? 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. ? ?
| Piyathilake, Chandrika J; Celedonio, Jorge E; Macaluso, Maurizio et al. (2008) Mandatory fortification with folic acid in the United States is associated with increased expression of DNA methyltransferase-1 in the cervix. Nutrition 24:94-9 |
| Piyathilake, Chandrika J; Azrad, Maria; Jhala, Darshana et al. (2006) Mandatory fortification with folic acid in the United States is not associated with changes in the degree or the pattern of global DNA methylation in cells involved in cervical carcinogenesis. Cancer Biomark 2:259-66 |
