Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease.
Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease.
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发表时间：
2000-07
期刊：
影响因子：
11.2
通讯作者：
S. Hussain;P. Amstad;Kamran Raja;S. Ambs;M. Nagashima;W. Bennett;P. Shields;A. Ham;J. Swenberg;A. Marrogi;C. Harris
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作者：
S. Hussain;P. Amstad;Kamran Raja;S. Ambs;M. Nagashima;W. Bennett;P. Shields;A. Ham;J. Swenberg;A. Marrogi;C. Harris
溃疡性结肠炎(UC)是一种慢性炎症性疾病，会产生活性氧和氮物质，增加患结直肠癌(CRC)的风险。P53抑癌基因在UC相关的异常增生性病变和结直肠癌中经常发生突变。我们正在探索一种假设，即在非癌症UC病例中，非肿瘤结肠组织中的P53突变表明暴露于外源性和内源性致癌物造成的基因损伤，并可能识别出癌症风险增加的个体。我们首次使用高灵敏的基因突变分析，对患有或不患有UC的捐赠者的非肿瘤结肠组织中特定的P53突变等位基因的频率进行了报道。UC患者结肠组织中第248位密码子G：C到A：T和第247位密码子C：G到T：A突变频率均高于正常成人(P=0.001和P=0.001)。UC患者结肠炎性病变部位P53基因第247位密码子和第248位密码子突变频率明显高于非病变部位(P<；0.001和P=0.001)。UC患者结肠一氧化氮合酶-2活性明显高于非UC成人对照组(P=0.02)。我们的数据与假设一致，即UC患者在氧化应激下可以产生更高频率的p53突变细胞。非癌性结肠组织中特定的P53突变等位基因频率的增加可能增加了在炎性微环境中发生结直肠癌的易感性。
Ulcerative colitis (UC) is a chronic inflammatory disease that produces reactive oxygen and nitrogen species and increases the risk of colorectal cancer (CRC). The p53 tumor suppressor gene is frequently mutated in UC-associated dysplastic lesions and CRC. We are exploring the hypothesis that p53 mutations in the nontumorous colonic tissue in noncancerous UC cases indicate genetic damage from exposure to exogenous and endogenous carcinogens and may identify individuals at increased cancer risk. We are reporting, for the first time, the frequency of specific p53 mutated alleles in nontumorous colon tissue from donors either with or without UC by using a highly sensitive genotypic mutation assay. Higher p53 mutation frequencies of both G:C to A:T transitions at the CpG site of codon 248 and C:G to T:A transitions at codon 247 were observed in colon from UC cases when compared with normal adult controls (P = 0.001 and P = 0.001, respectively). In the UC cases, higher p53 codon 247 and 248 mutation frequencies were observed in the inflamed lesional regions when compared with the nonlesional regions of their colon (P < 0.001 and P = 0.001). The colonic nitric oxide synthase-2 activity was higher in UC cases than in non-UC adult controls (P = 0.02). Our data are consistent with the hypothesis that a higher frequency of p53 mutant cells can be generated under oxidative stress in people with UC. The increased frequency of specific p53 mutated alleles in noncancerous UC colon tissue may confer susceptibility to the development of CRC in an inflammatory microenvironment.