RHAMM, p21 combined phenotype identifies microsatellite instability-high colorectal cancers with a highly adverse prognosis
RHAMM, p21 combined phenotype identifies microsatellite instability-high colorectal cancers with a highly adverse prognosis
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DOI：
10.1158/1078-0432.ccr-07-5103
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发表时间：
2008-06-15
影响因子：
11.5
通讯作者：
Lugli, Alessandro
中科院分区：
文献类型：
--
作者：
Zlobec, Inti;Baker, Kristi;Lugli, Alessandro
目的：本研究的目的是通过联合分析10个已建立的免疫组织化学肿瘤标志物和7个临床病理特征来确定微卫星不稳定性高（MSI-H）结直肠癌的预后亚组。实验设计：采用组织芯片技术，对223例MSI-H癌进行免疫组化检测，检测以下蛋白标志物：raf-1激酶抑制剂蛋白、透明质酸介导的运动受体、凋亡蛋白酶激活因子-1、哺乳动物不育样激酶1、p21、p27、p53、ephrin B2受体、Ki-67和表皮生长因子受体。七个临床病理特征和所有肿瘤标志物在单变量和多变量分析中进行评估。结果：RHAMM过表达[P < 0.001]；风险比[HR；95%可信区间（95% CI）], 3.86 (2.19-6.81)]， p21损失[P = 0.002；0.33(0.16-0.67)]，高N期[P < 0.001]；3.31(1.9-5.8)]是独立的不良预后因素。采用N分期对RHAMM/p21组合进行评价。不同RHAMM/p21组合的生存率差异有统计学意义（P < 0.001）。淋巴结阴性和淋巴结阳性的RHAMM-肿瘤患者存活时间均超过120个月。淋巴结阳性的RHAMM+患者预后差得多[16.0（10.0-63.0）个月]，可进一步分为p21-患者[14.0（9.0-27.0）个月]和p21+患者，生存期为47.0个月。RHAMM+/p21 -淋巴结阴性患者的生存时间明显短于RHAMM+/p21+肿瘤患者（P = 0.021）。结论：这些结果表明，RHAMM和p21表达的联合表型是MSI-H结直肠癌中一个宝贵的独立预后免疫组织化学特征。根据我们队列中确定的预后亚组，淋巴结阴性的过表达RHAMM但p21缺失的患者可能从术后治疗中获得潜在的益处，而对于MSI-H淋巴结阳性的RHAMM-肿瘤，应重新考虑辅助化疗。
Purpose: The aim of this study was to identify prognostic subgroups of microsatellite instability-high (MSI-H) colorectal cancers by combined analysis of 10 well-established immunohistochemical tumor markers and 7 clinicopathologic features.Experimental Design: Using a tissue microarray, immunohistochemistry was done on 223 cases of MSI-H cancers for the following protein markers: raf-1 kinase inhibitor protein, receptor for hyaluronic acid - mediated motility, apoptosis protease activating factor-1, mammalian sterile20-like kinase 1, p21, p27, p53, ephrin B2 receptor, Ki-67, and epidermal growth factor receptor. Seven clinicopathologic features and all tumor markers were evaluated in univariate and multivariable analyses.Results: RHAMM overexpression [P < 0.001; hazard ratio [HR; 95% confidence interval (95% CI)], 3.86 (2.19-6.81)], loss of p21 [P = 0.002; 0.33 (0.16-0.67)], and higher N stage [P < 0.001; 3.31 (1.9-5.8)] were independent adverse prognostic factors. RHAMM/p21 combinations were evaluated by N stage. Significant differences in survival were observed with various RHAMM/p21 combinations (P < 0.001). Both node-negative and node-positive patients with RHAMM- tumors survived more than 120 months. Node-positive RHAMM+ patients had a strikingly worse prognosis [16.0 (10.0-63.0) months] and could further be divided into p21- patients [14.0 (9.0-27.0) months] and p21+ patients surviving 47.0 months. RHAMM+/p21 - node-negative patients had a significantly shorter survival time than RHAMM+/p21+ tumors (P = 0.021).Conclusion: These results suggest that the combined phenotype of RHAMM and p21 expression is an invaluable independent prognostic immunohistochemical profile in MSI-H colorectal cancer. Based on the prognostic subgroups identified in our cohort, node-negative patients overexpressing RHAMM but with loss of p21 may derive a potential benefit from postoperative treatment, whereas adjuvant chemotherapy should be reconsidered for MSI-H node-positive RHAMM- tumors.