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Marc Ladanyi - One of the best experts on this subject based on the ideXlab platform.

  • syt SSX1 and syt ssx2 interfere with repression of e cadherin by snail and slug a potential mechanism for aberrant mesenchymal to epithelial transition in human synovial sarcoma
    Cancer Research, 2006
    Co-Authors: Tsuyoshi Saito, Makoto Nagai, Marc Ladanyi
    Abstract:

    Synovial sarcoma is a primitive mesenchymal neoplasm characterized in almost all cases by a t(X;18) fusing the SYT transcriptional coactivator gene with either SSX1 or SSX2, with the resulting fusion gene encoding an aberrant transcriptional regulator. A subset of synovial sarcoma, predominantly cases with the SYT-SSX1 fusion, shows foci of morphologic epithelial differentiation in the form of nests of glandular epithelium. The striking spontaneous mesenchymal to epithelial differentiation in this cancer is reminiscent of a developmental switch, but the only clue to its mechanistic basis has been the observation that most cases of synovial sarcoma with glandular epithelial differentiation (GED) contain SYT-SSX1 instead of SYT-SSX2. We report here that SYT-SSX1 and SYT-SSX2 interact preferentially with Snail or Slug, respectively, and prevent these transcriptional repressors from binding to the proximal E-cadherin promoter as shown by coimmunoprecipitation and chromatin immunoprecipitation. Luciferase reporter assays reveal that SYT-SSX1 and SYT-SSX2 can respectively overcome the Snail- or Slug-mediated repression of E-cadherin transcription. This provides a mechanism by which E-cadherin expression, a prerequisite of epithelial differentiation, is aberrantly derepressed in synovial sarcoma and may also explain the association of GED with the SYT-SSX1 fusion because it interferes with Snail, the stronger repressor of the E-cadherin promoter. Thus, our data provide a mechanistic basis for the observed heterogeneity in the acquisition of epithelial characteristics in synovial sarcoma and highlight the potential role of differential interactions with Snail or Slug in modulating this phenotypic transition.

  • impact of syt ssx fusion type on the clinical behavior of synovial sarcoma a multi institutional retrospective study of 243 patients
    Cancer Research, 2002
    Co-Authors: Marc Ladanyi, Cristina R Antonescu, Denis H Y Leung, James M Woodruff, Akira Kawai, John H Healey, Murray F Brennan, Julia A Bridge, James R Neff, Frederic G Barr
    Abstract:

    Synovial sarcomas are aggressive spindle cell sarcomas containing in some cases areas of epithelial differentiation. They consistently show a specific t(X;18;p11;q11), which usually represents either of two gene fusions, SYT-SSX1 or SYT-SSX2 , encoding putative transcriptional proteins differing at 13 amino acid positions. Previous studies have suggested that patients with SYT-SSX2 tumors do better than those with SYT-SSX1 tumors, but the study groups were too limited to be conclusive. To address this issue more definitively, we collected data on SYT-SSX fusion type, pathology, and clinical course in a retrospective multi-institutional study of 243 patients (age range, 6–82) with synovial sarcoma. SYT-SSX1 and SYT - SSX2 fusions were detected in 147 tumors (61%) and 91 tumors (37%), respectively. Histologically, 61 (25%) were classified as biphasic type and 180 (74%) as monophasic type based on the presence or absence of areas of glandular epithelial differentiation, respectively. Median and 5-year overall survivals for the SYT - SSX1 and SYT - SSX2 groups were 6.1 years and 53%, and 13.7 years and 73%, respectively. Overall survival was significantly better among SYT - SSX2 cases ( P = 0.03), among cases localized at diagnosis ( P P = 0.01). Age, sex, histological type, and axial versus peripheral primary site had no impact on overall survival. The impact of fusion type on survival remained significant when stratified for primary tumor size ( P = 0.03) but was no longer significant when stratified for disease status at presentation. This may reflect the tendency for patients with SYT - SSX1 tumors to present more often with metastatic disease ( P = 0.05). Cox regression identified disease status ( P P = 0.04) as the only factors independently predictive of overall survival in the subset of 160 patients with information on all of the factors. Within the subset of patients with localized disease at diagnosis ( n = 202), the median and 5-year survival for the SYT-SSX1 and the SYT-SSX2 groups were 9.2 years and 61% versus 13.7 years and 77%, respectively. Patients whose tumors contained the SYT-SSX2 fusion ( P = 0.08) or were smaller ( P = 0.12) showed a trend toward better survival by log-rank test, whereas tumor histology had no impact ( P = 0.8). In a Cox regression analysis considering all of the factors, SYT - SSX fusion type emerged as the only independent significant factor ( P = 0.04) for overall survival within the subset of 133 patients with localized disease at diagnosis who had information on all of the factors. Among other comparisons, there was a strong association of fusion type and morphology ( P SYT-SSX2 tumors showing absence of glandular differentiation (monophasic histology) and almost all of the biphasic tumors containing SYT-SSX1 . There was also a statistically significant association of fusion type and patient sex ( P = 0.03); specifically, the male:female ratio of SYT - SSX1 cases was 1:1, whereas for SYT - SSX2 cases, it was close to 1:2. Overall, SYT-SSX fusion type appears to be the single most significant prognostic factor by multivariate analysis in patients with localized disease at diagnosis. SYT-SSX fusion type also appears to exert part of its impact on prognosis before presentation through its association with stage at diagnosis. In addition, the associations of SYT-SSX fusion type with patient sex and tumor epithelial differentiation point to interesting mechanistic biological differences.

