Dr Mazda Jenab
Nutritional Epidemiology Group, Section of Nutrition and Metabolism
International Agency for Research on Cancer [IARC-WHO], The World Health Organization
Lyon, France
Project 1 title
Dietary, Lifestyle and Genetic Determinants of Esophageal Squamous Cell Carcinoma in three populations of the Jammu and Kashmir Region of Northern India - A Feasibility Study (2008/SD07)
Project 2 title
Pathways to Colorectal Cancer: Do excess energy consumption and the processes of oxidative stress interact and are they modulated by increased colonic permeability, inflammation, endotoxin exposure and toxic by-products of excess energy consumption? (2010/251)
Project 3 title
A pathway approach to study the biological effects of vitamin D on colorectal carcinogenesis: Exploration of gene-nutrient, gene-environment and gene-gene interactions (2011/443)
Scientific abstract 1
Esophageal Squamous cell carcinoma (ESCC) shows large worldwide variations in incidence. Although rates in developed countries are falling, ESCC is common in developing nations where 85% of cases occur. This is particularly true in the “Asian Esophageal Cancer Belt” ranging from northern Iran to north-central China and covering the Jammu and Kashmir region of Northern India which is home to several different ethnic populations (Kashmir, Jammu, Ladakh) with varying ESCC incidence rates. These populations have distinct lifestyle/dietary habits which may be related to ESCC aetiology but have not yet been studied. The feasibility study will determine the possibility of establishing a multi-centre case-control study whose objective will be to determine the dietary, lifestyle and genetic factors associated with ESCC in these populations. The study will complement ongoing projects in Iran, build upon the infrastructure of a small study in the Kashmiri population group and utilise existing collaborations with researchers from the University of Kashmir, the Digestive Diseases Research Centre (Iran) and the US NCI. Infrastructural feasibility will be assessed for case/control recruitment and biological/biopsy sample collection/transport/storage in the populations. Dietary/lifestyle questionnaires will be adapted to local customs/language from those developed in the Iranian study. Questionnaires will be validated in a series of local recruits and some case/control recruitment will be attempted.
Scientific abstract 2
Background: Colorectal cancer is one of the most common cancers worldwide. Its incidence currently ranks fourth in men and third in women with over 1 million new cases occurring every year. In their 2007 Expert Report, the World Cancer Research Fund (WCRF) concluded that colorectal cancer risk is probably or convincingly associated with specific dietary and lifestyle components, namely physical inactivity, large body size and abdominal obesity along with an excess consumption of energy, alcohol, red/processed meats, and a decreased intake of foods containing fiber, calcium/milk and garlic. These components may influence colorectal cancer risk via a number of possible mechanisms, including production of free radicals and other geno- or cyto-toxic compounds.
McKeown-Eyssen and colleagues have recently proposed pathways from these dietary and lifestyle components to colorectal cancer. These pathways involve individual effects of oxidative stress and endogenous energy excess, as well as their potential synergism, leading to increased colorectal cancer risk. Oxidative stress can arise directly from obesity and diet (high red/processed meats; low fruits/vegetables) but also from dietary factors that increase colonic permeability, translocation of toxic bacterial fragments (endotoxemia), and inflammation. Endogenous energy excess can result in hyperinsulinemia, hyperglycemia, triglyceridemia, insulin resistance and promotion of growth factors. The interaction of oxidative stress with endogenous energy excess results in the oxidation of early glycolysis products, the formation of reactive cytotoxic/genotoxic carbonyls, and eventually glyceraldehyde-derived advanced glycation end-products (AGEs).
Objectives: To date, colorectal cancer risk has been associated with higher oxidative stress and inflammation, as well as with excess energy consumption. However, there is little epidemiologic evidence for the role of increased colonic permeability and endotoxemia (exposure to lipopolysaccharide/flagellin), or for the formation of reactive carbonyls (e.g. glyceraldehyde-derived AGEs), in colorectal cancer etiology. It is the main objective of this proposed study to assess these biomarkers and test the direct and synergistic pathways towards colorectal cancer risk.
