Vitamin D Intake Is Negatively Associated with Promoter Methylation of the Wnt Antagonist Gene DKK1 in a Large Group of Colorectal Cancer Patients

Abstract

Diet and lifestyle influence colorectal cancer (CRC) risk but the molecular events that mediate these effects are poorly characterized. Several dietary and lifestyle factors can modulate DNA methylation suggesting that they may influence CRC risk through epigenetic regulation of cancer-related genes. The Wnt regulatory genes DKK1 and Wnt5a are important contributors to colonic carcinogenesis and are often silenced by promoter hypermethylation in CRC; however, the dietary contributions to these events have not been explored. To investigate the link between dietary/lifestyle factors and epigenetic regulation of these Wnt signaling genes, we assessed promoter methylation of these genes in a large cohort of Canadian CRC patients from Ontario (n = 549) and Newfoundland (n = 443) and examined associations to dietary/lifestyle factors implicated in CRC risk and/or DNA methylation including intake of vitamins, fats, cholesterol, fiber, and alcohol as well as body mass index (BMI), and smoking status. Several factors were associated with methylation status including alcohol intake, BMI, and cigarette smoking. Most significantly, however, dietary vitamin D intake was strongly negatively associated with DKK1 methylation in Newfoundland (P = 0.001) and a similar trend was observed in Ontario. These results suggest that vitamin D and other dietary/lifestyle factors may alter CRC risk by mediating extracellular Wnt inhibition.

ACKNOWLEDGMENTS

This work was undertaken at the Department of Laboratory Medicine and Pathobiology at the University of Toronto, Toronto, ON, Canada and was conducted at the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada. We sincerely thank the investigators, staff, and participants of the Colon Cancer Family Registry for their dedicated contributions leading to this work.

This work was supported by the National Cancer Institute, National Institutes of Health under RFA # CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry (Colon CFRs) and Principle Investigators. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR. This work was also supported by a Team Grant from the Canadian Institutes of Health Research (CTP-79845 awarded to John R. McLaughlin, Bharati Bapat, Julia A. Knight, Steven Gallinger, Roger C. Green, and Patrick S. Parfrey) and by funding within the Colon Cancer Familial Registry awarded to the Ontario Registry for Studies of Familial Colorectal Cancer (Grant no. U01 CA074783, Principle Investigator: Steven Gallinger). James B. Rawson was supported by graduate studentships from the Team in Interdisciplinary Research on Colorectal Cancer funded by the Canadian Institutes of Health Research and by graduate studentships from the University of Toronto (Open Fellowships, administered by the Department of Laboratory Medicine and Pathobiology).