Adiposity and Breast Cancer: The Role of Genetic and Modifiable Risk Factors Open Access

Teras, Lauren Rebecca (2010)

Permanent URL: https://etd.library.emory.edu/concern/etds/0g354f345?locale=en
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Abstract


Abstract
Adiposity and Breast Cancer: The Role of Genetic and Modifiable Risk Factors
By Lauren R. Teras
Obesity has been consistently associated with an increased risk of postmenopausal
breast cancer. However, the implications of this association for cancer prevention and the
genetic contributions to mechanisms by which obesity may affect breast cancer risk are
not fully understood. The goal of this dissertation was to address three unanswered
questions: 1) Does weight loss reduce breast cancer risk in overweight women? 2) Do
polymorphisms of genes that encode adipokines contribute to risk of postmenopausal
breast cancer? 3) Do genetic and non-genetic factors that impact estrogen level interact to
affect risk for breast cancer?
Study 1 found that weight loss was not associated with postmenopausal breast
cancer risk; however understanding the potential benefit of weight loss is challenged by
the rarity, timing, and sustainability of weight loss. Study 2 was a comprehensive
examination of the known variability in five genes that code for the two most abundantly
produced adipokines (leptin and adiponectin). This second study did not identify any
associations with postmenopausal breast cancer. Finally, Study 3 found no evidence of
gene-gene or gene-environment joint effects between estrogen-related factors using two
analytic methods: multifactor dimensionality reduction and logic regression. Other
methods that incorporate all known biological information may be needed to model more
complex relationships between the genes and the environment.


Adiposity and Breast Cancer: The Role of Genetic and Modifiable Risk Factors

By
Lauren R. Teras
B.A., University of Michigan, Ann Arbor, 1997
M.P.H., Emory University, 2000
Advisor: Michael Goodman, M.D., M.P.H.
A dissertation submitted to the Faculty of the
James T. Laney School of Graduate Studies of Emory University
in partial fulfillment of the requirements for the degree of
Doctor of Philosophy
in Epidemiology
2010

Table of Contents


Table of Contents
CHAPTER 1: INTRODUCTION AND BACKGROUND............................................ 1

1.1 INTRODUCTION .................................................................................................... 1
1.2 BACKGROUND ...................................................................................................... 3
1.2.1 Breast Cancer .................................................................................................... 3
1.2.2 Obesity ............................................................................................................... 9
1.2.3 Adipoisty and Breast Cancer: Association and Potential Mechanisms........... 11
1.2.4 Summary .......................................................................................................... 14
1.3 DISSERTATION AIMS ................................................................................................ 14
CHAPTER 2: WEIGHT LOSS AND POSTMENOPAUSAL BREAST CANCER IN
A PROSPECTIVE COHORT OF U.S. WOMEN ....................................................... 16

2.1 ABSTRACT................................................................................................................ 16
2.2 INTRODUCTION......................................................................................................... 17
2.3 METHODS................................................................................................................. 19
2.4 RESULTS .................................................................................................................. 22
2.5 DISCUSSION ............................................................................................................. 23
2.6 FIGURES AND TABLES .............................................................................................. 26
CHAPTER 3: NO ASSOCIATION BETWEEN POLYMORPHISMS IN LEP,
LEPR, ADIPOQ, ADIPOR1,
OR ADIPOR2 AND POSTMENOPAUSAL BREAST
CANCER RISK............................................................................................................... 36

3.1 ABSTRACT................................................................................................................ 36
3.2 INTRODUCTION......................................................................................................... 37
3.3 METHODS................................................................................................................. 41
3.4 RESULTS .................................................................................................................. 43
3.5 DISCUSSION ............................................................................................................. 43
3.6 FIGURES AND TABLES .............................................................................................. 46
CHAPTER 4: A SEARCH FOR JOINT EFFECTS OF GENETIC AND
ENVIRONMENTAL FACTORS ON BREAST CANCER RISK USING TWO
NOVEL PUBLISHED APPROACHES........................................................................ 57

