Abstract
Background Promoterhypermethylation plays a major role in cancer through transcriptional silencing of critical genes. The aim of our study is to evaluate the methylation status of these genes in the colonic mucosa without dysplasia or adenocarcinoma at the different steps of sporadic and UC-related carcinogenesis and to investigate the possible role of genomic methylation as a marker of CRC.ResultsThe expression of Dnmts 1 and 3A was significantly increased in UC-related carcinogenesis compared to non inflammatory colorectal carcinogenesis. In non-neoplastic colonic mucosa, the number of methylated genes resulted significantly higher in patients with CRC and in those with UC-related CRC compared to the HC and UC patients and patients with dysplastic lesion of the colon. The number of methylated genes in non-neoplastic colonic mucosa predicted the presence of CRC with good accuracy either in non inflammatory and inflammatory related CRC.MethodsColonic mucosal samples were collected from healthy subjects (HC) (n = 30) and from patients with ulcerative colitis (UC) (n = 29), UC and dysplasia (n = 14), UC and cancer (n = 10), dysplastic adenoma (n = 14), and colon adenocarcinoma (n = 10). DNA methyltransferases-1, -3a, -3b, mRNA expression were quantified by real time qRT-PCR. The methylation status of CDH13, APC, MLH1, MGMT1 and RUNX3 gene promoters was assessed by methylation-specific PCR.ConclusionsMethylation status of APC, CDH13, MGMT, MLH1 and RUNX3 in the non-neoplastic mucosa may be used as a marker of CRC: these preliminary results could allow for the adjustment of a patient's surveillance interval and to select UC patients who should undergo intensive surveillance.
Highlights
Ulcerative colitis (UC) is a chronic inflammatory disorder involving the rectum and the colon that expose patients to an increased risk of colorectal cancer (CRC) [1]
The latter component would be of particular benefit because dysplasia or CRC may be difficult to identify endoscopically in ulcerative colitis (UC), and a test that is not reliant on biopsies taken from dysplastic areas might be carried out by a simple sigmoidoscopy and it would be of particular interest as an adjuvant screening tool [11]
The promoter methylation status of five genes known to be associated with early stages of colon carcinogenesis was assessed in the colonic mucosa of 107 patients (Table 1)
Summary
Ulcerative colitis (UC) is a chronic inflammatory disorder involving the rectum and the colon that expose patients to an increased risk of colorectal cancer (CRC) [1]. Patients with UC at moderate or high risk for CRC are advised to undergo surveillance colonoscopy and biopsy, every 1 to 3 years to www.impactjournals.com/oncotarget different guidelines, where multiple random biopsies are histologically evaluated for the presence of pre-cancerous changes (colorectal dysplasia) or CRC [8,9,10]. CRC screening in healthy subject is based on occult blood in the stool but in patients with UC the screening imply yearly colonoscopy with a significant higher grade of invasiveness. This highlights the need to identify markers for UC-related cancer that can be detected in the non neoplastic areas of the colon.
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