Aberrant gene methylation in non-neoplastic mucosa as a predictive marker of ulcerative colitis-associated CRC
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Marco Scarpa1,*, Melania Scarpa1,*, Ignazio Castagliuolo2, Francesca Erroi3, Andromachi Kotsafti1, Silvia Basato3, Paola Brun2, Renata D’Incà3, Massimo Rugge4, Imerio Angriman3,*, Carlo Castoro1,*
1Surgical Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padova, Italy
2Department of Molecular Medicine, University of Padova, Padova, Italy
3Department of Surgery Oncology and Gastroenterology DISCOG, University of Padova, Padova, Italy
4Department of Medicine, University of Padova, Padova, Italy
*These authors have contributed equally to this work
Marco Scarpa, e-mail: [email protected]
Keywords: biomarker, ulcerative colitis, colorectal cancer, promoter methylation, APC
Received: October 08, 2015 Accepted: January 23, 2016 Published: February 04, 2016
Background Promoter: hypermethylation 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.
Results: The 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.
Methods: Colonic 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.
Conclusions: Methylation 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.
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