Setting and Methods: A case-control study (n cases=1500; n matched controls=1500) is proposed nested within the European Prospective Investigation into Nutrition and Cancer (EPIC) cohort. EPIC is composed of over 520,000 subjects from 23 centers in 10 Western European countries providing a wide range of cancer occurrence rates and heterogeneity in lifestyle and dietary habits. Dietary/lifestyle information and biological samples have already been prospectively collected.
Proposed biomarkers will be analysed by ELISA methods and secondary use will be made of a large number of relevant biomarkers that have already been measured in this dataset. Conditional logistic regression will be utilized to assess individual colorectal cancer risk associations and structural equation modeling will be used to develop simultaneously a complete model of all direct and mediated pathways between diet, lifestyle and risk of colorectal cancer.
Impact: The results of this proposed study will provide an improved understanding of the role and mechanisms of action of diet and lifestyle factors in colorectal cancer etiology. This insight can contribute to the evidence required for the development of effective cancer prevention strategies based on dietary and lifestyle modifications.
Scientific abstract 3
Background: Prospective epidemiologic evidence clearly suggests that higher circulating vitamin D levels are associated with decreased colorectal cancer (CRC) risk. It has been proposed that CRC protective effects of vitamin D may be due to its roles in cell cycle regulation (proliferation/differentiation/apoptosis), bile acid degradation, growth factor signaling, inflammation, and immune function. It has long been suggested that the vitamin D-CRC risk association may be modulated by polymorphisms in the vitamin D receptor (VDR) gene. However, data to date are inconsistent, largely because of small study sizes and consideration of only a few single nucleotide polymorphisms (SNPs). More recently, novel evidence highlights a wide array of VDR binding sites across the human genome, as well as genetic determinants of vitamin D insufficiency. Thus, it is plausible that the vitamin D-CRC risk association may be modulated by variation in a broad array of genes related to vitamin D metabolism (e.g. absorption, endogenous synthesis, transport, activation, deactivation) and action (including transcriptional activity/post-transcriptional effects). Many of these genes are polymorphic, but no studies to date have comprehensively investigated their individual and collective potential to modulate circulating vitamin D levels or the association of vitamin D with CRC incidence. It is also unknown whether these genes may interact with other factors shown to modulate vitamin D status, such as various nutrients, lifestyle exposures and physiological conditions. For an improved understanding of the vitamin D-CRC association and better insight into its preventive potential, it is necessary to move beyond existing concepts and apply novel approaches to further explore vitamin D-diet-lifestyle-gene interactions. In light of these points, a project is proposed within the European Prospective Investigation into Cancer and Nutrition (EPIC) study to build upon an existing infrastructure of detailed dietary/lifestyle data, and comprehensive biomarker/genetic information.
Objectives: To (a) investigate whether variation in genes related to vitamin D metabolism/action affect circulating blood vitamin D levels, (b) determine whether this genetic variation modulates the association of vitamin D with CRC risk and (c) explore potential gene-gene/nutrient/environment interactions of the vitamin D–CRC association with the use of novel methods, such as multifactor dimensionality reduction and structural equation modelling.
Setting & Methods: A case-control study (n cases=1500/n matched controls=1500) is proposed nested within the EPIC cohort, a prospective study of 520,000 subjects (23 centres/10 European countries). Advantages of the cohort are its large size, availability of biological samples and detailed dietary/lifestyle information collected prior to cancer diagnoses. We propose a comprehensive typing of genes within vitamin D related and responsive pathways. In addition, the project will build upon existing measures of a large number of relevant biomarkers (including blood measures of vitamin D, PTH, retinol, inflammation, and oxidative stress) to explore potential gene-gene/nutrient/environment interactions of the vitamin D–CRC association. Statistical methodology relevant to pathway analyses (structural equation and Bayesian modelling) will be employed.
Impact: This study will contribute considerably to understanding how vitamin D modulates CRC risk and will have implications relevant to targeted CRC prevention strategies based on dietary and lifestyle modifications.