  • monophasic and biphasic synovial sarcomas abundantly express cancer testis antigen ny eso 1 but not mage a1 or ct7
    International Journal of Cancer, 2001
    Co-Authors: Achim A Jungbluth, Cristina R Antonescu, Klaus J Busam, Kristin Iversen, Denise Kolb, Keren Coplan, Yao T Chen, Elisabeth Stockert, Marc Ladanyi
    Abstract:

    Synovial sarcomas are high-grade malignant mesenchymal tumors with biphasic (BSS) and monophasic (MSS) variants that carry a pathognomonic cytogenetic alteration, t(X;18), involving the SYT gene on chromosome 18 and one of several SSX genes on chromosome X, usually SSX1 or SSX2. Cancer/testis (CT) antigens are expressed in a variety of malignant neoplasms but, in normal tissues, are restricted to male germ cells. Previous analysis revealed a high incidence and homogeneous expression of MAGE CT antigen in synovial sarcomas. The present study was performed to analyze the expression of 3 CT antigens, NY-ESO-1, MAGE-A1 and CT7, by immunohistochemistry with 3 monoclonal antibodies (MAbs), ES121 (anti-NY-ESO-1), MA454 (anti-MAGE-A1) and CT7-33 (anti-CT7), in 25 synovial sarcomas (12 MSS, 13 BSS) typed for the t(X;18)-derived fusion transcript by RT-PCR (19 SYT-SSX1, 6 SYT-SSX2). NY-ESO-1 immunoreactivity was found in 20/25 (80%) cases, and antigen expression was homogeneous in 14/20 NY-ESO-1-positive cases. Both morphologic variants and both translocation types were NY-ESO-1-positive, whereas 5 SYT-SSX1 tumors (1 MSS, 4 BSS) were NY-ESO-1-negative. MAb MA454 was immunoreactive with 4/25 cases (2 MSS, 2 BSS; 3 SYT-SSX1, 1 SYT-SSX2), and MAb CT7-33 was immunoreactive with only 2/25 cases (both BSS, SYT-SSX1). Expression of MAGE-A1 and CT7 was heterogeneous in all positive cases. Our study shows that NY-ESO-1 is highly expressed in a homogeneous pattern in synovial sarcomas of both morphologic variants and both translocation types, making these tumors an attractive target for NY-ESO-1 antigen-based immunotherapy. © 2001 Wiley-Liss, Inc.

  • fusions of the syt and ssx genes in synovial sarcoma
    Oncogene, 2001
    Co-Authors: Marc Ladanyi
    Abstract:

    Synovial sarcomas are high grade spindle cell tumors that are divided into two major histologic subtypes, biphasic and monophasic, according to the respective presence or absence of a well-developed glandular epithelial component. They contain in essentially all cases a t(X;18) representing the fusion of SYT (at 18q11) with either SSX1 or SSX2 (both at Xp11). Neither SYT, nor the SSX proteins contain DNA-binding domains. Instead, they appear to be transcriptional regulators whose actions are mediated primarily through protein-protein interactions, with BRM in the case of SYT, and with Polycomb group repressors in the case of SSX. Ongoing work on the SYT–SSX fusion and synovial sarcoma should yield a variety of data of broader biological interest, in areas such as BRM and Polycomb group function and dysfunction, transcriptional targets of SYT–SSX proteins and their native counterparts, differential gene regulation by SYT–SSX1 and SYT–SSX2, control of glandular morphogenesis, among others.

