Bariatric Nursing and Surgical Patient CareVol. 5, No. 4 Roundtable DiscussionFree AccessObesity, Cancer and EpigeneticsPublished Online:1 Dec 2010https://doi.org/10.1089/bar.2010.9987AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Participants:Lisa Rowen, DNSc, RN, FAAN(Series Co-Editor and Moderator)University of Maryland Medical CenterBaltimore, MDSharon Ross, PhDProgram Director, Nutritional Science Research GroupDivision of Cancer PreventionNational Cancer InstituteNational Institutes of HealthBethesda, MDJohn A. Milner, PhDChief, Nutritional Science Research GroupDivision of Cancer PreventionNational Cancer InstituteNational Institutes of HealthBethesda, MDFood, obesity, cancer and gene expression connections are exciting, complex and alarming to consider. Our Roundtable participants provide an in-depth and expert discussion as well as fascinating examples readers will find educational and enlightening. Read on to hear about some concepts that will be new to many readers.—Lisa Rowen, DNSc, RN, FAANEditor-in-ChiefLisa Rowen:Our roundtable today is on obesity, cancer and epigenetics. How would you like to begin the discussion in order to frame it in the most understandable manner?John Milner: I would like to begin with the incidence of obesity and why we are concerned about it in relationship to cancer. We are increasingly recognizing that excess calories are associated with many cancers. In fact, I think it is fair to say that, historically, we have found that caloric restriction reduces cancer risk. Most people are aware that obesity is a growing concern in the United States. Being overweight or being obese is a growing concern, and we are now getting close to a disturbing reality that two-thirds of the U.S. population is either overweight or obese.Sharon Ross: The incidence of obesity also varies by ethnicity. The CDC [Centers for Disease Control and Prevention, Atlanta, Georgia] has created maps showing over time how obesity in different races and ethnicity groups has changed. It is increasing in every race, foremost in the African American population, next in the white Hispanic population, and while least, still increasing in Caucasians. I think it is important, and there has developed even a need to mention which cancers have been shown to be associated with the condition of obesity.There was a great report, in 2003, based on a very large U.S. cohort, about 900,000 individuals.1 The study looked at this association, between overweight, obesity, and cancer mortality, in both men and women 30 years of age or older (the average age of the participants at enrollment was 57 years). In women, obesity (defined as having a Body Mass Index of ≥ 30) was associated with postmenopausal breast, cervical, and uterine cancer deaths. In men, obesity was related to prostate cancer deaths. In both men and women, obesity was associated with colorectal, pancreatic, esophageal, and liver cancer deaths. One of the things we are interested in, of course, is why some cancers are associated with obesity and why some are not. Mechanistically, are there some differences in tissue specificity in that regard?There is also this intriguing finding from epidemiology, or observational studies, suggesting that body fatness decreases risk in premenopausal women for breast cancer.2 We are not certain why. We know that hormones are playing a role in postmenopausal breast cancer, but what is going on in premenopausal cases? It is an intriguing area.John Milner: I think we are raising an issue from an education standpoint, that there may need to be special strategies for subpopulations, those that may need more attention than others. Within the story or development of cancer, I think it is increasingly clear that not all sites are equally susceptible to excess calories or excess adiposity, in terms of tumor development. We do not understand why that is occurring. Is it that some of these sites have not been as well evaluated for this vulnerability, or is something else going on?I think the data, as Dr. Ross just mentioned with premenopausal women versus postmenopausal, have been fairly well established that in one case it looks like you receive a measure of protection and in the other case you have an increased risk. Those differences are hard to understand, to know exactly what is happening.Lisa Rowen:This is very interesting and, I have to say, a bit difficult to wrap your head around all of it.John Milner: Absolutely. We've started out with a question that points to the need to understand the mechanism(s) by which excess calories can influence can risk, either promoting or inhibiting. But before we continue, I want to make sure we set the stage early as to the severity of the problem by again saying that two-thirds of society are facing this problem, and that there are segments that are more vulnerable than others. You cannot just assume that all cancers are equally susceptible to adiposity. These are, I think, important messages for your readership.I think I would add, and I think it is very, very important, that data from the WHO [World Health Organization] indicate that cancer risk and mortality are increasing, globally. There are likely several reasons for this, but two of them are that we are an aging and a growing (out, not up) society, which tends to mean in general a little more sedentary and, therefore, increased adiposity. An aging society may be an important factor, accounting for what we are projecting has been a sizable increase in overall cancer incidence worldwide.Saying that, I think it is also important to note that at least the projections are that by 2010, “cancer” will become the leading cause of death worldwide, overshadowing all other major causes of death.Lisa Rowen:That raises a question for me. As an aging society is occurring worldwide, could that not be the reason we are seeing an increased incidence of cancer? Could age have an interactive effect with