Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, Korea.
Int J Cancer. 2014 Jul 1;135(1):128-37. doi: 10.1002/ijc.28675. Epub 2014 Jan 6.
Thymidylate synthase (TS), a critical enzyme for DNA synthesis and repair, is both a potential tumor prognostic biomarker as well as a tumorigenic oncogene in animal models. We have now studied the clinical implications of TS expression in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and compared these results to other cell cycle biomarker genes. Protein tissue arrays were used to study TS, Ki-67, Rb, pRb, E2F1, p18, p21, p27 and menin expression in 320 human GEP-NETs samples. Immunohistochemical expression was correlated with univariate and multivariate predictors of survival utilizing Kaplan Meier and Cox proportional hazards models. Real time RT-PCR was used to validate these findings. We found that 78 of 320 GEP-NETs (24.4%) expressed TS. NETs arising in the colon, stomach and pancreas showed the highest expression of TS (47.4%, 42.6% and 37.3%, respectively), whereas NETs of the appendix, rectum and duodenum displayed low TS expression (3.3%, 12.9% and 15.4%, respectively). TS expression in GEP-NETs was associated with poorly differentiated endocrine carcinoma, angiolymphatic invasion, lymph node metastasis and distant metastasis (p < 0.05). Patients with TS-positive NETs had markedly worse outcomes than TS-negative NETs as shown by univariate (p < 0.001) and multivariate (p = 0.01) survival analyses. Expression of p18 predicted survival in TS-positive patients that received chemotherapy (p = 0.015). In conclusion, TS protein expression was an independent prognostic biomarker for GEP-NETs. The strong association of increased TS expression with aggressive disease and early death supports the role of TS as a cancer promoting agent in these tumors.
胸苷酸合成酶（TS）是 DNA 合成和修复的关键酶，既是潜在的肿瘤预后生物标志物，也是动物模型中的肿瘤发生致癌基因。我们现在研究了 TS 表达在胃肠胰（GEP）神经内分泌肿瘤（NETs）中的临床意义，并将这些结果与其他细胞周期生物标志物基因进行了比较。使用组织蛋白芯片研究了 320 个人类 GEP-NETs 样本中的 TS、Ki-67、Rb、pRb、E2F1、p18、p21、p27 和 menin 的表达。利用 Kaplan-Meier 和 Cox 比例风险模型，对免疫组织化学表达与生存的单因素和多因素预测因素进行了相关性分析。使用实时 RT-PCR 验证了这些发现。我们发现，320 个 GEP-NETs 中有 78 个（24.4%）表达了 TS。起源于结肠、胃和胰腺的 NETs 表达了最高水平的 TS（分别为 47.4%、42.6%和 37.3%），而阑尾、直肠和十二指肠的 NETs 表达了低水平的 TS（分别为 3.3%、12.9%和 15.4%）。在 GEP-NETs 中，TS 表达与分化不良的内分泌癌、血管淋巴浸润、淋巴结转移和远处转移有关（p<0.05）。与 TS 阴性 NETs 相比，TS 阳性 NETs 患者的预后明显更差，单因素（p<0.001）和多因素（p=0.01）生存分析均显示如此。在接受化疗的 TS 阳性患者中，p18 的表达预测了生存（p=0.015）。总之，TS 蛋白表达是 GEP-NETs 的独立预后生物标志物。TS 表达增加与侵袭性疾病和早期死亡的强烈关联支持了 TS 在这些肿瘤中作为促进癌症的作用。
