结直肠癌组织AIM2和血清CEA表达与预后相关性分析

Relationship between tissue AIM2 and preoperative serum CEA expression and the prognosis of colorectal cancer patients

目的黑色素瘤缺乏因子2(absent in melanoma 2,AIM2)是近年来新发现的一种炎症小体,其与肿瘤发生发展的相关性研究备受关注。本研究分析联合检测结直肠癌组织中AIM2表达与术前血清癌胚抗原(carcinoembryonic antigen,CEA)水平与结直肠癌患者预后的关系并探讨两者联合检测的临床价值。方法应用免疫组化检测收集于2009-10-13-2014-04-09苏州大学附属第二医院普外科142例结直肠癌患者的肿瘤组织标本及其中41例癌旁正常组织标本中AIM2的表达水平,同时回顾性搜集该142例患者术前肿瘤血清CEA水平及临床病理参数,分析结直肠癌组织中AIM2表达水平和术前血清CEA水平与临床病理特征的关系。Spearman等级相关性分析结直肠癌组织中AIM2表达水平与术前血清CEA水平的相关性。Kaplan-Meier生存曲线分析不同AIM2、CEA表达水平组别总生存率的差异;Cox比例风险回归模型进行单因素和多因素生存分析AIM2表达水平和术前血清CEA水平与患者预后的关系。结果AIM2在结直肠癌组织中的表达率为32.4%(46/142),明显低于癌旁正常组织的80.5%(33/41),χ2=29.994,P<0.001;其表达水平与肿瘤的浸润深度(χ2=5.383,P=0.020)、TNM分期(χ2=8.648,P=0.013)和淋巴结转移(χ2=4.947,P=0.026)有关联。患者术前血清CEA的阳性率为41.5%(59/142),其表达与肿瘤大小(χ2=11.338,P=0.001)、肿瘤浸润深度(χ2=5.197,P=0.023)和TNM分期(χ2=6.607,P=0.037)有关联。结直肠癌组织中AIM2表达水平与术前血清CEA水平呈负相关,r=-0.217,P=0.009。Kaplan-Meier生存分析显示,AIM2高表达患者总生存率(78.3%)明显高于低表达组(50.0%),中位生存期分别为61和48个月,χ2=10.686,P=0.001;而术前CEA阳性患者总生存率(45.8%)明显低于阴性组(79.7%),中位生存期分别为45和62个月,χ2=8.549,P=0.003。与AIM2高表达+CEA阳性组、AIM2低表达+CEA阳性组和AIM2低表达+CEA阴性组相比,AIM2高表达+CEA阴性组总生存率最高(88.0%),中位生存期65个月,而AIM2低表达+CEA阳性组总生存率最低(34.3%),中位生存期33个月,χ2=22.268,P<0.001。此外,Cox比例风险回归模型单因素分析显示,肿瘤TNM分期(HR=2.423,P<0.001)、淋巴结转移(HR=2.719,P<0.001)、术前血清CEA水平(HR=2.121,P=0.004)及AIM2组织表达水平(HR=0.339,P=0.002)与患者的预后有关;多因素分析结果显示,AIM2组织表达水平(HR=0.361,P=0.007)及术前血清CEA水平(HR=2.057,P=0.012)是结直肠癌患者预后的独立影响因素。结论结直肠癌组织中AIM2表达下调与不良预后相关,联合检测结直肠癌组织中AIM2表达水平与术前血清CEA水平在判断结直肠癌预后中具有重要的价值。

OBJECTIVE Absent in melanoma 2 （AIM2） is a newly discovered inflammasome in recent years,which may play a key role in the pathogenesis of cancer. This study aims to investigate the relationship between the expression of AIM2 and the level of carcinoembryonic antigen （CEA） in colorectal cancer （CRC） and to explore the prognosis value of combination detection in CRC patients. METHODS Totally 142 CRC tissue specimens and 41 adjacent normal tissues were collected from October 13th, 2009 to April 9th, 2014 at the department of general surgery, the Second Affiliated Hos- pital of Soochow University. Immunohistochemical staining was used to detect the expression level of AIM2. The preoper- ative serum levels of CEA and clinicopathological parameters of 142 patients were retrospectively collected. Then,we ana- lyzed the relationship between AIM2 expression,preoperative serum CEA levels and elinicopathological features in CRC patients. Spearman analysis was used to examine the correlation between the expression of AIM2 and preoperative serum CEA levels in CRC. Kaplan-Meier method was used to analyze the survival. Univariate and multivariate Cox proportional hazard regression models were used to evaluate the roles of AIM2 expression combined with preoperative serum CEA level in prognosis prediction. RESULTS AIM2 expressed more lowly in the tumor tissues （32.4%） than in the tumor-adjacent normal tissues （80.5 % X^2 = 29. 994, P=0. 001） and the expression level was associated with depth of invasion （X^2=5. 383,P=0. 020） ,TNM stage （X2=8. 648,P=0. 013） and lymph node metastasis （ X^2=4.947,P=0.026）.Thepreoper_ ative positive rate of serum CEA was 41.5 % （59/142）. The preoperative serum CEA level was associated with tumor size （X^2=ll. 338,P=0. 001） ,depth of invasion （2：5.197,P=0.023） andTNM stage （X2=6. 607,P=0. 037）. There was a negative correlation between AIM2 expression and CEA levels in CRC tissue （r=- 0. 217, P=0. 009）. Kaplan-Meier curves revealed that the low AIM2 expression group had a significantly shorter overall survival rate compared to the high AIM2 expression group （50.0% vs 78.3%）,which the median survival time were 48 months and 61 months,respectively （Z2 ： 10. 686, P= 0. 001）. The over survival rate of patients with preoperative positive serum CEA was significantly lower than those with preoperative negative serum CEA （45.8% vs 79.7 %） （X2=8. 549, P=0. 003）. Furthermore, the Kaplan- Meier survival curve highlighted considerable differences between the four phenotypes （AIM2 ＋/CEA--, AIM2 ＋/CEA -k,AIM2--/CEA＋, AIM2 --/CEA-- ） with AIM2 -/CEA ＋ tumors having significantly worsened survival time com- pared to AIM2 ＋/CEA-- tumors （X^2 = 22. 268, P〈0.001） by combined detection of AIM2 and preoperative CEA. More- over, univariate analysis showed that TNM stage （ HR： 2. 423, P〈0. 001）, Lymph node metastasis （ HR： 2. 719, P〈0. 001） ,preoperative serum CEA （HR=2. 121,P=0. 004） and AIM2 expression （HR=0. 339,P=0. 002） were signifi- cantly associated with the prognosis of patients. A multivariate analysis showed that both AIM2 expression （HR=0. 361, P=0. 007） and preoperative serum CEA （HR= 2. 057, P= 0. 012） were independent prognostic factors for survival. CON- CLUSION The downregulation of AIM2 expression is associated with poor survival in colorectal cancer patients, and combination detection of AIM2 expression and preoperative serum CEA levels has significant value in predicting the prog- nosis of CRC.