  • strong association of syt ssx fusion type and morphologic epithelial differentiation in synovial sarcoma
    Diagnostic Molecular Pathology, 2000
    Co-Authors: Cristina R Antonescu, Denis H Y Leung, James M Woodruff, Akira Kawai, John H Healey, Fulvio Lonardo, Marc Ladanyi
    Abstract:

    Synovial sarcoma is characterized by a specific recurrent translocation t(X;18), resulting in either the SYT-SSX1 or SYT-SSX2 gene fusion. Because this is the primary genetic alteration in these tumors, we sought to identify the impact of molecular heterogeneity of the t(X;18) on cell proliferation,

Yuntao Xie - One of the best experts on this subject based on the ideXlab platform.

  • the syt SSX1 fusion type of synovial sarcoma is associated with increased expression of cyclin a and d1 a link between t x 18 p11 2 q11 2 and the cell cycle machinery
    Oncogene, 2002
    Co-Authors: Yuntao Xie, Bjorn Skytting, Gunnar Nilsson, R Grimer, Chas D Mangham, Cyril Fisher, Janet Shipley, Bodil Bjerkehagen, Ola Myklebost
    Abstract:

    A recent large multi-centre study convincingly confirmed previous observations that the SYT-SSX1 fusion type, compared to SYT-SSX2, of synovial sarcoma is associated with a worse clinical outcome. Apart from the clinical impact, this fact also suggests (1) that the SYT-SSX fusion gene may influence molecular mechanisms involved in tumour growth and progression; and (2) that the SYT-SSX1 fusion type has a stronger influence on these mechanisms than SYT-SSX2. The nature of the underlying mechanisms is, however, still unknown. In this study we made use of the SYT-SSX1 vs SYT-SSX2 concept to investigate whether major, tumour relevant, and growth regulatory proteins (e.g. cyclins and cyclin-dependent kinases) may be involved. Using Western blotting analysis on 74 fresh, fusion variant-typed, tumour samples from localized synovial sarcoma, we found a significant correlation between SYT-SSX1 and high expression of cyclin A (P=0.003) and D1 (P=0.025). Our data suggest that SYT-SSX may influence the cell cycle machinery, and that the more aggressive phenotype of the SYT-SSX1 variant is due to an accelerated tumour cell proliferation.

  • co existence of syt SSX1 and syt ssx2 fusions in synovial sarcomas
    Oncogene, 2002
    Co-Authors: Ke Yang, Wengonn Lui, Yuntao Xie, Anju Zhang, Bjorn Skytting, Nils Mandahl, Catharina Larsson, Olle Larsson
    Abstract:

    The chromosomal translocation t(X;18)(p11.2;q11.2) is tightly linked to the tumorigenesis of synovial sarcoma. Through this translation the SYT gene on chromosome 18 is fused with a testis/cancer antigen gene on the X chromosome, generating either a SYT-SSX1, SYT-SSX2, or less often a SYT-SSX4 fusion gene. It has been anticipated that the individual synovial sarcoma carries only one of these variants, however, in this study we demonstrated that SYT-SSX1 and SYT-SSX2 co-exist in a significant proportion of the cases. From 121 SYT-SSX positive primary tumors, co-expression of SYT-SSX1 and SYT-SSX2 was seen in 12 cases (10%), which were characterized in further detail both at the RNA, DNA and chromosomal level. In all 12 cases the SYT-SSX1 and SYT-SSX2 fusions resulted in identical SYT-SSX fusion transcripts. However, at the genomic level the translocations were different, and most likely occurred between variable intronic sites in the target genes. By interphase FISH analyses of 10 cases SYT-SSX2 translocations were found to be the most abundant in all but one of the cases, in which SYT-SSX1 was predominating. The findings reveal a new heterogenous feature of synovial sarcoma, accounting for approximately 10% of all cases, which may shed light on the molecular genetic mechanisms behind translocations in general, and on the etiology of synovial sarcoma in particular.

