散发性大肠息肉中的人错配修复蛋白hMLH1、人错配修复蛋白hMSH2和环氧化酶-2（cox-2）

hMLH1, hMSH2 and cyclooxygenase-2 (cox-2) in sporadic colorectal polyps.

作者信息

Balbinotti Raul Angelo, Ribeiro Ulysses, Sakai Paulo, Safatle-Ribeiro Adriana Vaz, Balbinotti Silvana Sartori, Scapulatempo Cristovam, Alves Venancio Avancini Ferreira, Corbett Carlos Eduardo Pereira, Carrilho Flair José

机构信息

Department of Gastroenterology, University of Caxias do Sul Medical School, Caxias do Sul, RS, Brazil.

出版信息

Anticancer Res. 2007 Nov-Dec;27(6C):4465-71.

PMID:18214062

Abstract

BACKGROUND

Colorectal adenomatous polyps are known as premalignant lesions. Mutations in the mismatch repair (MMR) enzymes hMLH1, hMSH2 and hMSH6 are recognized causes of hereditary non-polyposis colorectal cancer and act by inducing a mutator phenotype characterized by microsatellite instability (MSI). MSI is also detected in sporadic colorectal cancers. Cox-2 is an inducible enzyme that regulates prostaglandin synthesis and it is overexpressed at sites of inflammation, in colorectal adenomatous polyps and cancer. The aim of this study was to evaluate the immunoexpression of hMLH1, hMSH2 and Cox-2 in polyps resected through colonoscopy, and to examine their association with clinicopathological characteristics (age, gender, location, size, histology and grade of dysplasia).

PATIENTS AND METHODS

One hundred and sixty-seven colonic polyps, 6 normal colonic mucosa samples, and 23 samples of colorectal adenocarcinoma were used in this study. All patients had no family history of colorectal cancer. The samples were prospectively collected and immunostained for hMLH1, hMSH2 and Cox-2 using the ABC-immunohistochemistry technique with amplification by biotinylated tyramide. The mean age was 60.2+/-13.8 years (range 21-90 years) and 77 (55.8%) were men.

RESULTS

Tubular adenomas were present in 81.4%, tubulous-villous in 15.9%, serrated in 1.8%, and villous in 0.9%. The majority of the adenomas were located in the rectosigmoid region (63.5%), followed by ascendant in 14.2%, cecum in 7.5%, descendent in 8.2% and transverse in 6.7%. Low-grade dysplasia was detected in 59.6% of the adenomas. Loss of hMLH1 and hMLH2 immunoexpression was observed in 20% and 15.5% of the adenomas, respectively. Cox-2 expression was found in 9% of the adenomas, and in 40% of the adenocarcinomas. Moreover, Cox-2 immunoexpression was associated with the multiplicity of adenomas in the same patient (p=0.001). There was no association between marker immunoexpression and gender, age, location, size, histology or grade of dysplasia.

CONCLUSION

Loss of hMLH1 and hMLH2 immunoexpression in adenomas is relatively frequent in patients without colorectal cancer family history. Cox-2 is overexpressed in colorectal adenomatous polyps and adenocarcinomas, and its positivity in adenomas may indicate a higher risk for multiple lesions.

摘要

背景

结直肠腺瘤性息肉被认为是癌前病变。错配修复（MMR）酶hMLH1、hMSH2和hMSH6的突变是遗传性非息肉病性结直肠癌的公认病因，其作用机制是诱导以微卫星不稳定性（MSI）为特征的突变表型。MSI在散发性结直肠癌中也可检测到。Cox-2是一种诱导酶，可调节前列腺素合成，在炎症部位、结直肠腺瘤性息肉和癌症中过度表达。本研究的目的是评估通过结肠镜切除的息肉中hMLH1、hMSH2和Cox-2的免疫表达，并检查它们与临床病理特征（年龄、性别、位置、大小、组织学和发育异常分级）的相关性。

患者和方法

本研究使用了167个结肠息肉、6个正常结肠黏膜样本和23个结直肠癌样本。所有患者均无结直肠癌家族史。样本前瞻性收集，并采用ABC免疫组织化学技术，通过生物素化酪胺放大法对hMLH1、hMSH2和Cox-2进行免疫染色。平均年龄为60.2±13.8岁（范围21 - 90岁），77例（55.8%）为男性。

结果

管状腺瘤占81.4%，管状绒毛状腺瘤占15.9%，锯齿状腺瘤占1.8%，绒毛状腺瘤占0.9%。大多数腺瘤位于直肠乙状结肠区域（63.5%），其次是升结肠（14.2%）、盲肠（7.5%）、降结肠（8.2%）和横结肠（6.7%）。59.6%的腺瘤检测到低级别发育异常。分别在20%和15.5%的腺瘤中观察到hMLH1和hMLH2免疫表达缺失。9%的腺瘤和40%的腺癌中发现Cox-2表达。此外，Cox-2免疫表达与同一患者腺瘤的多发性相关（p = 0.001）。标志物免疫表达与性别、年龄、位置、大小、组织学或发育异常分级之间无相关性。