Project 1 plain language abstract
Worldwide, the incidence of Squamous cell carcinoma of the esophagus (ESCC) shows large variations indicating that lifestyle, dietary and environmental factors play a strong role in its development. About 85% of ESCC cases occur in developing nations, particularly in a region called the “Asian Esophageal Cancer Belt” that ranges from Northern Iran to Northern China. The Jammu and Kashmir region of Northern India is part of this “Belt” region and is characterized by distinct ethnic and socio-cultural groups with varying ESCC incidence rates. The three main population groups are Kashmiris (mostly Muslim), Jammus (mostly Hindu), and Ladakhs (mostly Buddhist). The differences in ESCC incidence between these population groups may be related to different dietary/lifestyle factors which have not at all been well studied in this region. Thus, a feasibility study is proposed to determine the possibility of establishing a multi-centre case-control study whose objective will be to determine the dietary, lifestyle and genetic factors associated with ESCC in this region of India. This proposed study will complement similar ongoing projects in Iran and will be conducted in collaboration with scientific research institutions in Kashmir and the USA. If feasible, the resulting case-control study will provide valuable insight into the factors that affect ESCC development in different populations in a high risk region and may lead to public health strategies for its eventual prevention.
Project 2 plain language abstract
Background: Colorectal cancer is one of the most common cancers worldwide. Its incidence currently ranks fourth in men and third in women with a global number of over 1 million new cases occurring every year. To date, a number of dietary and lifestyle habits have been proposed to be either probably or convincingly linked to risk of colorectal cancer. These include lack of physical activity and having a large body size, particularly abdominal fatness. In terms of diet, the factors associated with increased risk of colorectal cancer are high intake of total energy, alcohol, red/processed meats, and a decreased intake of foods that contain dietary fiber, of calcium, milk and garlic. Each of these dietary and lifestyle components may influence colorectal cancer by way of various mechanisms that can lead to the production of different compounds which cause cellular or genetic damage leading to cancer causation. Recently, McKeown-Eyssen and colleagues proposed several pathways leading to colorectal cancer from these dietary and lifestyle components. These proposed pathways are by way of oxidative stress as well as metabolites produced from excess consumption of energy. The latter can cause production of compounds which stimulate cell growth. The theory also proposes that oxidative stress, which can arise from obesity and diet, can also arise from endotoxemia which is defined as exposure to endotoxins from colonic bacteria. Certain dietary and lifestyle components can cause a breakdown in the colonic barrier, leading to leakage of endotoxins into the blood stream. Another novel aspect of the theory is a third proposed pathway- the synergistic effect of the first two pathways resulting in the formation of toxic compounds that can be assessed, for example glyceraldehyde-derived advanced glycation end-products (AGEs). Endotoxin exposure and AGE production can be measured as biomarkers in the blood.
Aims and Goals: The proposed study aims to measure the above biomarkers in the blood of colorectal cancer subjects and to explore the three proposed pathways leading from diet and lifestyle factors to colorectal cancer risk.
How It Will Be Done: The proposed study will be performed within EPIC- a large cohort of over 520,000 subjects from 10 Western European countries. The cohort has already collected detailed dietary and lifestyle data along with blood samples for biomarker measures. To date, a total of 1500 colorectal cancer cases have developed within EPIC. For this study, they will be matched with 1500 healthy subjects. A number of other relevant biomarker measures already exist for these subjects and they will also be used in this study. The dietary/lifestyle habits and biomarker measures will be compared between the cases and controls and associations with colorectal cancer will be analysed. In addition, a statistical technique called structural equation modelling will be used to combine dietary and biomarker data and explore the three proposed pathways leading to the formulation of a comprehensive model of their associations with colorectal cancer risk.
Potential Impact: It is expected that the results will provide a more complete understanding of how dietary/lifestyle factors may affect colorectal cancer risk and some potential mechanisms of action. This information can be combined with what is already known about colorectal cancer development to propose dietary and lifestyle changes to reduce colorectal cancer risk and prevent this disease.
