DOI: 10.25549/usctheses-c40-331373
title: Diet, ethnicity, genetic susceptibility, and cancer risk

description: Cancer is a complex disease, the consequence of joint effects of environmental and genetic risk factors. The overarching theme of this thesis project is two-fold: 1) to investigate the association between dietary intake of meat and fish and cancer risk, and how this association may be modified by genetic variations in key biological pathways, and 2) to investigate the role played by race/ethnicity in cancer etiology, both in terms of race specific risk factors and as a modifying factor for potential risk factors such as dietary meat intake. ❧ Generally speaking, a diet high in meat intake is associated with poor health outcomes, including cancer. Epidemiological evidence points to an association between meat intake and cancers of various sites—in 2015, the International Agency for Research on Cancer (IARC) performed an extensive literature review that culminated in the reclassification of processed meats as Group I carcinogens i.e. “enough evidence to conclude that it can cause cancer in humans”. Nevertheless, evidence for associations between red meat and fish intake and cancer risk remains equivocal, with many studies reporting null associations. Furthermore, the mechanism of action of meat intake is still under investigation and not completely well understood. We aim to investigate potential interactions between meat intake and genetic variants in key pathways. Accounting for gene/environment interactions provides better insight into the mechanisms of action of meat intake, and may also explain the lack of association found in many a number of epidemiological studies of diet/cancer. In these projects we mainly focus on two pathways. Meat associated carcinogens—three key carcinogens considered in this project are polycyclic aromatic hydrocarbons (PAH), heterocyclic aromatic amines (HAA), and N-nitroso compounds (NOC). All are potent carcinogens found in meat and fish; their formation depends largely on cooking and preservation methods employed when preparing foods. Upon intake, these compounds must undergo metabolism by various Phase I/II enzymes in order to exert their carcinogenic properties, culminating in either excretion or the creation of intermediate molecules capable of forming DNA adducts and generating oxidative DNA damage, thus increasing the likelihood of mutation events. Variants found within these genes may influence metabolic efficiency of these compounds, rendering subsets of the population more or less susceptible to exposures to meat related carcinogens. Inflammatory pathways—diet is a large driver of chronic inflammation, creating an environment rich in reactive oxygens species and continuous tissue remodeling that is conducive to DNA damage and tumorigenesis. We investigate interactions between meat intake and variants in genes involved in the inflammatory response pathways, such as innate response elements (Toll-like receptors, or TLR), signaling proteins/cytokines, and transcription factor pathways such as Mitogen-activated protein kinases (MAPK), Phosphoinositide 3-kinase/Protein Kinase B (PIK3/AKT), and Nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) that mediate inflammatory responses, cell growth, differentiation, and apoptosis. ❧ Hispanics are an admixed population. Cancer rate disparities between non-Hispanic white (NHW) and Hispanics are well-documented. In breast cancer specifically, Hispanics experience lower incidence rates but are diagnosed at more advanced disease stages compared to NHW women. A number of contributing factors are implicated, including reproductive history and genetic susceptibility. However, differences in rates vary by immigration status, such that Hispanic women who live in the US experience higher rates of breast cancer compared to Hispanics residing in their native countries, suggesting the influence of lifestyle/environmental factors such as diet. In this project we explore whether associations between meat intake and breast cancer, and interactions with genetic variations, are influenced by race/ethnicity. We also explore subpopulation differences in distributions of breast cancer risk factors. Hispanics are often grouped together in epidemiological studies due to lack data. However, they are composed of many different ethnic groups, each with distinct sets of environmental and cultural exposures and genetic backgrounds. In our last project, we perform descriptive analyses of common breast cancer risk factors, accounting for Hispanic subpopulations. ❧ In summary, cancer is the result of a complex interplay between various environmental and genetic causal factors. Here we focus on the roles of meat intake, genetic susceptibility, and race/ethnicity on cancer etiology, with the goal of better understanding the mechanisms of these associations and ultimately informing population specific, more finely targeted public health recommendations.