Role for p16INK4a in progression of gastrointestinal stromal tumors of the stomach: alteration of p16INK4a network members
Role for p16INK4a in progression of gastrointestinal stromal tumors of the stomach: alteration of p16INK4a network members
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DOI：
10.1016/j.humpath.2011.01.005
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发表时间：
2011-10-01
期刊：
影响因子：
3.3
通讯作者：
Yao, Takashi
中科院分区：
文献类型：
--
作者：
Mitomi, Hiroyuki;Fukui, Naoshi;Yao, Takashi
胃肠道间质瘤具有广泛的生物学行为，从良性到极端恶性。为了确定p16（INK 4a）改变在胃胃肠道间质瘤进展中的作用，我们研究了蛋白质表达和基因甲基化的相关性。与临床病理因素和生存率的关系。除了对95例患者进行p16（INK 4a）免疫组化分析外，还对随机选择的样本进行了p16（INK 4a）实时定量甲基化特异性聚合酶链反应和细胞周期蛋白D1、细胞周期蛋白E、pRb、DP-1、E2 F-1和Ki-67的免疫染色。p16（INK 4a）标记指数范围为0%至74%（中位数为21%），与大小呈显著负相关（P = 0.046）。在单变量（P = 0.003）和多变量（P = 0.067）分析中，p16（INK 4a）表达的缺失增加了肿瘤相关生存率差的可能性。此外，肿瘤大小（P = 0.036）和核分裂指数（P = 0.005）具有独立的预后影响。p16（INK 4a）甲基化指数范围为0%至100%（中位数为17%），在较大肿瘤（P <0.001）和高风险类别病变（P = 0.001）中显著较高，并与蛋白表达呈负相关。基于p16（INK 4a）网络成员表达的分层聚类分析在27个随机选择的肿瘤样本中鉴定出2个聚类，每个聚类包含11个和16个肿瘤。前一组样本显示出更高的风险类别（P = 0.022）、更高的p16（INK 4a）甲基化（P <0.001）和更多的pRb表达降低（P <0.018）。此外，p16（INK 4a）网络成员可分为两组：（1）p16（INK 4a）蛋白表达下调，cyclin D1和DP-1表达上调;（2）pRb表达下调，E2 F-1表达上调。我们的结论是，p16（INK 4a）的改变有一个重要的作用，胃肠道间质瘤的进展。此外，该研究提供了p16（INK 4a）网络成员的调节与胃肠道间质瘤之间的可能联系。(C)2011 Elsevier Inc. All rights reserved.
Gastrointestinal stromal tumors feature a wide spectrum of biologic behavior, ranging from benign to extremely malignant. To determine the role of p16(INK4a) alteration in progression of gastrointestinal stromal tumors of the stomach, we have investigated protein expression and gene methylation in correlation. with clinicopathologic factors and survival. In addition to immunohistochemical analysis of p16(INK4a) in a series of 95 cases, real-time quantitative methylation specific polymerase chain reaction for p16(INK4a) and immunostaining for cyclin D1, cyclin E, pRb, DP-1, E2F-1, and Ki-67 were also evaluated in randomly selected samples. The p16(INK4a) labeling indices ranged from 0% to 74% (median, 21%), demonstrating a significant inverse correlation with size (P = .046). On univariate (P = .003) and multivariate (P = .067) analyses, loss of p16(INK4a) expression increased the likelihood of a poor tumor-related survival. In addition, size (P = .036) and the mitotic index (P = .005) had independent prognostic influence. The p16(INK4a) methylation index, which ranged from 0% to 100% (median, 17%), was significantly higher in larger tumors (P < .001) and in high-risk category lesions (P = .001) and inversely correlated with protein expression. Hierarchical cluster analysis based on expression of p16(INK4a) network members identified 2 clusters in 27 randomly selected tumor samples, containing 11 and 16 tumors each. Former cluster samples demonstrated higher risk category (P = .022), higher p16(INK4a) methylation (P < .001), and more reduced pRb expression (P < .018). In addition, p16(INK4a) network members clustered into 2 groups: (1) showing down-regulated p16(INK4a) protein and up-regulating of both cyclin D1 and DP-1 and (2) down-regulated pRb and up-regulated E2F-1. We conclude that p16(INK4a) alteration has an important role in progression of gastrointestinal stromal tumors of the stomach. Furthermore, the study provides a possible link between regulation of p16(INK4a) network members and gastrointestinal stromal tumors. (C) 2011 Elsevier Inc. All rights reserved.