  • the syt SSX1 variant of synovial sarcoma is associated with a high rate of tumor cell proliferation and poor clinical outcome
    Cancer Research, 1999
    Co-Authors: Gunnar Nilsson, Yuntao Xie, Bjorn Skytting, Nils Mandahl, Bertha Brodin, Roland Perfekt, Joakim Lundeberg, Mathias Uhlen, Olle Larsson
    Abstract:

    Cytogenetically, synovial sarcoma (SS) is characterized by the translocation t(X;18)(p11.2;q11.2), resulting in a fusion between the SYT gene on chromosome 18 and SSX1 or SSX2 on the X chromosome and the formation of new chimeric genes, SYT-SSX1 or SYT-SSX2 . We examined the potential clinical relevance of SYT-SSX1 and SYT-SSX2 fusion transcripts together with tumor proliferation. In a series of 33 patients with primary SS, the type of fusion transcript was assessed by reverse transcription-PCR and sequence analysis. The proliferation rate was analyzed using anti-Ki-67 antibodies. One case carrying an atypical transcript with a 57-bp insert was excluded, leaving 13 SYT-SSX1 and 19 SYT-SSX2 cases for analysis. The hazard ratio (with respect to metastasis-free survival for patients with SYT-SSX1 versus patients with SYT-SSX2 fusion transcripts was 7.4 (95% confidence interval, 1.5–36; log-rank P = 0.004). There was also an association with reduced overall survival for patients with SYT-SSX1 compared to patients with SYT-SSX2 (hazard ratio, 8.5; 95% confidence interval, 1.0–73; log-rank P = 0.02). The 5-year metastasis-free survival for patients with SYT-SSX1 was 42% versus 89% for patients with SYT-SSX2 . There was a significant association between SYT-SSX1 and a high tumor proliferation rate ( P = 0.02). We conclude that the findings suggest that the type of SYT-SSX fusion transcript determines the proliferation rate and is an important predictor of clinical outcome in patients with SS.

Cristina R Antonescu - One of the best experts on this subject based on the ideXlab platform.

  • bcor upregulation in a poorly differentiated synovial sarcoma with ss18l1 SSX1 fusion a pathologic and molecular pitfall
    Genes Chromosomes and Cancer, 2017
    Co-Authors: Yu Chien Kao, Yun Shao Sung, Lei Zhang, Samuel Kenan, Samuel Singer, William D Tap, David Swanson, Brendan C Dickson, Cristina R Antonescu
    Abstract:

    The diagnosis of poorly differentiated synovial sarcoma (PD-SS) may be challenging due to overlapping morphologic features with other undifferentiated round cell sarcomas (URCS). Particularly relevant is the histologic overlap and shared BCOR overexpression between a subset of SS and URCS with various BCOR genetic abnormalities. Here, we report a case of PD-SS lacking the canonical SS18-SSX gene fusion, but showing strong BCOR immunoreactivity and BCOR gene abnormalities by FISH, which were misinterpreted as a URCS with BCOR gene rearrangements. The tumor had an unusual clinical presentation arising as an intraneural tumor in the ankle of a 29-year-old female. The tumor displayed a mixture of fascicular spindle cells and undifferentiated round cell components. FISH studies showed no SS18 gene abnormality; however, RNA sequencing identified a fusion transcript involving SS18L1 (a paralog gene of SS18 at 20q13.33) and SSX1. Further FISH testing validated rearrangements in SSX1 and SS18L1 genes, in addition to complex structural abnormalities of the Xp11.22-4 region. This is the second reported SS case harboring an SS18L1-SSX1 alternative fusion variant, similarly occurring in association with a large nerve. The lack of SS18 gene rearrangements by FISH corroborated with the BCOR overexpression at both mRNA and protein level may result in diagnostic pitfalls with URCS with BCOR gene abnormalities. Our results further suggest that BCOR upregulation is emerging as a common downstream pathway for SS with either typical SS18-SSX transcript or with rare fusion variants, such as SS18L1-SSX. © 2017 Wiley Periodicals, Inc.

