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

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.

Epigenetic biomarkers of promoter DNA methylation in the new era of cancer treatment

“…Cases with CDO1 hypermethylation also showed poorer prognosis than those with hypomethylation in primary breast, prostate, colorectal, gallbladder and esophageal cancers . Interestingly, in primary breast cancer, CDO1 hypermethylation did not correlate significantly with markers of tumor progression such as TNM factors, while CDO1 hypermethylation was the strongest independent prognostic factor .…”

“…Specifically in esophageal cancer, CDO1 methylation was significantly higher in advanced SCC tumors with cStage II/III than in the superficial tumors with cStage I, 36 and was significantly higher in larger-sized adenocarcinomas than in smaller-sized adenocarcinomas. 37 Aberrant methylation of the CDO1 gene accumulated as the tumor progressed, as demonstrated in colorectal 38 and gallbladder tumorigenesis 44 (Figure 4A,B). These findings indicate that promoter DNA methylation of the CDO1 gene commonly accumulates with progression in human cancers.…”

“…Since 2010, the frequent hypermethylation of the CDO1 gene has been reported in primary breast, 33,34 lung, 19 biliary tract, 35 esophageal squamous cell carcinoma (SCC) 36 and adenocarcinoma, 37 gastric, 19 colorectal, 19,38 bladder, 19 penile (SCC), 39 kidney, 40 prostate, 41 endometrial, 42 pancreatic 43 and gallbladder cancer. 44 The frequencies of the aberrations in CDO1 methylation in these cancers are high ( Figure 3A).…”

Diagnostic potential of hypermethylation of the cysteine dioxygenase 1 gene (CDO1) promoter DNA in pancreatic cancer

“…CDO1 plays a role as a tumor suppressor gene. As it is a methylation‐specific gene in human cancer, CDO1 methylation has been recently reported in a variety of cancers, such as esophageal, lung, gastric, breast, biliary tract, colorectal, kidney, prostate, bladder, penile, and uterine cancers . However, there has been no report on the involvement of CDO1 in PDAC.…”

Changes in melanocyte RNA and DNA methylation favour pheomelanin synthesis and may avoid systemic oxidative stress after dietary cysteine supplementation in birds

“…Interestingly, CDO1 also exhibited an increase in RNA m 6 A in cysteine‐supplemented birds. Recent studies have linked high DNA methylation levels in CDO1 with several tumour types in humans (Deckers et al, ; Kojima et al, ), although also showing a decrease in gene expression (Meller et al, ). To our knowledge, this is the first time that an increase in RNA methylation has been observed in CDO1 as a response to a physiologically damaging effect, and future studies should investigate if this is associated with the lack of downregulation of this gene despite increased DNA m 5 C (see also below).…”