Castells Antoni, Payá Artemio, Alenda Cristina, Rodríguez-Moranta Francisco, Agrelo Rubén, Andreu Montserrat, Piñol Virgínia, Castellví-Bel Sergi, Jover Rodrigo, Llor Xavier, Pons Elisenda, Elizalde J Ignasi, Bessa Xavier, Alcedo Javier, Saló Joan, Medina Enrique, Naranjo Antonio, Esteller Manel, Piqué Josep M
Department of Gastroenterology, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona.
Clin Cancer Res. 2006 Mar 15;12(6):1686-92. doi: 10.1158/1078-0432.CCR-05-1581.
Cyclooxygenase 2 (COX-2) overexpression is a frequent but not universal event in colorectal cancer. It has been suggested that COX-2 protein expression is reduced in colorectal cancer with a defective mismatch repair (MMR) system, a phenomenon commonly associated with hereditary nonpolyposis colorectal cancer (HNPCC) but also present in up to 15% of sporadic tumors.
To assess COX-2 expression in a large series of fully characterized colorectal cancer patients with respect to the MMR system and to dissect the mechanisms responsible for altered COX-2 expression in this setting.
MMR-deficient colorectal cancer were identified in a nationwide, prospective, multicenter study (EPICOLON project). Control MMR-proficient colorectal cancer patients were randomly selected. COX-2 expression was evaluated by immunohistochemistry. Personal and familial characteristics, as well as MSH2/MLH1 expression and germ line mutations, were evaluated.
One hundred fifty-three patients, 46 with MMR deficiency and 107 with MMR proficiency, were included in the analysis. Overall, tumor COX-2 overexpression was observed in 107 patients (70%). COX-2 overexpression was observed in 85 patients (79%) with a MMR-proficient system, but only in 22 patients (48%) with a MMR-deficient colorectal cancer (P < 0.001). The lack of COX-2 overexpression was independently associated with a MMR-deficient system (odds ratio, 3.89; 95% confidence interval, 1.78-8.51; P = 0.001) and a poor degree of differentiation (OR, 3.83; 95% CI, 1.30-11.31; P = 0.015). In the subset of patients with a MMR-deficient colorectal cancer, lack of COX-2 overexpression correlated with a poor degree of differentiation, no fulfillment of Amsterdam II criteria, absence of MSH2/MLH1 germ line mutations, presence of tumor MSH2 expression, and lack of tumor MLH1 expression. CpG island promoter hypermethylation of COX2 was observed in 6 of 18 (33%) tumors lacking COX-2 expression in comparison with 2 of 28 (7%) tumors expressing this protein (P = 0.04).
Up to half of MMR-deficient colorectal cancer do not show COX-2 overexpression, a fact observed almost exclusively in patients with sporadic forms. COX2 hypermethylation seems to be responsible for gene silencing in one third of them. These results suggest the potential utility of nonsteroidal anti-inflammatory drugs in HNPCC chemoprevention and may explain the lack of response of this approach in some sporadic tumors.
环氧化酶2（COX-2）过表达在结直肠癌中很常见，但并非普遍现象。有人提出，在错配修复（MMR）系统存在缺陷的结直肠癌中，COX-2蛋白表达会降低，这种现象通常与遗传性非息肉病性结直肠癌（HNPCC）相关，但在高达15%的散发性肿瘤中也存在。
评估一大系列特征明确的结直肠癌患者中COX-2的表达情况，并分析在这种情况下导致COX-2表达改变的机制。
在一项全国性、前瞻性、多中心研究（EPICOLON项目）中识别出MMR缺陷的结直肠癌。随机选择MMR功能正常的对照结直肠癌患者。通过免疫组织化学评估COX-2表达。评估个人和家族特征，以及MSH2/MLH1表达和种系突变。
153例患者纳入分析，其中46例MMR缺陷，107例MMR功能正常。总体而言，107例患者（70%）肿瘤COX-2过表达。MMR功能正常的系统中85例患者（79%）观察到COX-2过表达，但MMR缺陷的结直肠癌中仅22例患者（48%）观察到COX-2过表达（P<0.001）。COX-2未过表达与MMR缺陷系统独立相关（比值比，3.89；95%置信区间，1.78 - 8.51；P = 0.001）以及低分化程度相关（OR，3.83；95%CI，1.30 - 11.31；P = 0.015）。在MMR缺陷的结直肠癌患者亚组中，COX-2未过表达与低分化程度、未满足阿姆斯特丹II标准、不存在MSH2/MLH1种系突变、肿瘤MSH2表达的存在以及肿瘤MLH1表达的缺乏相关。与28例（COX-2）表达该蛋白的肿瘤中的2例（7%）相比，18例COX-2未表达的肿瘤中有6例（33%）观察到COX2启动子CpG岛高甲基化（P = 0.04）。
高达一半的MMR缺陷结直肠癌未显示COX-2过表达这一情况几乎仅在散发性患者中观察到。COX2高甲基化似乎是其中三分之一病例基因沉默的原因。这些结果提示非甾体抗炎药在HNPCC化学预防中的潜在效用，并可能解释这种方法在一些散发性肿瘤中缺乏反应的原因。