  • impact of syt ssx fusion type on the clinical behavior of synovial sarcoma a multi institutional retrospective study of 243 patients
    Cancer Research, 2002
    Co-Authors: Marc Ladanyi, Cristina R Antonescu, Denis H Y Leung, James M Woodruff, Akira Kawai, John H Healey, Murray F Brennan, Julia A Bridge, James R Neff, Frederic G Barr
    Abstract:

    Synovial sarcomas are aggressive spindle cell sarcomas containing in some cases areas of epithelial differentiation. They consistently show a specific t(X;18;p11;q11), which usually represents either of two gene fusions, SYT-SSX1 or SYT-SSX2 , encoding putative transcriptional proteins differing at 13 amino acid positions. Previous studies have suggested that patients with SYT-SSX2 tumors do better than those with SYT-SSX1 tumors, but the study groups were too limited to be conclusive. To address this issue more definitively, we collected data on SYT-SSX fusion type, pathology, and clinical course in a retrospective multi-institutional study of 243 patients (age range, 6–82) with synovial sarcoma. SYT-SSX1 and SYT - SSX2 fusions were detected in 147 tumors (61%) and 91 tumors (37%), respectively. Histologically, 61 (25%) were classified as biphasic type and 180 (74%) as monophasic type based on the presence or absence of areas of glandular epithelial differentiation, respectively. Median and 5-year overall survivals for the SYT - SSX1 and SYT - SSX2 groups were 6.1 years and 53%, and 13.7 years and 73%, respectively. Overall survival was significantly better among SYT - SSX2 cases ( P = 0.03), among cases localized at diagnosis ( P P = 0.01). Age, sex, histological type, and axial versus peripheral primary site had no impact on overall survival. The impact of fusion type on survival remained significant when stratified for primary tumor size ( P = 0.03) but was no longer significant when stratified for disease status at presentation. This may reflect the tendency for patients with SYT - SSX1 tumors to present more often with metastatic disease ( P = 0.05). Cox regression identified disease status ( P P = 0.04) as the only factors independently predictive of overall survival in the subset of 160 patients with information on all of the factors. Within the subset of patients with localized disease at diagnosis ( n = 202), the median and 5-year survival for the SYT-SSX1 and the SYT-SSX2 groups were 9.2 years and 61% versus 13.7 years and 77%, respectively. Patients whose tumors contained the SYT-SSX2 fusion ( P = 0.08) or were smaller ( P = 0.12) showed a trend toward better survival by log-rank test, whereas tumor histology had no impact ( P = 0.8). In a Cox regression analysis considering all of the factors, SYT - SSX fusion type emerged as the only independent significant factor ( P = 0.04) for overall survival within the subset of 133 patients with localized disease at diagnosis who had information on all of the factors. Among other comparisons, there was a strong association of fusion type and morphology ( P SYT-SSX2 tumors showing absence of glandular differentiation (monophasic histology) and almost all of the biphasic tumors containing SYT-SSX1 . There was also a statistically significant association of fusion type and patient sex ( P = 0.03); specifically, the male:female ratio of SYT - SSX1 cases was 1:1, whereas for SYT - SSX2 cases, it was close to 1:2. Overall, SYT-SSX fusion type appears to be the single most significant prognostic factor by multivariate analysis in patients with localized disease at diagnosis. SYT-SSX fusion type also appears to exert part of its impact on prognosis before presentation through its association with stage at diagnosis. In addition, the associations of SYT-SSX fusion type with patient sex and tumor epithelial differentiation point to interesting mechanistic biological differences.

  • monophasic and biphasic synovial sarcomas abundantly express cancer testis antigen ny eso 1 but not mage a1 or ct7
    International Journal of Cancer, 2001
    Co-Authors: Achim A Jungbluth, Cristina R Antonescu, Klaus J Busam, Kristin Iversen, Denise Kolb, Keren Coplan, Yao T Chen, Elisabeth Stockert, Marc Ladanyi
    Abstract:

