SMAD4 as a prognostic marker in colorectal cancer
SMAD4 as a prognostic marker in colorectal cancer
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DOI：
10.1158/1078-0432.ccr-04-1458
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发表时间：
2005-04-01
影响因子：
11.5
通讯作者：
Arango, D
中科院分区：
文献类型：
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作者：
Alazzouzi, H;Alhopuro, P;Arango, D
超过50%的Dukes C结直肠癌患者在手术切除原发肿瘤后5年内复发并死亡。目前尚无法区分预后良好和不良的患者。SMAD 4是一个重要的肿瘤抑制基因，介导转化生长因子-P超家族信号传导，位于染色体18 q21，这是这些肿瘤中经常发生遗传丢失的区域。18 q中的等位基因不平衡与结直肠癌患者的预后不良有关。因此，我们产生了一个组织微阵列，其中包含来自86名Dukes C患者的三份肿瘤样本，并使用免疫组织化学来评估SMAD 4的相对表达水平及其作为预后标志物的价值。此外，SMAD 4的突变进行了筛选，并使用两个多态性微卫星标记来评估这些肿瘤中等位基因不平衡的存在。SMAD 4高表达患者的总体生存率（P < 0.025）和无病生存率（P < 0.013）明显优于SMAD 4低表达患者。这将SMAD 4确定为Dukes C结直肠癌的预后标志物。尽管所有缺乏SMAD 4染色的肿瘤显示18 q21等位基因失衡，但与没有等位基因失衡的肿瘤相比，具有18 q21等位基因失衡的肿瘤作为一组显示SMAD 4水平没有差异，表明存在SMAD 4下调的其他机制。此外，尽管在5个肿瘤中发现了SMAD 4突变，但它们与较短的生存期无关。总之，SMAD 4的表达水平被认为是比18 q21等位基因失衡和SMAD 4突变更敏感的标志物，这对这些患者没有预后意义。
More than 50% of patients with Dukes C colorectal cancer have disease recurrence and die within 5 years after surgical removal of their primary tumor. It is currently not possible to distinguish patients with good and bad prognosis. SMAD4 is an important tumor suppressor gene that mediates transforming growth factor-P superfamily signaling and is located in chromosome 18q21, a region with frequent genetic losses in these tumors. Allelic imbalance in 18q has been linked to poor prognosis in a subset of colorectal cancer patients. Therefore, we generated a tissue microarray containing triplicate tumor samples from 86 Dukes C patients and used immunohistochemistry to assess the relative expression level of SMAD4 and its value as a prognostic marker. In addition, SMAD4 was screened for mutations and two polymorphic microsatellite markers were used to assess the presence of allelic imbalance in these tumors. Patients with tumors expressing high SMAD4 levels had significantly better overall (P < 0.025) and disease-free (P < 0.013) survival than patients with low levels. This identifies SMAD4 as a prognostic marker for Dukes C colorectal cancer. Although all tumors with absent SMAD4 staining showed allelic imbalance in 18q21, tumors with 18q21 allelic imbalance as a group showed no difference in SMAD4 levels compared with tumors without allelic imbalance, suggesting that additional mechanisms of SMAD4 down-regulation exist. In addition, although SMAD4 mutations were found in five tumors, they were not associated with shorter survival. In conclusion, the level of expression of SMAD4 was found to be a more sensitive marker than 18q21 allelic imbalance and SMAD4 mutations, which were of no prognostic significance for these patients.