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

Keita Kojima,Keigo Yokoi,Makoto Ohbu,Satoru Ishii,Masahiko Watanabe,Takeo Sato,Takatoshi Nakamura,Keishi Yamashita,Nobuyuki Nishizawa,Yosuke Ooizumi,Toshimichi Tanaka,Hiroshi Katoh,Kazuko Yokota,Kazuharu Igarashi,Yoshimasa Kosaka,Masaru Katoh

doi:10.1371/journal.pone.0194785

Abstract

BackgroundProgression 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.MethodsThe 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.ResultsThe 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.ConclusionsCDO1 methylation accumulates during the ACS process, and consistently contributes to CRC progression.

Highlights

Colorectal cancer (CRC) is a major cause of cancer deaths in Western countries [1]
The methylation level increased along with the adenoma-carcinoma sequence (ACS) process (p < 0.0001), and statistically significant differences were found between normal-appearing mucosa (NAM) and lowgrade 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
cysteine dioxygenase 1 (CDO1) methylation accumulates during the ACS process, and consistently contributes to CRC progression

Summary

Introduction

Colorectal cancer (CRC) is a major cause of cancer deaths in Western countries [1]. In Japan, CRC was the second most common cause of death from cancer in 2014 [2]. CRC is caused by genetic abnormalities such as genetic mutations or deletions, and accumulation of epigenetic abnormalities such as methylation of DNA. Two oncogenic pathways have mainly been proposed in CRC. The other is de novo carcinogenesis: cancer directly occurs in normal colorectal mucosa without adenoma [5]. Genetic abnormalities and epigenetic abnormalities involved in ACS have been reported [7]. 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

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Methods

Results

Conclusion