the obesity incidence? Because as people age they are … John Milner: More sedentary?Lisa Rowen:Yes. Exactly.John Milner: I think you are right and that your point is part of the complexity of this issue, this relationship. I think the problem that we have is that adiposity is occurring earlier and earlier in life. President and Mrs. Obama have raised concerns about childhood obesity. If you start out obese, then maybe it is the multiple years of the adiposity that are going to increase the risk of acquiring several cancers.Sharon Ross: Yes. The early dysfunction of insulin and some of the other signaling pathways might make age less an impact here.John Milner: Insulin is a hormone that helps regulate glucose. It can be not functioning properly during obesity.3Sharon Ross: The interaction between early insulin dysfunction and cancer is an interesting one. I think that will surface soon, that is, the implications of increasing childhood obesity, insulin dysfunction, and onset of cancer.John Milner: What I would add to this discussion is that the pre- and postmenopausal breast cancers are actually different cancers. They are not the same cancers, and by teasing apart these factors we have been discussing, we likely will be able to understand how energy is actually involved or fat, per se. I am not sure if energy or fat is the culprit at this point. Maybe neither is culpable in some situations.Lisa Rowen:If we take the issue down to its lowest, most basic level—we are trying to understand the relationship between cancer and obesity and all the factors within it. Is it “what” you are eating that both makes you obese and puts you at greater risk for cancer? Is it that being obese creates some different kind of adverse metabolic event in your body? Is one more predisposed to cancer as well as becoming obese? At this point, the fascinating concept and field of epigenetics and its relationship to cancer and obesity start rolling around in your head. Trying to understand it means dealing with complexities we are only beginning to grasp, simplify. In truth, it is multifactorial, and it is hard to break down, That makes it difficult to even know how to think about it, how to get, as they say, your arms around it.John Milner: I agree. Let's say, for the purpose of our discussion, we start from a slightly different view. Yes, we start out with our genes, but we should actually talk first about genomics, that branch of genetics that studies our full DNA sequences;4 let us get to broad health issues as a backdrop before we start talking about the rich but complex field of epigenomics, all right? I'd like to talk about vulnerable populations first. We set the tone a little bit at the start by saying there are differences in susceptibility to obesity across various groups, among different racial groups, or in females who are pre- and postmenopausal, for example. I said as well that caloric restriction invariably is associated with a reduction in tumors. But some people just cannot get into caloric restriction well enough to have maybe this level of impact. So, we are also trying to come up with alternate approaches; maybe there are food components that can be added that actually might offset the harmful effects of excess calories. This is one area in which we are promoting research.In addition, there are studies in preclinical models that are investigating various isolated components with which we are all familiar, whether it is resveratrol from grapes or wine, or black pepper. There are a few studies whose outcomes suggest we might be able to offset some of the complications that are due to excess calories.5 But I think in this scenario, clearly, we need to know a lot more about what strategies there might be for those who are vulnerable and cannot limit their intake of nutrients.I want to add one other quick item. We are not all equally vulnerable to taking in an excess number of calories and cancer risk. There is a nice publication that suggests there is a subpopulation of people who have a certain gene profile that, even though they eat more and more calories and more and more fat, they do not put on weight.6 Wouldn't it be nice to be part of that group?Lisa Rowen:I cannot tell you how many times I have wished just that.John Milner: It is probably 20% of the population. When you think about it, don't you know people who eat approximately the same as you do, and their response is quite different? There are some people that seem to believe if they just look at food they are going to put on weight, albeit figuratively. Saying this to oneself with any frequency, of course, does not bode well for a positive ability to lose weight. I am not sure it is quite that bad for those people, but I think there are differences in the way people metabolize nutrients that predispose some to put on weight and others to not. What this does is bring our discussion to genes, to genetics. We are starting to identify obesity-associated genes now, but I'd like to ask Sharon to address the genetic component.Sharon Ross: Of course. It is true there have been more and more studies looking at the association of genetic variation to different diseases and conditions, one of those conditions being obesity. In fact, in the last 2 years in large population studies, several genes have been identified as associated with obesity. There were even multiple genetic loci, but each of the loci still does not explain much of the variability in obesity, which is kind of interesting.Some investigators have looked at these genetic loci, where variations in genetic susceptibility to obesity may exist. If you add them all up, maybe stack them all up, you can see more of the variability explained or see the reason why one person might be different in weight gain than another.4,7 So there is definitely a genetic component that we are starting to identify. But whether it will be a large component or not is not certain. It is