Mancuso T, Mezzelani A, Riva C, Fabbri A, Dal Bo L, Sampietro G, Perego P, Casali P, Zunino F, Sozzi G, Pierotti M A, Pilotti S
Division of Anatomic Pathology and Cytology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy.
Lab Invest. 2000 Jun;80(6):805-13. doi: 10.1038/labinvest.3780085.
Synovial sarcomas (SS) are characterized by a chromosomal translocation t(X;18)(p11.2;q11.2) which usually fuses the SYT gene from chromosome 18 to SSX1 or SSX2 genes on chromosome X. Also, a variant SYT-SSX4 fusion gene has recently been shown in a single SS case. In addition to these cytogenetic changes, bcl-2 expression, as assessed by immunohistochemistry, has been reported to be an almost general constitutive alteration of SS. In the present work, we analyze a series of 36 SS surgical samples (from 34 patients) by RT-PCR for the presence of the SYT-SSX1 or the SYT-SSX2 fusion transcript. The analysis was extended to SYT-SSX4 on SYT-SSX1-negative and SYT-SSX2-negative cases only. Our results showed a significant correlation between the SYT-SSX2 fusion and the monophasic SS histologic subtype. SYT-SSX1 fusion transcripts were present in both monophasic and biphasic tumors. The SYT-SSX4 fusion type was detected in a single monophasic SS. In the same series of SS cases, we also confirmed and extended the previously reported constitutive expression of bcl-2 protein, by using both immunohistochemical and western blot analysis. Moreover, we demonstrated that the BCL-2 gene is not rearranged or amplified at genomic level, indicating that the high levels of bcl-2 expression observed in SS might result from transcriptional activation of the gene and/or protein stabilization. Finally, we show that bcl-2 is not phosphorylated in tumors from patients who had been preoperatively treated with radio/chemotherapy, in tumors from untreated patients, or in an SS cell line (CME-1) after in vitro treatment with cytotoxic concentrations of DNA-damaging agents or taxanes. These data indicate that SS cells are unable to activate an apoptosis pathway involving bcl-2 phosphorylation/inactivation and may provide a possible explanation for the limited effectiveness of conventional pharmacological treatments of this tumor type.
滑膜肉瘤（SS）的特征是染色体易位t(X;18)(p11.2;q11.2)，该易位通常将18号染色体上的SYT基因与X染色体上的SSX1或SSX2基因融合。此外，最近在一例SS病例中发现了一种变异的SYT-SSX4融合基因。除了这些细胞遗传学改变外，通过免疫组织化学评估的bcl-2表达据报道几乎是SS的普遍组成性改变。在本研究中，我们通过逆转录聚合酶链反应（RT-PCR）分析了36例SS手术样本（来自34例患者），以检测SYT-SSX1或SYT-SSX2融合转录本的存在。仅对SYT-SSX1阴性和SYT-SSX2阴性病例的分析扩展至SYT-SSX4。我们的结果显示SYT-SSX2融合与单相SS组织学亚型之间存在显著相关性。SYT-SSX1融合转录本存在于单相和双相肿瘤中。在一例单相SS中检测到SYT-SSX4融合类型。在同一组SS病例中，我们还通过免疫组织化学和蛋白质印迹分析证实并扩展了先前报道的bcl-2蛋白的组成性表达。此外，我们证明BCL-2基因在基因组水平未发生重排或扩增，这表明在SS中观察到的高水平bcl-2表达可能是由于该基因的转录激活和/或蛋白质稳定化。最后，我们表明，在术前接受过放疗/化疗的患者的肿瘤中、未治疗患者的肿瘤中，或在体外经细胞毒性浓度的DNA损伤剂或紫杉烷处理后的SS细胞系（CME-1）中，bcl-2未被磷酸化。这些数据表明SS细胞无法激活涉及bcl-2磷酸化/失活的凋亡途径，这可能为这种肿瘤类型的传统药物治疗效果有限提供一种可能的解释。
