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Methylated Eyes Absent 4 (EYA4) Gene Promotor in Non-neoplastic Mucosa of Ulcerative Colitis Patients with Colorectal Cancer: Evidence for a Field Effect

Kisiel, John B. MD*; Garrity-Park, Megan M. BS; Taylor, William R. MS*; Smyrk, Thomas C. MD; Ahlquist, David A. MD*

doi: 10.1097/MIB.0b013e31829b3f4d
Original Basic Science Articles

Background: Aberrant methylation of the EYA4 gene (mEYA4) highly discriminates ulcerative colitis (UC) cases with colorectal neoplasia from UC controls in both tissue and stool. It is not known if mEYA4 is also present in nonadjacent non-neoplastic mucosa (NNM) of UC patients with colorectal neoplasia.

Methods: Formalin-fixed tissues from 25 UC cases with colorectal cancer (CRC) and 25 UC controls with neither CRC nor dysplasia were matched on gender, age, disease duration, disease extent, and coexistence of primary sclerosing cholangitis. DNA was extracted from sections of CRC and NNM from cases and UC control mucosae. Bisulfite-treated DNA was amplified using real-time methylation-specific PCR. The Wilcoxon rank-sum test assessed differences in mEYA4 levels from CRC, NNM, and control samples. Logistic regression was used to estimate sensitivity and specificity.

Results: Sufficient DNA was available for 20 cases and 20 controls. The median mEYA4 level (with interquartile range) was 2 (0–5.7) in control mucosae but 93 (38.5–306) in CRC (P < 0.0001) and 27.4 (3–140) in NNM (P = 0.0009). At 95% specificity, mEYA4 was present in 80% of CRC and 50% of NNM tissue samples. The odds ratio of mEYA4 in NNM as an indicator of synchronous CRC was 19 (95% confidence interval, 2–170).

Conclusions: The authors demonstrate significantly higher mEYA4 levels in NNM and synchronous CRC from UC cases than in colorectal mucosae of UC controls without neoplasia. The finding of this CRC-associated field change has important implications to the use of mEYA4 as a potential UC surveillance marker in tissue or stool.

Article first published online 17 July 2013

*Division of Gastroenterology and Hepatology,

Division of Experimental Pathology and Laboratory Medicine, and

Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota.

Reprints: John B. Kisiel, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905 (e-mail:

Supported by the Charles Oswald Foundation and the Maxine and Jack Zarrow Family Foundation of Tulsa Oklahoma.

Portions of this manuscript were presented in abstract form at Digestive Diseases Week 2011, May 7, 2011 in Chicago, IL.

Mayo Clinic has entered into a licensing agreement with Exact Sciences (Madison, WI) whereby inventors (W.RT., J.B.K., and D.A.A.) could share in equity or future royalties in accordance with Mayo Clinic policy.

The authors have no other conflicts of interest to disclose.

Received April 15, 2013

Accepted May 09, 2013

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