almost part of the human condition to put on weight when in positive energy balance, except for some of those people that John mentioned, people who have a really different metabolism.Lisa Rowen:Could it be that the people who metabolize food maybe faster or differently in some way, that 20% who stay thin—while still eating as much as the rest of us (who do not stay thin)—could it be that their increased metabolic rate protects them somehow or puts them at a lower risk to develop cancer, because the “harmfulness” of the food is in them for a shorter period of time?John Milner: It is a possibility that whatever is occurring metabolically in those individuals may be reducing their risk to develop some tumors, and it may be a hormonal shift. It also may be some other type of phenomenon that is occurring, which has yet to be defined. If you step back and think about it, what we are really saying is that being leaner is associated with a reduction in cancer risk at most sites. So genetically, we are predisposed to be leaner. We are protected, so to speak. As Sharon has said, there are a few genes that we have started to identify as being associated with being leaner and some genes associated with being more obese.Sharon Ross: Also, in the mix of all of this, I think there is a study that came out in the news recently about people who live longer, and their set of genes may be different.8 That is another whole area to explore and may even include some of the same people about whom we are speaking, but we do not know as yet.John Milner: I agree.Sharon Ross: It seems, however, that a lot of the genes that have been identified with regard to a link to obesity also seem to be related in some way to eating behavior or to something that is going on in the brain, the neural aspect, if you will.9 It's important to keep in mind that we do not know the activity or function of many of the variant genes that have been found, which is another ripe area for research.John Milner: I want to make one other point, and that is while we have identified some of these genes, in many cases, they are guilty only by association, so far. What we have done is draw a correlation between the gene and the phenotype. No one has actually described exactly why that gene is leading to that phenotype, and that is something that is pretty fundamental. So it could be that it is only a surrogate marker and not really reflective of what is going on metabolically.Sharon Ross: It is correlated, but as to cause and effect, as John mentions, we just are not there.John Milner: I want to come back to your prior comment about epigenetics, and we are certainly going to get there in the discussion. First, when I say something about gene polymorphism, that being a factor, you have to understand that that is a relationship. And it may be that all we are really doing is noticing that those individuals who have that gene polymorphism also have some epigenetic change. It just happens that we find it with the gene polymorphism, and we have not looked at it from the epigenetic standpoint. So it is really hard to tease it apart at this point as to what is causing a difference in susceptibility.Lisa Rowen:Now that you have used the term epigenetics, could we define it?Sharon Ross: What is the definition of epigenetics? Well, when we are talking about genetic variations, we are talking about changes in the DNA sequence that disrupt a gene that becomes a protein, if you will. So, epigenetics is not a change in the DNA sequence, but the other mechanisms or processes, beyond changes in the DNA sequence, that have been identified to regulate how the protein ultimately is expressed. A definition that is often used is that epigenetics is the study of heritable changes in gene expression that occur without a change in DNA sequence.10John Milner: The DNA sequence would be the bases, the four bases that are there. They either would be there in perhaps an abnormal way or be there in higher concentration. It is abnormal, obviously. So you have a substitution, you have a deletion, you have an overexpression, let us say, of some of these bases or an incorporation of some of these bases.Lisa Rowen:If I understand this, at some point in one's life, there can be this change that occurs via epigenetics?John Milner: Yes. You are born with the genomic one, and then the epigenetic can be an acquired influence, I guess is what we are going to say.Sharon Ross: This is not fully understood. We believe that there are vulnerable periods for which these epigenetic marks, if you will, or mechanisms may be more modifiable. We know there is a set change in utero for epigenetics.11 But a lot of it is established from the mom and dad initially. There are times during which we think there can be a modification, such as in utero, or there might be a vulnerable period just before weaning, if you will. The pubescent period may be another period that is vulnerable. In addition, there is also the observation of changes in epigenetics with aging.12 There is also speculation that there are regions of the DNA that may be more susceptible to these epigenetic changes. In truth, we do not really know the triggers for what will cause the changes in epigenetics, but we are working on them.Lisa Rowen:It is interesting that the things you have just described are time periods in a person's life versus stress events.Sharon Ross: Yes.Lisa Rowen:As you were talking, I was thinking how we have learned that a lot of times following a sexual assault, a woman may move toward obesity, someone who was not at all obese before the assault. It makes me wonder if that is a person who is just coping, or is the obesity representative of something that has actually happened metabolically? You are describing time periods of potentiality versus a potential event that could occur in someone's life that actually alters them—I guess I am saying, alters them chemically.Sharon Ross: Yes. I think