    Synovial sarcomas are high-grade malignant mesenchymal tumors with biphasic (BSS) and monophasic (MSS) variants that carry a pathognomonic cytogenetic alteration, t(X;18), involving the SYT gene on chromosome 18 and one of several SSX genes on chromosome X, usually SSX1 or SSX2. Cancer/testis (CT) antigens are expressed in a variety of malignant neoplasms but, in normal tissues, are restricted to male germ cells. Previous analysis revealed a high incidence and homogeneous expression of MAGE CT antigen in synovial sarcomas. The present study was performed to analyze the expression of 3 CT antigens, NY-ESO-1, MAGE-A1 and CT7, by immunohistochemistry with 3 monoclonal antibodies (MAbs), ES121 (anti-NY-ESO-1), MA454 (anti-MAGE-A1) and CT7-33 (anti-CT7), in 25 synovial sarcomas (12 MSS, 13 BSS) typed for the t(X;18)-derived fusion transcript by RT-PCR (19 SYT-SSX1, 6 SYT-SSX2). NY-ESO-1 immunoreactivity was found in 20/25 (80%) cases, and antigen expression was homogeneous in 14/20 NY-ESO-1-positive cases. Both morphologic variants and both translocation types were NY-ESO-1-positive, whereas 5 SYT-SSX1 tumors (1 MSS, 4 BSS) were NY-ESO-1-negative. MAb MA454 was immunoreactive with 4/25 cases (2 MSS, 2 BSS; 3 SYT-SSX1, 1 SYT-SSX2), and MAb CT7-33 was immunoreactive with only 2/25 cases (both BSS, SYT-SSX1). Expression of MAGE-A1 and CT7 was heterogeneous in all positive cases. Our study shows that NY-ESO-1 is highly expressed in a homogeneous pattern in synovial sarcomas of both morphologic variants and both translocation types, making these tumors an attractive target for NY-ESO-1 antigen-based immunotherapy. © 2001 Wiley-Liss, Inc.

  • strong association of syt ssx fusion type and morphologic epithelial differentiation in synovial sarcoma
    Diagnostic Molecular Pathology, 2000
    Co-Authors: Cristina R Antonescu, Denis H Y Leung, James M Woodruff, Akira Kawai, John H Healey, Fulvio Lonardo, Marc Ladanyi
    Abstract:

    Synovial sarcoma is characterized by a specific recurrent translocation t(X;18), resulting in either the SYT-SSX1 or SYT-SSX2 gene fusion. Because this is the primary genetic alteration in these tumors, we sought to identify the impact of molecular heterogeneity of the t(X;18) on cell proliferation,

  • syt ssx gene fusion as a determinant of morphology and prognosis in synovial sarcoma
    The New England Journal of Medicine, 1998
    Co-Authors: Akira Kawai, Cristina R Antonescu, James M Woodruff, John H Healey, Murray F Brennan, Marc Ladanyi
    Abstract:

    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 function 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 pathologica...

Olle Larsson - One of the best experts on this subject based on the ideXlab platform.

  • co existence of syt SSX1 and syt ssx2 fusions in synovial sarcomas
    Oncogene, 2002
    Co-Authors: Ke Yang, Wengonn Lui, Yuntao Xie, Anju Zhang, Bjorn Skytting, Nils Mandahl, Catharina Larsson, Olle Larsson
    Abstract:

    The chromosomal translocation t(X;18)(p11.2;q11.2) is tightly linked to the tumorigenesis of synovial sarcoma. Through this translation the SYT gene on chromosome 18 is fused with a testis/cancer antigen gene on the X chromosome, generating either a SYT-SSX1, SYT-SSX2, or less often a SYT-SSX4 fusion gene. It has been anticipated that the individual synovial sarcoma carries only one of these variants, however, in this study we demonstrated that SYT-SSX1 and SYT-SSX2 co-exist in a significant proportion of the cases. From 121 SYT-SSX positive primary tumors, co-expression of SYT-SSX1 and SYT-SSX2 was seen in 12 cases (10%), which were characterized in further detail both at the RNA, DNA and chromosomal level. In all 12 cases the SYT-SSX1 and SYT-SSX2 fusions resulted in identical SYT-SSX fusion transcripts. However, at the genomic level the translocations were different, and most likely occurred between variable intronic sites in the target genes. By interphase FISH analyses of 10 cases SYT-SSX2 translocations were found to be the most abundant in all but one of the cases, in which SYT-SSX1 was predominating. The findings reveal a new heterogenous feature of synovial sarcoma, accounting for approximately 10% of all cases, which may shed light on the molecular genetic mechanisms behind translocations in general, and on the etiology of synovial sarcoma in particular.

