , 1995, The Journal of pathology.

[18]  P. Cin,et al.  Two categories of synovial sarcoma defined by divergent chromosome translocation breakpoints in Xp11.2, with implications for the histologic sub-classification of synovial sarcoma. , 1995, Cytogenetics and cell genetics.

[19]  A. Pappo,et al.  Synovial sarcoma in children and adolescents: the St Jude Children's Research Hospital experience. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  C. Cooper,et al.  Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma , 1994, Nature Genetics.

[21]  M. Ladanyi,et al.  Chromosomal aberrations in soft tissue tumors. Relevance to diagnosis, classification, and molecular mechanisms. , 1994, The American journal of pathology.

[22]  G. Rosen,et al.  Synovial sarcoma. Uniform response of metastases to high dose ifosfamide , 1994, Cancer.

[23]  A. Monaco,et al.  The t(X;18)(p11.2;q11.2) translocation found in human synovial sarcomas involves two distinct loci on the X chromosome. , 1994, Oncogene.

[24]  E. van den Berg,et al.  Distinct Xp11.2 breakpoint regions in synovial sarcoma revealed by metaphase and interphase FISH: relationship to histologic subtypes. , 1994, Cancer genetics and cytogenetics.

[25]  G. Rosen,et al.  Synovial sarcoma. A study of intensive chemotherapy in 14 patients with localized disease , 1993, Cancer.

[26]  Y. Oda,et al.  Survival in Synovial Sarcoma: A Multivariate Study of Prognostic Factors with Special Emphasis on the Comparison Between Early Death and Long-Term Survival , 1993, The American journal of surgical pathology.

[27]  M. Burt,et al.  Tendosynovial sarcoma. Clinicopathologic features, treatment, and prognosis , 1992, Cancer.

[28]  F. Mitelman,et al.  Cytogenetics of Synovial Sarcoma: Presentation of Ten New Cases and Review of the Literature , 1991, Genes, chromosomes & cancer.

[29]  A. Rydholm,et al.  Prognostic factors in synovial sarcoma , 1989, Cancer.

[30]  J. Mirra,et al.  Histologic features relating to prognosis in synovial sarcoma , 1987, Cancer.

[31]  A. Patchefsky,et al.  Synovial sarcoma: A clinical, pathological, and ultrastructural study of 26 cases supporting the recognition of a monophasic variant , 1981, The American journal of surgical pathology.

[32]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .