Nutrient-Gene Interactions in Cancer

Sang-Woon Choi, Simonetta Friso

• Publisher: CRC Press
• Year: 2006
• ISBN:
  9781000611335
• Edition: 1
• Topic: Art
• Subtopic: Arts culinaires

The complete mapping of the human genome, along with the development of sophisticated molecular technologies, has accelerated research on the relationship between nutrients and genes. This has led to compelling evidence garnered from epidemiological and experimental observations supporting the idea that the interaction between nutrients and genes i

1 Nutrient and Gene Interactions in Cancer

Edward Giovannucci

CONTENTS

1.1Introduction

1.2Types of Epidemiological Studies

1.3Ecological Studies

1.4Analytic Epidemiology: Case-Control and Prospective Cohort Studies

1.5Confounding

1.6Randomized Intervention Trials

1.7The Combined Study of Genetics and Nutrition in Epidemiological Studies

1.8Public Health Implications of Nutrient-Environment Interactions

1.9Summary and Conclusion

References

1.1INTRODUCTION

The idea that diet and nutrition play an important role in carcinogenesis is not new. Much has been learned in this area during the past several decades through traditional epidemiological methods, but many questions remain unanswered. The present is a particularly exciting time for researching how genetic and nutritional factors interact to influence the risk of various cancers. With new methods that help us better identify genetic susceptibility, clearer answers are likely to emerge in the field of nutrition and cancer. The first part of this chapter will briefly summarize the role of various epidemiological strategies that are used to understand cancer causation and prevention. In particular, the strengths and weaknesses of various epidemiological approaches will be described. Building upon this, the second part of the chapter will examine how our evolving understanding of genetic susceptibility can be integrated into traditional epidemiological methods to help refine our understanding of diet, nutrition, and cancer.

1.2TYPES OF EPIDEMIOLOGICAL STUDIES

A summary of the major epidemiological designs, including important strengths and weaknesses, that have been used in the study of nutrition and cancer is given in Table 1.1. The studies can be divided into observational studies, which encompass ecological and analytic case–control and cohort studies, and intervention studies. In principle, the distinction between observational and intervention studies is most critical because, in essence, causality can be “proved” only in the context of a randomized intervention trial. This is generally well appreciated by most researchers, but if results from randomized clinical trials are accepted uncritically and observational studies are relegated as inferior studies, important insights may be missed. Ultimately, when considering a nutrient–disease relationship, it is best to consider the total evidence, ranging from in vitro studies, animal studies, human metabolic studies, ecological and analytic epidemiological studies, and intervention studies. When the various lines of evidence are viewed as complementary and the strengths and limitations of each approach are appreciated, the most correct answers are likely to emerge. The strengths and limitations in human study designs are discussed here.

TABLE 1.1
Study Designs Addressing the Effect of Diet on Human Cancer

Study Design	Methods	Potential Strengths/Limitations
Ecological	Comparison of cancer rates in populations having different dietary patterns by assessing per capita intake of specific nutrients and relating them to cancer incidence or mortality; migrant studies compare cancer rates in immigrants to a new region or country with different diets	Examines a wide range of exposures and population diets, which may be more stable over time than individual diets; diet is only one of many variables that differ among populations, so the potential for confounding is great; intakes may be biased when based on food disappearance rather than actual intakes
Case–control	Earlier, prediagnostic diets as reported by patients with a particular type of cancer (or their proxies for fatal cancers) are compared with diets during a comparable time period reported by cancer-free controls; controls can be typically hospital-based patients with other medical conditions or individuals chosen randomly from the underlying population at risk	Useful for rare cancers, although difficult to implement for rapidly developing fatal cancers; confounding other factors cannot be excluded in observational (nonrandomized studies); recall bias can result when patients systematically differ from the controls in their dietary recall; selection bias can occur if controls do not accurately represent the population from which the cases arise; in hospital-based studies, selection bias can arise if the conditions for which controls are hospitalized are related to diet; in population-based case–control studies, response rates may be low for controls, leading to selection bias
Cohort (prospective or follow-up)	Diets and other factors are determined in individuals who are then followed for cancer; cancer rates are compared, for example, in high-fat vs. low-fat groups, controlling for potentially confounding factors	As for case–control studies, confounding factors cannot be definitively excluded, but selection bias and recall bias are unlikely to occur; cohort studies for cancer must generally enroll tens or even hundreds of thousands of participants, and then follow them for many years, with high follow-up response rates necessary for valid inference
Intervention	Incidence of cancer or a surrogate endpoint is compared in two groups randomized to specific interventions vs. placebo	The only study design that can definitely exclude confounding; compliance with substantial dietary changes is difficult for many people; subjects cannot be easily blinded to the treatment or placebo; optimal dosages (e.g., of supplemental nutrients) and dose–response relationships can be difficult to ascertain; duration of intervention required is generally unknown, but it may be decades for specific cancers

1.3ECOLOGICAL STUDIES

Ecological studies can be quite useful in enhancing our understanding of nutrition and cancer. These studies have been critical in establishing that most, if not all, human cancer types exhibit marked variation by geographic region and that rates are susceptible to change over time. Interestingly, although overall cancer rates among adults vary only modestly worldwide, the types of cancers are dramatically different across populations [1,2]. In general, in most affluent countries, particularly in North America and Europe, cancers of the lung, colon, breast, and prostate predominate, whereas in less-affluent regions and the Far East, cancers of the stomach, liver, oral cavity, esophagus, and uterine cervix are the most common. In addition, cancer incidence rates have been shown to be highly dynamic; for example, immigrants who move from countries with low rates of specific cancers to countries with high rates typically attain the rates characteristic of the new country, or the reverse [3, 4 and 5]. The time required to attain the new rate, which can vary, may provide important clues as to how quickly exposure to the new factor may influence cancer rates.

In general, ecological studies can provide invaluable information regarding diet and cancer. The large variations in cancer rates around the world and changes over time illustrate rather conclusively that many cancers are potentially avoidable if we were able to identify and remove the causal factors or increase the exposure to protective factors. Although genetic factors undoubtedly influence the development of various malignancies, the changes in cancer rates that occur within countries demonstrate the importance of noninherited factors. As discussed in the preceding text, ecological studies can also indicate the potential time frame of exposures becoming important and what time period may be required to obtain optimal benefits. For example, this time can range from several decades in the case of colon cancer to about three generations for breast cancer [5, 6, 7 and 8]. Finally, ecological studies may provide clues to dietary and nutritional factors that may account for many of these variations in cancer rates. For example, early observations that national rates of colon, breast, and prostate cancers are strongly correlated with aspects of diet such as per capita consumption of fat generated the hypothesis that fat consumption or some close correlate accounts for the excess of these cancers in Western or economically developed countries [9].

Given the strong suggestions from ecological studies and animal studies that dietary manipulations can influence tumorigenesis [10], three important questions need to be addressed: Which dietary factors are actually important determinants of human cancer? What is the nature of the dose–response and temporal relationships? What other factors, environmental or genetic, modify the relationship?

Ecological studies may help establish the framework of these questions but are probably unable to provide the most precise answers. The most important drawback in ecological studies is that the populations for which rates of specific cancers vary tend to differ markedly in many characteristics, rendering it difficult, if not impossible, to identify the precise causal factors. For example, rates of colon cancer tend to be low in agrarian populations and high in affluent populations. Not surprisingly, if we compare colon cancer rates across populations, we find that they are highly correlated with consumption of fat, animal protein, and meat. However, correlations with body mass, attained height, and level of physical activity, to name a few, are also likely to exist. These factors may work together to some extent to influence cancer risk: high availability of meat and fat, coupled with little need for physical activity, could lead to higher growth rates in childhood (thus, greater height) and greater body mass in adulthood. Subsequent exposure to growth factors such as insulin and insulin-like growth factors throughout the life span could enhance cancer risk [11]. Although this knowledge may be theoretically useful, it does not answer specific questions such as whether a reduction of the percentage of energy in fat from 45% to 30% in adulthood lowers the risk of colon or breast cancer in U.S. postmenopausal women. Such a specific question is unlikely to be adequately addressed by ecological studies. For example, rapid gains in height during the last several decades [12] have corresponded with increases in breast cancer rates; thus, one conclusion from ecological studies is that energy restriction sufficient to restrict attained height could lower breast cancer rate; population per capita dietary fat intake could simply be a correlate of this phenomenon.

1.4ANALYTIC EPIDEMIOLOGY: CASE–CONTROL AND PROSPECTIVE COHORT STUDIES

Regarding observational studies, the case–control and prospective cohort studies may be better suited to address such a question as that of the percentage of energy from fat in relation to the aforementioned postmenopausal breast cancer risk. These studies assess dietary intake at the individual level in the population of interest by using dietary assessment methods that are generally more precise than ecological studies, which often rely on food disappearance data. For example, in ecological studies, when we compare a high-fat-consuming to a low-fat-consuming population, the comparison may actually be high fat intake/sedentary/obese vs. low fat intake/active/lean. In analytic epidemiological studies, we may better address the question of whether this reduction in fat composition influences cancer risk independently of body mass and physical activity. Of course, in any observational study, ecological or analytic, fat may be a correlate of another behavior or dietary factor, but in order to determine a potentially independent role of fat, analytic studies generally have three distinctive advantages. First, individuals within a population are likely to ...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• Preface
• About the Editors
• Contributor
• 1 Nutrient and Gene Interactions in Cancer
• 2 Candidate Mechanisms for Interactions between Nutrients and Genes
• 3 Biomarkers for Nutrient–Gene Interactions
• 4 Interaction between Folate and Methylene-tetrahydrofolate Reductase Gene in Cancer
• 5 Genetic Variability in Folate-Mediated One-Carbon Metabolism and Cancer Risk
• 6 S-Adenosylmethionine and Methionine Adenosyltransferase Genes
• 7 Effects of Carotenoid Supplementation on Signal Transduction Pathways: Significance in Lung Cancer Prevention
• 8 The Actions of the Vitamin D Receptor in Health and Malignancy; Polymorphic Associations and Gene Regulatory Actions
• 9 The Role of Alcohol Dehydrogenase Polymorphism in Alcohol-Associated Carcinogenesis
• 10 Genetic Polymorphism of N-Acetyltransferase Genes as Risk Modifiers of Colorectal Cancer from Consumption of Well-Done Meat
• 11 Ferritin and Serine Hydroxymethyltransferase
• 12 Brassica–Gene Interactions and Cancer Risk
• 13 Conclusions and Future Perspectives
• Index