  • the syt SSX1 variant of synovial sarcoma is associated with a high rate of tumor cell proliferation and poor clinical outcome
    Cancer Research, 1999
    Co-Authors: Gunnar Nilsson, Yuntao Xie, Bjorn Skytting, Nils Mandahl, Bertha Brodin, Roland Perfekt, Joakim Lundeberg, Mathias Uhlen, Olle Larsson
    Abstract:

    Cytogenetically, synovial sarcoma (SS) is characterized by the translocation t(X;18)(p11.2;q11.2), resulting in a fusion between the SYT gene on chromosome 18 and SSX1 or SSX2 on the X chromosome and the formation of new chimeric genes, SYT-SSX1 or SYT-SSX2 . We examined the potential clinical relevance of SYT-SSX1 and SYT-SSX2 fusion transcripts together with tumor proliferation. In a series of 33 patients with primary SS, the type of fusion transcript was assessed by reverse transcription-PCR and sequence analysis. The proliferation rate was analyzed using anti-Ki-67 antibodies. One case carrying an atypical transcript with a 57-bp insert was excluded, leaving 13 SYT-SSX1 and 19 SYT-SSX2 cases for analysis. The hazard ratio (with respect to metastasis-free survival for patients with SYT-SSX1 versus patients with SYT-SSX2 fusion transcripts was 7.4 (95% confidence interval, 1.5–36; log-rank P = 0.004). There was also an association with reduced overall survival for patients with SYT-SSX1 compared to patients with SYT-SSX2 (hazard ratio, 8.5; 95% confidence interval, 1.0–73; log-rank P = 0.02). The 5-year metastasis-free survival for patients with SYT-SSX1 was 42% versus 89% for patients with SYT-SSX2 . There was a significant association between SYT-SSX1 and a high tumor proliferation rate ( P = 0.02). We conclude that the findings suggest that the type of SYT-SSX fusion transcript determines the proliferation rate and is an important predictor of clinical outcome in patients with SS.

James M Woodruff - One of the best experts on this subject based on the ideXlab platform.

  • impact of syt ssx fusion type on the clinical behavior of synovial sarcoma a multi institutional retrospective study of 243 patients
    Cancer Research, 2002
    Co-Authors: Marc Ladanyi, Cristina R Antonescu, Denis H Y Leung, James M Woodruff, Akira Kawai, John H Healey, Murray F Brennan, Julia A Bridge, James R Neff, Frederic G Barr
    Abstract:

    Synovial sarcomas are aggressive spindle cell sarcomas containing in some cases areas of epithelial differentiation. They consistently show a specific t(X;18;p11;q11), which usually represents either of two gene fusions, SYT-SSX1 or SYT-SSX2 , encoding putative transcriptional proteins differing at 13 amino acid positions. Previous studies have suggested that patients with SYT-SSX2 tumors do better than those with SYT-SSX1 tumors, but the study groups were too limited to be conclusive. To address this issue more definitively, we collected data on SYT-SSX fusion type, pathology, and clinical course in a retrospective multi-institutional study of 243 patients (age range, 6–82) with synovial sarcoma. SYT-SSX1 and SYT - SSX2 fusions were detected in 147 tumors (61%) and 91 tumors (37%), respectively. Histologically, 61 (25%) were classified as biphasic type and 180 (74%) as monophasic type based on the presence or absence of areas of glandular epithelial differentiation, respectively. Median and 5-year overall survivals for the SYT - SSX1 and SYT - SSX2 groups were 6.1 years and 53%, and 13.7 years and 73%, respectively. Overall survival was significantly better among SYT - SSX2 cases ( P = 0.03), among cases localized at diagnosis ( P P = 0.01). Age, sex, histological type, and axial versus peripheral primary site had no impact on overall survival. The impact of fusion type on survival remained significant when stratified for primary tumor size ( P = 0.03) but was no longer significant when stratified for disease status at presentation. This may reflect the tendency for patients with SYT - SSX1 tumors to present more often with metastatic disease ( P = 0.05). Cox regression identified disease status ( P P = 0.04) as the only factors independently predictive of overall survival in the subset of 160 patients with information on all of the factors. Within the subset of patients with localized disease at diagnosis ( n = 202), the median and 5-year survival for the SYT-SSX1 and the SYT-SSX2 groups were 9.2 years and 61% versus 13.7 years and 77%, respectively. Patients whose tumors contained the SYT-SSX2 fusion ( P = 0.08) or were smaller ( P = 0.12) showed a trend toward better survival by log-rank test, whereas tumor histology had no impact ( P = 0.8). In a Cox regression analysis considering all of the factors, SYT - SSX fusion type emerged as the only independent significant factor ( P = 0.04) for overall survival within the subset of 133 patients with localized disease at diagnosis who had information on all of the factors. Among other comparisons, there was a strong association of fusion type and morphology ( P SYT-SSX2 tumors showing absence of glandular differentiation (monophasic histology) and almost all of the biphasic tumors containing SYT-SSX1 . There was also a statistically significant association of fusion type and patient sex ( P = 0.03); specifically, the male:female ratio of SYT - SSX1 cases was 1:1, whereas for SYT - SSX2 cases, it was close to 1:2. Overall, SYT-SSX fusion type appears to be the single most significant prognostic factor by multivariate analysis in patients with localized disease at diagnosis. SYT-SSX fusion type also appears to exert part of its impact on prognosis before presentation through its association with stage at diagnosis. In addition, the associations of SYT-SSX fusion type with patient sex and tumor epithelial differentiation point to interesting mechanistic biological differences.

  • strong association of syt ssx fusion type and morphologic epithelial differentiation in synovial sarcoma
    Diagnostic Molecular Pathology, 2000
    Co-Authors: Cristina R Antonescu, Denis H Y Leung, James M Woodruff, Akira Kawai, John H Healey, Fulvio Lonardo, Marc Ladanyi
    Abstract:

    Synovial sarcoma is characterized by a specific recurrent translocation t(X;18), resulting in either the SYT-SSX1 or SYT-SSX2 gene fusion. Because this is the primary genetic alteration in these tumors, we sought to identify the impact of molecular heterogeneity of the t(X;18) on cell proliferation,

  • syt ssx gene fusion as a determinant of morphology and prognosis in synovial sarcoma
    The New England Journal of Medicine, 1998
    Co-Authors: Akira Kawai, Cristina R Antonescu, James M Woodruff, John H Healey, Murray F Brennan, Marc Ladanyi
    Abstract:

    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 function 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 pathologica...

  • molecular diagnosis of synovial sarcoma and characterization of a variant syt ssx2 fusion transcript
    American Journal of Pathology, 1995
    Co-Authors: I Fligman, James M Woodruff, F Lonardo, Suresh C Jhanwar, William L Gerald, M Ladanyi
    Abstract:

    The translocation t(X;18)(p11;q11) is seen in > 80% of synovial sarcomas (SS) with informative karyotypes. The breakpoints of the t(X;18) have been cloned and shown to involve two novel genes, SSX (at Xp11) and SYT (at 18q11), which produce a chimeric SYT-SSX transcript as a result of the translocation. Recently, SSX has been shown to be duplicated, with both copies, SSX1 and SSX2, located within distinct subregions of Xp11. We performed a reverse transcriptase polymerase chain reaction (RT-PCR) assay for both chimeric SYT-SSX transcripts in a series of 35 SS (29 monophasic, 6 biphasic) to assess its usefulness in molecular diagnosis and to evaluate the incidence of molecular variants. Of the 35 cases, 29 (83%) showed a specific SYT-SSX RT-PCR product, using a consensus primer for SSX1 and SSX2 Upon excluding three negative cases that had poor quality RNA, the proportion of positives rose to 91% (29/32). The 29 positive cases were further studied using primers specific for either SSX1 or SSX2; 19 cases were positive for SYT-SSX1 and 10 for SYT-SSX2. The relationship of histological subtype (monophasic versus biphasic) to SSX1 or SSX2 involvement was not statistically significant. In a single histologically unremarkable monophasic SS, a slightly larger SYT-SSX2 RT-PCR product was observed. Sequencing of this novel variant showed a 129-bp segment inserted between the usual SYT and SSX2 fusion points, of which 126 bp were derived from a more proximal (5') portion of SSX2 The 3 bp immediately 5' to the fusion point could not be assigned to either SYT or SSX2 and may represent an insertion-deletion or a cryptic splicing event. This fragment maintains the reading frame of the chimeric product and encodes a predicted protein larger by 43 amino acids, which nevertheless replaces the region homologous to the transcriptional repression domain Kruppel-associated box, recently recognized in the 5' portion of the SSX genes, with all but the 3' end of the SYT transcript. Thus, a diagnosis of SS may be confirmed in > 90% of cases using RT-PCR detection of the chimeric transcript resulting from the t(X;18), and the incidence of molecular variants appears low.