Hypermethylation of p14^ARF may be predictive of colitic cancer in patients with ulcerative colitis

PURPOSE: The microsatellite instability and CpG island hypermethylation of p14^ARF and p16^INK4a are related to the pathogenesis of neoplasia in ulcerative colitis. This study was designed to assess the significance of those genetic or epigenetic alterations for cancer surveillance in ulcerative colitis. METHODS: During surveillance colonoscopy in 39 patients with ulcerative colitis, biopsy specimens were obtained from the cecum and the rectum as well as from any other areas suspected of being neoplasia by chromoscopy. Using DNA extracts, the methylation status of p14^ARF and p16^INK4a and the microsatellite status were determined. RESULTS: Microsatellite instability was positive in one of five dysplasias, but it was negative in the cecum and the rectum. The incidence of hypermethylation of p14^ARF was 0 percent in the cecum, 26 percent in the rectum, and 100 percent in dysplasia, whereas that of p16^INK4a was 10, 10, and 0 percent, respectively. Patients who were positive for the hypermethylation of p14^ARF in the rectum had a longer duration of ulcerative colitis than those who were negative for such hypermethylation. Two of 10 patients who were positive for p14^ARF hypermethylation in the rectum and 1 of 29 patients who were negative for the hypermethylation had dysplasia. During the subsequent surveillance of 36 patients, dysplasia was detected in 2 of 8 patients with p14^ARF hypermethylation and in none of 28 patients without hypermethylation (P=0.044). CONCLUSIONS: In patients with ulcerative colitis, hypermethylation of p14^ARF seems to be associated with an early stage of dysplasia. The hypermethylation may be one of candidates for potential biomarker to identify patients at a high risk of dysplasia.