it could be described that way. But there has been work that looked at stress and epigenetic changes. A lot of the work regarding epigenetics is in animal models or within cell culture environments, and not so much in human studies as we are discussing now. A lot of it is circumstantial evidence that this might be happening in humans.That being said, I think there is a researcher who does animal behavioral work having to do with grooming behavior changes in animals occurring at a specific time period, too, a stress at a specific time, when the animals are young and still being fed by their mother. Picture, for example, a large litter of rodents, where a group of the newborns are removed from the litter and from their mother, and reared by a different pseudo-mom, or surrogate. I believe that when they looked at these two groups, those offspring reared with the real mom and those by the surrogate, there were some changes, differences in grooming behavior by the mom that influences the epigenetic marks of the offspring.13 I think that is how the study went. I have not looked at the story for a while. In this particular study, they are looking at both a possible vulnerable period in life as well as a stressor.John Milner: If I could just step back for a second and say further what epigenetics is about on still another level. I typically think of epigenetic events as comprising four categories or elements, and maybe Sharon will modify my comments. But, certainly, one of those categories is methylation. We put methyl groups onto one of the bases, which then changes the expression of the genes. Second, one of the epigenetic events involves histone proteins, which are important for how we coil the DNA together. We can modify histones, and we actually have some evidence that food components can modify both methylation and histones. Third, and I do not know if Sharon and I are on the same page on this or not, is the role of noncoding RNA, which is an emerging topic. I think we have some evidence that a lot of different nutrients can modify noncoding RNA that, in turn, modify or regulate how genes are then expressed. The final category is how we put the whole complex together, sometimes referred to as the chromatin. But it is really a complex structure, and how everything is put on the genetic code for reading.So, those are the four elements of epigenetics, and what I have said as well is that I think we have pretty good evidence that nutrients can modify all four of those processes. We are still working out the concentrations that are needed to modify them. In some cases, you modify by limitations in the diet; in other cases, by providing more of something in the diet. A classic example would be methyl donors, that when you have inadequacies, you change the methylation patterns, at least in some tissues. As well, some of the polyphenols that are in green tea and chocolates and other foods can actually modify epigenetic events. Those foods would clearly be providing more of these type substances into the diet.14,15Lisa Rowen:Do we have a sense of what food choices, beyond what you just mentioned, could assist in decreasing our relative risk of cancer or of developing tumors? As well, in terms of translating this science to care of patients, when we see patients in ambulatory clinics and want to educate them to decrease their risk, when we have patients come through the hospital and we try to have brief interventions with our patients to encourage and educate them about smoking cessation or other kinds of lifestyle alterations, things that would result in a decreased risk of harm—is there anything from what you have learned that we could offer them? I mean in how we educate about dietary choices or food choices that would be helpful in decreasing their relative risks, not just about obesity. I think we are pretty knowledgeable about obesity and risk reduction, but what about reducing the risk of cancer, of developing a tumor? Is there education that is relevant about a connection between cancer and obesity?John Milner: For a proper discussion of all those issues, Lisa, we may need to have another panel conference, because that is a whole different topic overall, which is actually one that is near and dear to our hearts as well. However, it is a lengthy discussion, because we probably have half a dozen foods that we typically talk about that are associated with a reduction in risk of cancer. That promise does not occur in all individuals, however. Again, we are back to the same story. Is this risk reduction because of genes or because of epigenetic events that are determining who responds and who does not respond? But if you want to know which foods, I think it is a varied diet, if you really put it in the broadest context, but in moderation.Sharon Ross: It is close to a diet for heart disease risk prevention, similar to the DASH [Dietary Approaches to Stop Hypertension] diet.John Milner: Yes, absolutely. Invariably, what you end up doing is talking about adding soybeans, broccoli, and including some fish products. It is the omega-3 fatty acid story, cutting down on inflammatory responses. Invariably, with obesity, you have some inflammation that is occurring. So there is the simple logic of eating some fish, for one. There is the logic of eating broccoli, because broccoli modifies the histones, an epigenetic event.Sharon Ross: To reinforce what John has said, a lot of our studies are actually on the polyphenols from a plant-based diet. Resveratrol is one that is found in grapes and red wine, our favorite wine. And in peanuts, it turns out. That has been very interestingly studied with regard to obesity and longevity, as well.John Milner: Let me add another food, one of the old good favorites is also one that “legendarily” kept away werewolves and vampires: good old garlic. Certainly, the World Cancer Research Report suggested garlic was one of those food items that could