Effects of Folate Fortification on Cancer Prevention

描述（由申请人提供）： 1998年开始的叶酸强化食品，旨在预防神经管缺陷。尽管许多流行病学、动物和人类研究表明叶酸状态调节致癌作用，但叶酸强化对癌症预防和控制的影响尚不清楚。由于DNA和组蛋白的甲基化改变以及DNA损伤是叶酸在癌症预防和控制中发挥作用的重要机制，因此了解叶酸强化对这些参数的影响非常重要。我们建议评估这些变化在宫颈组织中，因为叶酸在预防宫颈癌的可接受性，因为获得正常的，癌前病变和肿瘤病变的宫颈通过我们的机构的可行性。我们假设，在叶酸强化食物后，宫颈正常、异型增生和癌细胞的DNA和/或病史的整体甲基化水平、CpG岛的甲基化、DNA甲基转移酶的表达和DNA损伤标志物（微核的存在）发生了变化;被诊断为宫颈癌的受试者的生存率在叶酸强化食物后发生了变化。我们建议在叶酸强化开始前（1990-92年）和叶酸强化后（2000-2002年）诊断的年龄、吸烟状态和种族匹配的相似病变的受试者的宫颈特定类型细胞（正常、发育异常和浸润性癌细胞）中评估这些参数。我们还将评估1990-92年诊断为宫颈癌的受试者与2000-2002年诊断为宫颈癌的年龄、吸烟状况、种族、分期、组织学亚型（鳞状或腺癌）和治疗相匹配的受试者之间的生存差异。鉴于人们对DNA甲基化作为肿瘤预后生物标志物、治疗靶点和可能逆转耐药性的兴趣越来越大，现在研究叶酸强化食品相关的甲基化变化是及时的。该研究将产生重要的初步数据，可用于规划未来的研究，这些研究将调查叶酸途径酶的遗传多态性对叶酸强化相关的表观遗传变化的影响以及叶酸强化在癌症预防和控制中的长期影响。

DESCRIPTION (provided by applicant): Food fortification with folate, which began in 1998, is directed toward prevention of neural tube defects. Although many epidemiological, animal and human studies suggest that folate status modulates carcinogenesis, the effects of folate fortification on cancer prevention and control are unknown. Since altered methylation of DNA and histones and DNA damage are important mechanisms through which folate may play a role in cancer prevention and control, it is important to know the effects of folate fortification on these parameters. We propose to evaluate these changes in cervical tissues because of the plausibility of folate in preventing cervical cancer and because of the feasibility of obtaining normal, pre-neoplastic and neoplastic lesions from the cervix through our institution. We hypothesize that the levels of global methylation of DNA and/or histories, methylation of CpG islands, the expression of DNA methyltransferases and markers of DNA damage (presence of micronuclei) in normal, dysplastic and cancerous cells of the cervix have changed after food fortification with folate; and that the survival of subjects diagnosed with cervical cancer has changed after the food fortification with folate. We propose to evaluate these parameters in specific types of cells (normal, dysplastic and invasive carcinoma cells) of the cervix of subjects who were diagnosed with these lesions before the folate fortification started (1990-92) and in similar lesions of age, smoking status and race matched subjects who were diagnosed after folate fortification (2000-2002). We will also evaluate survival differences between subjects diagnosed with cervical cancer in 1990-92 and subjects matched for age, smoking status, race, stage, histological subtype (squamous or adenocarcinoma) and treatment who were diagnosed with cervical cancer in 2000-2002. In light of an increasing interest in DNA methylation as a prognostic tumor biomarker, a therapeutic target and a possible reversal of drug resistance, it is timely to investigate the changes in methylation associated with food fortification with folate. The study will generate important preliminary data that can be used to plan future studies that will investigate the effects of genetic polymorphisms of folate pathway enzymes on folate-fortification associated epigenetic changes and long-term effects of folate fortification in cancer prevention and control.