Adiposity and Breast Cancer: The Role of Genetic and Modifiable Risk Factors Público
Teras, Lauren Rebecca (2010)
Published
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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