High telomerase activity is associated with cell cycle deregulation and rapid progression in endometrioid adenocarcinoma of the uterus
High telomerase activity is associated with cell cycle deregulation and rapid progression in endometrioid adenocarcinoma of the uterus
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DOI：
10.1053/hupa.2001.25002
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发表时间：
2001-06-01
期刊：
影响因子：
3.3
通讯作者：
Rudolph, P
中科院分区：
文献类型：
--
作者：
Bonatz, G;Frahm, SO;Rudolph, P
端粒酶活性是一种赋予细胞永生的机制，已在大多数癌症实体中检测到，但其与临床，组织病理学和预后参数的关系尚不完全清楚。我们研究了定量端粒酶水平是否与已建立的预后因素、端粒长度、细胞周期动力学和子宫内膜样腺癌（EC）的临床病程相关。采用改良的端粒重复序列扩增法（TRAP）对53例原发性肿瘤的相对端粒酶活性进行定量分析。通过Southern印迹分析测定平均端粒长度。在石蜡切片上，使用针对两种不同增殖特异性蛋白的单克隆抗体对细胞周期动力学进行了免疫化学研究：Ki-67，其在整个细胞周期中表达;以及一种新的细胞周期相关蛋白repp 86，其表达仅限于细胞周期S、G（2）和M期。2种免疫标记指数的比值定义了通过限制点的转变速率。53例EC中50例（94%）检测到端粒酶活性。其水平与FIGO分期（P = .01）和FIGO分级（P = .003）显著相关，但与子宫肌层浸润无关。它们与总体增殖活性（Ki-67，r = 0.48）弱相关，但与repp 86指数（r = 0.64）显著相关，甚至与repp 86：Ki-67比率（r = 0.77）更强相关。与平均端粒长度无相关性。在高端粒酶活性肿瘤组中，5例患者复发，2例在中位随访29个月内死于疾病。复发与FIGO分级、分期无关。在低端粒酶活性组中未观察到事件。在包括肿瘤分期、组织病理学分级、子宫肌层浸润深度和Ki-67指数的多变量模型中，端粒酶活性成为疾病进展的唯一独立预测因子（P = .0002）。它的结论是，超出了链接到增殖，高端粒酶活性反映了失调的细胞周期与细胞进入S期和更高程度的恶性程度的增加率。因此，端粒酶活性的定量分析可能是有用的，以确定EC患者在高风险的复发。Copyright（C）2001 by W.B.桑德斯公司
Telomerase activity, a mechanism granting cellular immortality, has been detected in most cancer entities, but its association with clinical, histopathologic, and prognostic parameters is not fully understood. We investigated whether quantitative telomerase levels are correlated to established prognostic factors, telomere lengths, cell cycle kinetics, and the clinical course in endometrioid adenocarcinoma of the uterus (EC). A modified telomeric repeat amplification protocol (TRAP) was used to quantify the relative telomerase activity in a series of 53 primary tumors. Mean telomere length was determined by Southern blot analysis. Cell cycle kinetics were studied immunohistochemically on paraffin sections using monoclonal antibodies to 2 distinct proliferation-specific proteins: Ki-67, which is expressed throughout the cell cycle, and a novel cell cycle-associated protein, repp86, the expression of which is restricted to the cell cycle phases S, G(2), and M. The ratio of the 2 immunolabeling indices defines the rate of transition through the restriction point. Telomerase activity was detected in 50 of 53 ECs (94%). Its levels correlated significantly with FIGO stage (P = .01) and FIGO grade (P = .003) but not with myometrial invasion. They were weakly associated with the overall proliferative activity (Ki-67, r = .48) but significantly with the repp86 index (r = .64) and even more strongly with the repp86: Ki-67 ratio (r = .77). There was no correlation with mean telomere length. In the group of tumors with high telomerase activity, 5 patients had relapses and 2 died of the disease within a median follow-up period of 29 months. Recurrence showed no relation to FIGO grade and stage. No events were observed in the group with low telomerase activity. In a multivariate model including tumor stage, histopathologic grade, depth of myometrial invasion, and Ki-67 indices, telomerase activity emerged as the only independent predictor of disease progression (P = .0002). It is concluded that beyond a link to proliferation, high telomerase activity reflects a deregulation of the cell cycle associated with an increased rate of cells entering S phase and a higher degree of malignancy. Therefore, quantitative analysis of telomerase activity may be useful for identifying EC patients at high risk for recurrence. Copyright (C) 2001 by W.B. Saunders Company.