SMAD7 is a prognostic marker in patients with colorectal cancer
SMAD7 is a prognostic marker in patients with colorectal cancer
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DOI：
10.1002/ijc.10908
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发表时间：
2003-04-20
影响因子：
6.4
通讯作者：
Rochlitz, C
中科院分区：
文献类型：
--
作者：
Boulay, JL;Mild, G;Rochlitz, C
染色体18 q21区域在结直肠癌（CRC）中经常缺失，并与预后不良相关。18 q21缺失改变的潜在肿瘤抑制机制包括SMADs介导的TGF β信号传导。在将SMAD 4缺失定义为CRC患者化疗获益的阴性预测标志物后，我们旨在评估聚集在该区域的其他SMAD基因缺失的临床相关性：来自先前临床研究的264例CRC活检中的SMAD 2和SMAD 7。与SMAD 2缺失（未观察到临床相关性）相反，SMAD 7缺失相关的多变量分析中的风险比（HR）[总生存期（OS）：HR = 0.43，p = 0.0012;无病生存期（DFS）：HR = 0.50，p = 0.0033]表明这些患者的结局良好。此外，SMAD 7重复对存活具有危险影响[OS：HR = 2.10，p = 0.020; DFS：HR = 2.06，p = 0.015]。此外，与SMAD 7的一个额外拷贝相关的HR分别为1.76，p = 0.00024 [OS]和1.64，p = 0.00048 [DFS]，显示SMAD 7对患者结果的分级效应取决于基因拷贝数，这表明剂量-效应基础。由于SMAD 7阻断TGF β信号传导，这些数据与SMAD 7的丧失一致，使得癌细胞对TGF β的细胞生长停滞/凋亡作用更敏感，而SMAD 7功能的获得可能导致TGF β抗性，从而强调TGF β在肿瘤抑制中的作用。(C)2003 Wiley-Liss，Inc.
Chromosomal region 18q21 is frequently deleted in colorectal cancer (CRC) and is associated with poor prognosis. Potential tumor suppressor mechanisms altered by 18q21 deletion include mediation of TGFbeta signaling by SMADs. Following the definition of SMAD4 deletion as a negative predictive marker for chemotherapy benefit in patients with CRC, we aimed to evaluate the clinical relevance of the deletion of other SMAD genes clustered in this region: SMAD2 and SMAD7 in 264 CRC biopsies from a previous clinical study. In contrast to SMAD2 deletion, for which no clinical relevance was observed, hazard ratios (HR) in a multivariate analysis associated with SMAD7 deletion [overall survival (OS): HR = 0.43, p = 0.0012; disease-free survival (DFS): HR = 0.50, p = 0.0033] indicated a favorable outcome for these patients. In addition, SMAD7 duplication had a hazardous effect on survival [OS: HR = 2.10, p = 0.020; DFS: H R = 2.06, p = 0.015]. Moreover, the HRs associated with one additional copy of SMAD7 were 1.76, p = 0.00024 [OS] and 1.64, p = 0.00048 [DFS] respectively, showing a graded effect of SMAD7 on patient outcome depending on gene copy number that suggests a dose-and-effect basis. Since SMAD7 blocks TGFbeta signaling, these data are consistent with the loss of SMAD7 rendering carcinoma cells more sensitive to cell growth arrest/apoptotic effect of TGFbeta, whereas gain of SMAD7 function might result in TGFbeta resistance, thereby emphasizing the role of TGFbeta in tumor suppression. (C) 2003 Wiley-Liss, Inc.