? DNA methylation within promoter-associated CpG islands marks and/or mediates epigenetic silencing in human cells. In normal colon, aberrant DNA methylation arises as a function of age and has been proposed as a mechanism contributing to age-related risk for colorectal tumors. Separately, a subset of colorectal tumors is characterized by intense hypermethylation of multiple genes, a process termed CpG Island Methylator Phenotype (CIMP). The factors that initiate and/or modulate age-related methylation and CIMP remain unknown. Based on preliminary data suggesting that dietary (fiber, folate) and/or lifestyle factors (alcohol, smoking) could modulate these processes, we propose the following hypotheses: (1) dietary factors influence the methylation status of genes in normal colon epithelium, (2) dietary factors influence the prevalence of CIMP in colorectal tumors and (3) Constitutive polymorphisms (MTHFR) modify the interactions between diet and hypermethylation in the colon. To test these hypotheses, we will use the unique resource of a wellcharacterized patient population enrolled in a trial of the prevention of colorectal adenomas by folate supplementation.
Our specific aims are: (1) To determine associations between diet (folate, fiber, fat) and gene-specific DNA methylation (for multiple genes), as well as global DNA methylation (Alu methylation) in colon mucosa biopsies, controlling for MTHFR genotype, (2) to determine associations between diet (folate, fiber, fat) and CIMP status in colonic adenomas, controlling for MTHFR genotype and (3) to determine the effect of folate supplementation on DNA methylation (gene-specific and global) in colon mucosa and colon adenomas. These studies should provide definitive information on interactions between diet and DNA methylation in human colorectal mucosa and cancer. ? ?
| Watanabe, Yoshiyuki; Castoro, Ryan J; Kim, Hyun Soo et al. (2011) Frequent alteration of MLL3 frameshift mutations in microsatellite deficient colorectal cancer. PLoS One 6:e23320 |
| Konishi, Kazuo; Watanabe, Yoshiyuki; Shen, Lanlan et al. (2011) DNA methylation profiles of primary colorectal carcinoma and matched liver metastasis. PLoS One 6:e27889 |
| Maegawa, Shinji; Hinkal, George; Kim, Hyun Soo et al. (2010) Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res 20:332-40 |
| Wallace, Kristin; Grau, Maria V; Levine, A Joan et al. (2010) Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa. Cancer Prev Res (Phila) 3:1552-64 |
| Issa, Jean-Pierre J; Kantarjian, Hagop M (2009) Targeting DNA methylation. Clin Cancer Res 15:3938-46 |
| Konishi, Kazuo; Shen, Lanlan; Jelinek, Jaroslav et al. (2009) Concordant DNA methylation in synchronous colorectal carcinomas. Cancer Prev Res (Phila Pa) 2:814-22 |
| Watanabe, Yoshiyuki; Kim, Hyun Soo; Castoro, Ryan J et al. (2009) Sensitive and specific detection of early gastric cancer with DNA methylation analysis of gastric washes. Gastroenterology 136:2149-58 |
| Figueiredo, Jane C; Grau, Maria V; Wallace, Kristin et al. (2009) Global DNA hypomethylation (LINE-1) in the normal colon and lifestyle characteristics and dietary and genetic factors. Cancer Epidemiol Biomarkers Prev 18:1041-9 |
| Boumber, Yanis A; Kondo, Yutaka; Chen, Xuqi et al. (2008) An Sp1/Sp3 binding polymorphism confers methylation protection. PLoS Genet 4:e1000162 |
| Estecio, Marcos R H; Gharibyan, Vazganush; Shen, Lanlan et al. (2007) LINE-1 hypomethylation in cancer is highly variable and inversely correlated with microsatellite instability. PLoS One 2:e399 |
Showing the most recent 10 out of 18 publications