Project 3 plain language abstract
Background: Colorectal cancer (CRC) is the third most common cancer in women and the fourth most common cancer in men worldwide. Various lines of evidence suggest that it should be highly preventable by modifications of diet and lifestyle, yet to date, the only clearly established dietary and dietary-/lifestyle-related factors are red/processed meats, alcohol, physical activity, adult attained height, and obesity. Recent research indicates that vitamin D is one of the most promising candidates for the prevention of CRC. It may protect against colorectal cancer by way of various mechanisms that lead to decrease in cell replication, lower chronic inflammation and oxidative stress, and improved immune function; however the exact mechanisms/pathways underlying these effects of vitamin D are not clear. The degree to which vitamin D protects against colorectal carcinogenesis may depend on a person's genetic background. Variation in genes involved in vitamin D synthesis, transport, activation and deactivation may alter individual's vitamin D status and subsequently his/her CRC risk. Also, variation in genes responsive to vitamin D signaling may alter molecular pathways that play an important role in colorectal carcinogenesis. To date, very few human studies have investigated variation within these genes, and none have considered the biologically plausible interrelationships between genes, vitamin D status biomarker, and dietary/lifestyle/nutrient factors in relation to CRC risk. Herein, a comprehensive pathway approach is proposed, which will improve our understanding of the vitamin D-CRC association and will help to identify individuals that may be genetically susceptible to the beneficial effects of vitamin D in relation to CRC.
Aims and Goals: The proposed study aims to measure variation within the genes involved in vitamin D pathway and genes modulated by vitamin D and explore potential interactions between genes, vitamin D biomarkers and environment in relation to CRC risk.
How it will be done: The proposed study will be done within a large cohort of over 520,000 participants from ten Western European countries known as the European Prospective Investigation into Cancer and Nutrition (EPIC). The study has already collected dietary and lifestyle information along with blood samples for genetic analyses. This project focuses on 1,500 colorectal cancer cases that have developed within the EPIC cohort over a period of 11 years. For this study, they will be matched with 1,500 healthy participants on age, study centre, and other risk factors. Some of the biomarkers and genetic variants relevant to vitamin D pathway have been already measured for these subjects and they will be used in this study. Genetic variation in the genes related to vitamin D metabolism and action, and in the genes that are regulated by vitamin D will be measured by standard techniques. The dietary/lifestyle factors, genetic variation and vitamin D biomarker will be compared between CRC cases and healthy controls in relation to CRC risk. Special statistical techniques will be used to identify interactions between measured genetic variation and dietary/lifestyle factors and biomarkers. These techniques include multifactor dimensionality reduction and structural equation modelling. The latter utilizes a novel comprehensive pathway approach to combine dietary/lifestyle/biomarker and genetic data and to explore their potential interrelations in association with CRC risk.
Potential Impact: This study offers a unique opportunity to investigate comprehensively vitamin D pathway in relation to CRC risk. It will contribute considerably to a more complete understanding of how vitamin D modulates CRC risk and some potential mechanisms of its action. This information in combination with what is already known about CRC development may be used to develop targeted prevention strategies based on dietary and lifestyle modifications.
| Institution and location | Degree | Year | Scientific Field |
|---|---|---|---|
| University of Toronto, Toronto, ON, Canada | Bachelor of Science | 1992 | Specialist Nutritional Sciences/Human Biology |
| University of Toronto, Toronto, ON, Canada | Master of Science | 1995 | Nutritional Sciences |
| University of Toronto, Toronto, ON, Canada | Ph.D. | 2000 | Nutritional Sciences |
| University of Toronto, Toronto, ON, Canada | Postdoctoral Training | 2000 | Nutritional Sciences |
| International Agency for Research on Cancer, Lyon, France | Postdoctoral Training | 2001-2004 | Nutritional Epidemiology |
| 2007–present | Scientists, Nutritional Epidemiology Group, Section of Nutrition and Metabolism, International Agency for Research on Cancer [IARC-WHO], The World Health Organization, Lyon, France |
| 2004 - 2007 | Scientist, Nutrition and Hormones Group, International Agency for Research on Cancer, Lyon, France. |
| 2001 | Scientist, Department of Clinical Research and Regulatory Affairs, Dimethaid Incorporated, Markham, Ontario, Canada. |
Research interests
The influence of diet, nutrition and genetics on cancer risk and aetiology.
