结直肠肿瘤癌变过程中胱硫醚双加氧酶 1（CDO1）基因启动子甲基化。

Cysteine dioxygenase type 1 (CDO1) gene promoter methylation during the adenoma-carcinoma sequence in colorectal cancer.

机构信息

Department of Surgery, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan.

Department of Pathology, Kitasato University School of Allied Health Sciences, Minami-ku, Sagamihara, Kanagawa, Japan.

出版信息

PLoS One. 2018 May 10;13(5):e0194785. doi: 10.1371/journal.pone.0194785. eCollection 2018.

BACKGROUND

Progression of colorectal cancer (CRC) has been explained by genomic abnormalities along with the adenoma-carcinoma sequence theory (ACS). The aim of our study is to elucidate whether the promoter DNA methylation of the cancer-specific methylation gene, cysteine dioxygenase 1 (CDO1), contributes to the carcinogenic process in CRC.

METHODS

The study group comprised 107 patients with CRC who underwent surgical resection and 90 adenomas treated with endoscopic resection in the Kitasato University Hospital in 2000. We analyzed the extent of methylation in each tissue using quantitative TaqMan methylation-specific PCR for CDO1.

RESULTS

The methylation level increased along with the ACS process (p < 0.0001), and statistically significant differences were found between normal-appearing mucosa (NAM) and low-grade adenoma (p < 0.0001), and between low-grade adenoma and high-grade adenoma (p = 0.01), but not between high-grade adenoma and cancer with no liver metastasis. Furthermore, primary CRC cancers with liver metastasis harbored significantly higher methylation of CDO1 than those without liver metastasis (p = 0.02). As a result, the area under the curve by CDO1 promoter methylation was 0.96, 0.80, and 0.67 to discriminate cancer from NAM, low-grade adenoma from NAM, and low-grade adenoma from high-grade adenoma, respectively.

CONCLUSIONS

CDO1 methylation accumulates during the ACS process, and consistently contributes to CRC progression.

背景

结直肠癌（CRC）的进展可以通过基因组异常以及腺瘤-癌序列理论（ACS）来解释。我们的研究旨在阐明癌症特异性甲基化基因胱硫醚双加氧酶 1（CDO1）的启动子 DNA 甲基化是否有助于 CRC 的致癌过程。

方法

该研究组包括 2000 年在北里大学医院接受手术切除的 107 例 CRC 患者和 90 例经内镜切除的腺瘤患者。我们使用定量 TaqMan 甲基化特异性 PCR 分析了每个组织中 CDO1 的甲基化程度。

结果

甲基化水平随着 ACS 过程而增加（p<0.0001），在正常外观黏膜（NAM）和低级别腺瘤（p<0.0001）、低级别腺瘤和高级别腺瘤（p=0.01）之间存在统计学显著差异，但在高级别腺瘤和无肝转移的癌症之间没有差异。此外，有肝转移的原发性 CRC 癌症的 CDO1 启动子甲基化水平明显高于无肝转移的癌症（p=0.02）。因此，CDO1 启动子甲基化的曲线下面积分别为 0.96、0.80 和 0.67，用于区分癌症与 NAM、低级别腺瘤与 NAM 以及低级别腺瘤与高级别腺瘤。