通过对溃疡性结肠炎患者非肿瘤性上皮中雌激素受体基因进行定量甲基化分析预测结直肠肿瘤

Prediction of colorectal neoplasia by quantitative methylation analysis of estrogen receptor gene in nonneoplastic epithelium from patients with ulcerative colitis.

作者信息

Tominaga Keiichi, Fujii Shigehiko, Mukawa Kenichiroh, Fujita Mikio, Ichikawa Kazuhito, Tomita Shigeki, Imai Yasuo, Kanke Kazunari, Ono Yuko, Terano Akira, Hiraishi Hideyuki, Fujimori Takahiro

机构信息

Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Japan.

出版信息

Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8880-5. doi: 10.1158/1078-0432.CCR-05-1309.

DOI:10.1158/1078-0432.CCR-05-1309

PMID:16361578

Abstract

PURPOSE

The incidence of colorectal neoplasia has increased among patients with longstanding and extensive ulcerative colitis (UC). Therefore, surveillance colonoscopy has been widely recommended. However, there is controversy about the impact of cancer surveillance, and ways to improve its effectiveness are being sought. The estrogen receptor (ER) gene shows age-related methylation in the colorectal epithelium and is frequently methylated in colorectal neoplasia, suggesting that ER methylation occurs early in the process of colorectal tumorigenesis.

EXPERIMENTAL DESIGN

To clarify whether methylation analysis of the ER gene in nonneoplastic epithelium can help predict an increased risk for UC-associated neoplasia, a total of 105 nonneoplastic colorectal epithelia from 18 patients with longstanding and extensive UC, including 8 patients with neoplasia and 10 patients without neoplasia, were analyzed. In all patients, multiple samples were taken from six regions of the colorectum. The combined bisulfite restriction analysis method was used to determine the methylation status of the ER gene.

RESULTS

The mean methylation level of the ER gene was 25.4% in the nonneoplastic epithelia from UC patients with neoplasia, whereas it was only 4.0% in those without neoplasia (P<0.001). The methylation level of the ER gene in UC patients with neoplasia was significantly higher than in UC patients without neoplasia throughout the colorectum except for the cecum. In UC patients with neoplasia, the mean ER methylation level in the distal colon (36.1%) was significantly higher than in the proximal colon (14.6%; P<0.001).

CONCLUSIONS

These results suggest that the analysis of ER gene methylation in nonneoplastic colorectal epithelium could have the potential to be a useful adjunct for identifying individuals with longstanding and extensive UC who are at increased risk of neoplasia and contribute to more effective cancer surveillance.

摘要

目的

在长期广泛性溃疡性结肠炎（UC）患者中，结直肠肿瘤的发病率有所上升。因此，广泛推荐进行监测性结肠镜检查。然而，癌症监测的影响存在争议，人们正在寻求提高其有效性的方法。雌激素受体（ER）基因在结直肠上皮中显示出与年龄相关的甲基化，并且在结直肠肿瘤中经常发生甲基化，这表明ER甲基化在结直肠肿瘤发生过程中早期就会出现。

实验设计

为了阐明非肿瘤性上皮中ER基因的甲基化分析是否有助于预测UC相关肿瘤风险的增加，对18例长期广泛性UC患者的105个非肿瘤性结直肠上皮进行了分析，其中包括8例患有肿瘤的患者和10例未患肿瘤的患者。在所有患者中，从结直肠的六个区域采集了多个样本。采用联合亚硫酸氢盐限制性分析方法来确定ER基因的甲基化状态。

结果

患有肿瘤的UC患者的非肿瘤性上皮中ER基因的平均甲基化水平为25.4%，而未患肿瘤的患者中仅为4.0%（P<0.001）。除盲肠外，患有肿瘤的UC患者在整个结直肠中ER基因的甲基化水平显著高于未患肿瘤的UC患者。在患有肿瘤的UC患者中，远端结肠的平均ER甲基化水平（36.1%）显著高于近端结肠（14.6%；P<0.001）。