4.1 ABSTRACT................................................................................................................ 57
4.2 INTRODUCTION......................................................................................................... 58
4.3 METHODS................................................................................................................. 60
4.4 RESULTS .................................................................................................................. 64
4.5 DISCUSSION ............................................................................................................. 66
4.6 FIGURES AND TABLES .............................................................................................. 70
CHAPTER 5: CONCLUSIONS, STRENGTHS, AND LIMITATIONS, FUTURE
DIRECTIONS ................................................................................................................. 83

REFERENCES .................................................................................................................. 89



List of Tables

Table 2.1

. Exclusion cascade to create analytic cohort.................................... 26

Table 2.2. Characteristics of overweight and obese women who lost or
maintained weight between 1982-1992 ............................................................ 27

Table 2.3. Hazard ratios of breast cancer incidence according to weight loss
between 1982 and 1992 among overweight and obese women........................ 29

Table 2.4. Hazard ratios of breast cancer incidence according to weight loss
between 1982 and 1992 stratified by postmenopausal hormone (PMH) use and
baseline body mass index (BMI) among overweight and obese women.......... 30

Table 2.5. Hazard ratios of breast cancer incidence according to percent weight
loss between 1982 and 1992 among overweight and obese women................. 31

Table 3.1. Previous studies of LEP, LEPR single nucleotide polymorphisms
(SNPs) and breast cancer .................................................................................. 46

Table 3.2. Association between single nucleotide polymorphisms representing
linkage disequilibrium bins in LEP, LEPR, ADIPOQ, ADIPOR1, and
ADIPOR2 and risk of postmenopausal breast cancer ....................................... 47

Table 4.1. Characteristics of cases and controls selected from the American
Cancer Society Cancer Prevention Study-II Lifelink Cohort ........................... 70

Table 4.2. Odds ratios and 95% confidence intervals for estrogen biosynthesis
polymorphisms and postmenopausal breast cancer .......................................... 71

Table 4.3. Multifactor dimensionality reduction models for estrogen
biosynthesis genes and breast cancer................................................................ 80

Table 4.4. Multifactor dimensionality reduction models for prediction of
postmenopausal breast cancer by estrogen biosynthesis genes and non-genetic
factors................................................................................................................ 81

Table 4.5. Logic regression models for breast cancer prediction..................... 82


List of Figures

Figure 2.1

. Previous population-based studies of weight loss and breast cancer
........................................................................................................................... 32

Figure 2.2. Histogram of reported weight loss over ten years during adulthood
(1982-1992) in the American Cancer Society Cancer Prevention Study-II
Nutrition Cohort................................................................................................ 33

Figure 2.3. Multivariate spline of weight loss between 1982 and 1992 among
overweight and obese women........................................................................... 34

Figure 2.4. Multivariate spline of weight loss between 1982 and 1992 among
overweight and obese women who maintained the weight loss ....................... 35

Figure 3.1. Dominant model p-values for the statistical interaction between
single nucleotide polymorphisms in LEP, LEPR, ADIPOQ, ADIPOR1, and
ADIPOR2 and body mass index (BMI) ............................................................ 53

Figure 3.2 Dominant model p-values for the statistical interaction between
single nucleotide polymorphisms in LEP, LEPR, ADIPOQ, ADIPOR1, and
ADIPOR2 and physical activity ........................................................................ 54

Figure 3.3. Dominant model p-values for the statistical interaction between
single nucleotide polymorphisms in LEP, LEPR, ADIPOQ, ADIPOR1, and
ADIPOR2 and weight change ........................................................................... 55

Figure 3.4. Dominant model p-values for the statistical interaction between
single nucleotide polymorphisms in LEP, LEPR, ADIPOQ, ADIPOR1, and
ADIPOR2 and location of weight gain ............................................................ 56

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