Methylation status of genes in non-neoplastic mucosa from patients with ulcerative colitis-associated colorectal cancer.
OBJECTIVE
Patients with ulcerative colitis (UC) are at increased risk for developing colorectal cancer (CRC). Surveillance in this at-risk population remains challenging. We assessed the methylation status of genes in the non-neoplastic mucosa of UC-CRC patients and controls to identify potential biomarkers of CRC.


METHODS
We evaluated the methylation status of 10 genes (p16, p14, runt-related transcript factor-3 (RUNX3), cyclooxygenase-2 (COX-2), E-cadherin, methylated-in-tumor-1 (MINT1), MINT31, HPP1, estrogen receptor, SLC5A8) in UC-CRC tumors and non-neoplastic sections from both UC-CRC cases and UC controls (n=114 for each) using methylation-specific PCR.


RESULTS
Amplification was successful for 96 UC controls, 83 tumors, and 66 non-adjacent, non-neoplastic samples. The prevalence of methylation was significantly greater in UC-CRC tumors for p16, RUNX3, MINT1, MINT31, and HPP1. Methylation of COX-2 and E-cadherin was greater in UC controls than in tumors. Univariate testing of these genes using non-adjacent, non-neoplastic sections from UC-CRC cases indicated that associations between p16, RUNX3, MINT1, MINT31, E-cadherin, and COX-2 and UC-CRC remained significant. In multivariable analysis of the six genes, only RUNX3, MINT1, and COX-2 remained significantly associated with the UC-CRC cases (odds ratio=12.6, 9.0, and 0.2, respectively). The results remained unaffected by the presence of PSC or severity of inflammation. Logistic regression modeling with the three genes showed interactions that increased the odds ratio for each gene.


CONCLUSIONS
RUNX3, MINT1, and COX-2 are potential biomarkers for detecting the presence of CRC in patients with UC. These genes should be evaluated as biomarkers for colorectal dysplasia.
Garrity-Park
Megan M
MM
Division of Experimental Pathology and Lab Medicine, Mayo Clinic, Garrity-Park, 200 First Street SW, Stabile 2-50, Rochester , MN 55905, USA. garrity.megan@mayo.edu
Loftus
Edward V
EV
Sandborn
William J
WJ
Bryant
Sandra C
SC
Smyrk
Thomas C
TC
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D003093:Colitis, Ulcerative / Q000150:complications / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D016015:Logistic Models; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D012307:Risk Factors
C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D050677:Core Binding Factor Alpha 3 Subunit; D009419:Nerve Tissue Proteins; C493729:Runx3 protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human