reduce the risk of some gastrointestinal cancers. I think there are a variety of foods that are out there that we need, again, more information on. But I would suggest to you that even with those foods, we still do not know the optimum intake, and we do not really know who is going to benefit most. I think it would be rather naïve for us to assume that everybody will get the same benefit, and I think it is a major point to make in this panel discussion.There was a report from the World Cancer Research Fund of the American Institute for Cancer Research, published almost 2 years ago. The title is “Food, Nutrition, Physical Activity and the Prevention of Cancer: A Global Perspective” (www.dietandcancerreport.org). I think it is the best compilation of information that we have to date on the importance of diet in modifying cancer risk. What it really suggests is that, overall, about 35% of our cancers relate to dietary habits. Clearly, what that also shows is that some cancer sites are much, much more influenced by what we eat than others.Sharon Ross: There is a section in the report on obesity and physical activity and on cancer survivorship, I believe. The National Cancer Institute (NCI) does not make recommendations of diet for primary prevention or for secondary prevention of cancer. So, I guess we cannot really officially endorse these things from the report.Lisa Rowen:But you are recommending reading the report, right?John Milner: Absolutely. I also want to raise one other issue. We have not really discussed why genetic or epigenetic events might lead to obesity and how that might influence cancer. I am not sure that we know the answer to these things at this point. It is clearly an active area of investigation.But I want to point out one other thing that we know does occur. I am only using it as a proof of principle, however. When a person is heavier than he or she should be, invariably, vitamin D concentrations decrease.16 What that then means is that the effective dose of that nutrient is decreased across tissues. Very importantly, this translates to a situation that if vitamin D is associated with avoiding or preventing cancer, you have less of an inhibition to the cancer process.I think it raises certain issues that it may not be the ingestion of excess calories per se, but that all of a sudden what you are doing is causing a shift in nutrient availability, and that then causes a shift in the risk of cancer. I think it is just something to think about. No one has taken heavier people and given them vitamin D to see if it protects against cancer, but the issue has been raised.Lisa Rowen:That is very interesting.John Milner: Yes, so, I think when we started with this panel discussion, we spoke as though the issue was excess calories being the culprit. But I am saying to you now that excess calories may be merely precipitating a secondary deficiency that is actually changing the cancer risk.Lisa Rowen:If you fill up on empty calories, then you can actually be nutritionally deficient.John Milner: That is a very important point. In fact, that may be something we do want to include. I said earlier that the cancer risks we are concerned about are occurring globally and that they are going to be increasing. But if you look at global cancer risk, you certainly see it in underdeveloped as well as developed countries. It could be in the developed countries that because of the types of calories that one is consuming, you are also creating an inadequacy of nutrients. So, I think your point is a good one, that it could be both sides of the coin, excess calories and/or a shift in the availability of some essential or nonessential nutrients.Lisa Rowen:That is an interesting topic and actually one that I asked about when I spoke with the First Lady's director. I asked her about child hunger in economically depressed areas and where healthy food is not available to children and their families. If they are then filling up on types of food that really keep them “hungry” for good nutrition, as a result, they become obese despite efforts to help them nutritionally. So, she was talking about what Mrs. Obama is really pushing in the “Let's Move” program to address that.John Milner: You know, I just have to say something. This is not done from the standpoint that we should not be concerned about obesity, because I think it is a global issue. There is no question about that. But there is actually an animal model system that has been developed here at NIH [National Institutes of Health, Bethesda, Maryland], actually as part of the NCI—an animal that cannot produce fat. They have no adiposity, and you would actually think that they would be less prone to cancer, but it turns out that they are more prone to cancer.17 And you have to say to yourself, “How can that be?”Some of the metabolic changes that occur in those animals are likely increasing the risk for at least some types of cancers. So that situation may be that it is not the excess calories per se, but it is the metabolic changes that occur in the individual that are actually changing his or her cancer risk.Sharon Ross: Just a point to follow up on is that I think there are many routes, if you will, to cancer.John Milner: Yes.Sharon Ross: This is part of the complexity. The differences in susceptibility are a part of it, but also many signaling pathways when they are involved. It depends on what is going on within the individual.Lisa Rowen:Are either of you aware of any cancer risk associated with the Roux-en-Y bypass, whether it be a gastric or intestinal malignancy?John Milner: No, I am not.Lisa Rowen:The Roux-en-Y is a gastric bypass procedure, a weight loss surgery treatment for morbid obesity. There are different surgical options for people who cannot lose weight any other way and choose a surgical option. Roux-en-Y and gastric banding are different approaches but both practiced surgical treatments. Have you heard of any