Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: A cancer-prone chronic inflammatory disease

Ulcerative colitis (UC) is a chronic inflammatory disease that produces rea ctive oxygen and nitrogen species and increases the risk of colorectal canc er (CRC), The p53 tumor suppressor gene is frequently mutated in UC-associa ted dysplastic lesions and CRC, We are exploring the hypothesis that p53 mu tations In the nontumorous colonic tissue in noncancerous UC cases indicate genetic damage from exposure to exogenous and endogenous carcinogens and m ay identify individuals at increased cancer risk, We are reporting, fur the first time, the frequency of specific p53 mutated alleles in nontumorous c olon tissue from donors either with or without UC by using a highly sensiti ve genotypic mutation assay, Higher p53 mutation frequencies of both G:C to A:T transitions at the CpG site of codon 248 and C:C to T:A transitions at codon 247 were observed in colon From UC cases when compared with normal a dult controls (P = 0.001 and P = 0.001, respectively), in the UC cases, hig her p53 codon 247 and 248 mutation frequencies were observed in the inflame d lesional regions when compared with the nonlesional regions of their colo n (P < 0.001 and P = 0.001), The colonic nitric oxide synthase-2 activity w as higher in UC cases than in non-UC adult controls (P = 0.02), Our data ar e consistent with the hypothesis that a higher Frequency of p53 mutant cell s can be generated under oxidative stress in people with UC, The increased frequency of specific p.53 mutated alleles in noncancerous UC colon tissue may confer susceptibility to the development of CRO in an inflammatory micr oenvironment.