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Immunohistochemical staining for p53 suppressor gene mutations is sensitive and, therefore, has potential for use as a complementary test for dysplasia to improve ulcerative colitis (UC) cancer surveillance program performance.A cohort of 95 patients with long standing pan-UC enrolled in a surveillance program was studied. Archival colonic biopsy specimens were stained for p53 mutations and clinical information was obtained from medical records.The 37 patients who developed p53 mutations were significantly more likely to develop dysplasia or cancer (relative risk [RR] 4.53, 95% confidence interval [Cl] 2.16–9.48). The p53 mutations developed approximately 8 months before low grade dysplasia, 26 months before high grade dysplasia, and 38 months before cancer. Three of seven cancer patients with p53 mutations had Dukes' stage C or D, whereas only one of five cancer patients without p53 mutations had Dukes' C or D; all three patients who died from metastatic cancer had p53 mutations (three of 37vs0 of 58,p< 0.03). Folic acid supplementation had a small, significant protective effect for p53 mutations (RR 0.97, Cl 0.94–1.00).p53 Mutations 1) are associated with, and likely precede, dysplasia and cancer, 2) are associated with cancer-related mortality, and 3) may possibly be prevented by folic acid supplementation.