1a. Objectives (from AD-416):
1. To define the role that availability of each of the one-carbon nutrients plays in determining the risk of common cancers and to determine the nature of the interactions between these nutrients in this regard. 2. Determine how genetic differences interact with dietary antagonists of one-carbon nutrients in determining cancer risk. (PDRAM NAA09). 3. To determine how obesity enhances the risk of cancer, to find means of ameliorating this risk, and to define other factors that interact with obesity to further modify its effects.
1b. Approach (from AD-416):
Appropriate alterations in dietary and nutritional habits have an important role to play in cancer prevention. The nutrients involved in one-carbon metabolism (methionine, choline and the B-vitamins, folate, B12, B6, and B2), as well as obesity, have drawn considerable attention in this regard and are the focus of this laboratory. Our mission is to examine the complex roles that obesity and these 1-carbon nutrients play in modifying metabolic and genetic pathways that lead to human carcinogenesis and thereby define the means by which cancers can be nutritionally prevented. The program of research emphasizes how dietary intake interacts with genetic background to modify molecular and signaling pathways which alter the development of cancers and to examine how other exogenous factors, such as alcohol consumption also play a role. The laboratory focuses on colorectal cancer and breast cancer and utilizes animal studies, cell culture studies, and human studies to accomplish our research goals.
3. Progress Report:
Considerable effort was exerted over the past year examining the cellular pathways by which obesity might increase the risk of colon cancer. We performed a couple of experiments in obese mice and found that the chronic, low-grade state of inflammation (=irritation) that is produced by obesity also exists within the large bowel of the mouse and that this process seems to activate cellular pathways that lead to cancer. We also wished to determine whether what we found in mice applies to obese humans, so we initiated a study in the gastroenterology clinic at Tufts Medical Center of individuals undergoing routine screening colonoscopy, some of whom are obese and some whom are lean, and we have already enrolled nearly 80% of our desired population of subjects. Once we complete enrollment, we will analyze these samples to determine whether the obese subjects—like mice—have inflammation in their colon and whether that activates the same pathways. We continued our work, in mice, to examine how the intake of B-vitamins in parents affects the risk of developing intestinal cancer in the offspring. Previously, we have shown that B-vitamin supplements in the pregnant mother diminishes the risk of cancer in the offspring, and we are presently conducting a followup study to examine the molecular basis of this effect. In addition, we have completed a study to examine whether B-vitamin intake in the father alters cancer risk in the offspring. Although there is a precedent in prior studies to believe that the father’s intake should affect cancer risk, our preliminary analysis of the data indicates no affects. However, we did observe that the level of B-vitamins in the father’s diet alters the DNA in his sperm, and we are following up on that to determine the potential consequences of those alterations. Under certain conditions, the level of dietary B-vitamin intake does alter certain modifications of DNA such as the addition of a chemical structure called a methyl group: this is called DNA methylation. Human cancers are known to have low levels of DNA methylation. We therefore examined, in two large populations of Italian subjects, whether the extent of DNA methylation in blood cells predicts the subsequent occurrence of cancer. The results indicate that the extent of DNA methylation does have a high predictive value for determining the likelihood of developing cancer in the future. More recently, a variant of DNA methylation called DNA hydroxymethylation, has been identified as another modification of DNA. In a preliminary study of human liver cancers, we observed that the cancerous tissue has low levels of DNA hydroxymethylation compared to normal liver tissue adjacent to the cancers, suggesting that this measure could also have some utility as a predictive test for cancer.
1. Obesity in mice produces inflammation (=irritation) of the large bowel and activates pathways that lead to cancer. It is widely-accepted that obesity leads to an increased risk of colon cancer, although the cellular pathway by which this effect is mediated is unknown. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, at Boston, Massachusetts showed that obesity in mice produced by a high fat diet results in elevated concentrations of inflammatory proteins in the lining of the colon and alters several elements of a particular cellular pathway that is known to play a seminal role in the evolution of colon cancer. Since the high prevalence of obesity in the U.S. is unlikely to diminish in the coming decade, it is important to find ways to block this effect of obesity since identifying the pathway by which it operates provides targets that can potentially be blocked.
2. DNA methylation can feasibly be used to predict who will develop cancer. It is far preferable to prevent a cancer, or detect it in its earliest stages, than to treat it after it has become advanced. Strategies that can accurately predict the likelihood of cancer in an individual are therefore desirable. This study examined the ability of genomic DNA methylation of blood cells to predict the likelihood of cancer, and was studied within the context of two human populations. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, at Boston, Massachusetts found that individuals possessing a level of DNA methylation less than 4.74% were nearly 5-fold more likely to have cancer than those whose DNA methylation exceeded that threshold. Subjects with cancer at follow-up had, already at enrollment, reduced DNA methylation as compared with controls. Moreover, those individuals who possessed a low folate level, and carried the common genetic variant of the folate-metabolizing enzyme, MTHFR, had the lowest levels of DNA methylation as well as a 7-fold increased risk of having cancer. These observations imply that measurement of blood cell DNA methylation could possibly find utility as a cancer predictive tool.