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FOXE1 and SYNE1 Genes Hypermethylation Panel as Promising Biomarker in Colitis-associated Colorectal Neoplasia

Papadia, Cinzia MD*,†; Louwagie, Joost PhD; Del Rio, Paolo MD§; Grooteclaes, Madeleine PhD; Coruzzi, Alessandro MD; Montana, Chiara MD§; Novelli, Marco PhD; Bordi, Cesare MD; de’ Angelis, Gian Luigi MD; Bassett, Paul PhD**; Bigley, Joseph PhD; Warren, Bryan MD††; Atkin, Wendy PhD‡‡; Forbes, Alastair MD*

doi: 10.1097/01.MIB.0000435443.07237.ed
Original Clinical Articles

Background: Colitis-associated colorectal cancer affects individuals with inflammatory bowel disease (IBD) more often and earlier than cancer in the general population. Colonoscopy provides the surveillance gold standard. Changes to the surveillance intervals depending on endoscopic activity have been made, given data demonstrating that this is an important predictor of future dysplasia or cancer, but adjuvant, noninvasive clinical tools are still warranted to improve surveillance outcomes and to assist in management and interpretation of dysplasia. Methylation markers may be able to do this.

Methods: SYNE1, FOXE1, NDRG4, and PHACTR3 genes were screened using methylation-specific PCR that permit the methylation status of the genes to be determined directly on biopsies. Ninety-three patients with long-standing IBD undergoing a cancer surveillance program, and 30 healthy controls were studied. These included colorectal adenocarcinomas on a background of IBD of various stages (n = 25), IBD-associated dysplastic lesions (n = 29), adenomas arising on a background of ulcerative colitis (n = 8), samples from patients with no evidence of dysplasia or cancer but long-standing IBD (n = 31), and symptomatic patients found to have normal colonoscopy (controls) (n = 30).

Results: Gene promotor hypermethylation of SYNE1 and FOXE1 genes varied significantly between the groups and was increasingly likely with increased disease severity. Neither occurred in controls, whereas promotor hypermethylation was detected in biopsies of 60% of patients with colitis-associated colorectal cancer for FOXE1 and 80% for SYNE1. Promotor hypermethylation of either gene was highly significantly different between the groups overall.

Conclusions: FOXE1 and SYNE1 hypermethylation markers demonstrated significantly increased expression in neoplastic tissue. Promoter methylation analysis of these genes might be a useful marker of neoplasia in long-standing IBD.

Article first published online 25 November 2013

*Gastroenterology, University College Hospital, London, United Kingdom;

Gastroenterology, Parma University Hospital, Parma, Italy;

Research and Development, MDxHealth SA, Liege, Belgium;

§Department of Surgery, Parma University Hospital, Parma Italy;

Department of Pathology, University College London, London, United Kingdom;

Department of Pathology, University of Parma, Parma, Italy;

**Statsconsultancy Ltd, Amersham, United Kingdom;

††Department of Pathology, University of Oxford, Oxford, United Kingdom; and

‡‡Surgery and Cancer, Imperial College, London, United Kingdom.

Reprints: Alastair Forbes, MD, Centre for Gastroenterology and Clinical Nutrition, University College London, Rockefeller Building, Gower Street, London, WC1E 6BT, United Kingdom 9217 (e-mail:

Supported by Cariparma Foundation as independent sponsorship and Comprehensive Biomedical Research Center at University College Hospital and University College London, which is funded by the United Kingdom National Institute for Health Research.

The authors have no conflicts of interest to disclose.

The article is dedicated to the memory of our colleague, Bryan Warren, who himself dedicated so much of his working life to the question of colitis-related colon cancer and ironically and tragically perished from this very complication of his own disease.

Received August 06, 2013

Accepted September 11, 2013

© Crohn's & Colitis Foundation of America, Inc.
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