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Proquest Dissertations mn u Ottawa L'Université canadienne Canada's university FACULTÉ DES ÉTUDES SUPÉRIEURES l===J FACULTY OF GRADUATE AND et POSTOCTORALES u Ottawa posdoctoral studies L'Université canadienne Canada's university Jessica Dennis TUTËÏÏRDlI^tÏÏÉTÉ7XUTÎOR0"FTHËsTS~ M.Sc. (Epidemiology) GRADE /DEGREE Department of Epidemiology & Community Medicine Alcohol Consumption and Breast Cancer Risk - Modification by Genetic Susceptibility TITRE DE LA THESE / TITLE OF THESIS Daniel Krewski DIRECTEUR (DIRECTRICE) DE LA THESE / THESIS SUPERVISOR Julian Little CO-DIRECTEUR (CO-DIRECTRICE) DE LA THESE / THESIS CO-SUPERVISOR Yue Chen Kenneth Johnson Gary W.Slater Le Doyen de la Faculté des études supérieures et postdoctorales / Dean of the Faculty of Graduate and Postdoctoral Studies ALCOHOL CONSUMPTION AND BREAST CANCER RISK - MODIFICATION BY GENETIC SUSCEPTIBILITY JESSICA DENNIS Thesis submitted to the Faculty of Graduate and Postdoctoral Studies in partial fulfillment of the requirements for the MSc degree in Epidemiology Epidemiology and Community Medicine Faculty of Medicine University of Ottawa ©Jessica Dennis, Ottawa, Canada, 2010 Library and Archives Bibliothèque et ?F? Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l'édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre référence ISBN: 978-0-494-69046-8 Our file Notre référence ISBN: 978-0-494-69046-8 NOTICE: AVIS: The author has granted a non- L'auteur a accordé une licence non exclusive exclusive license allowing Library and permettant à la Bibliothèque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l'Internet, prêter, telecommunication or on the Internet, distribuer et vendre des thèses partout dans le loan, distribute and sell theses monde, à des fins commerciales ou autres, sur worldwide, for commercial or non- support microforme, papier, électronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriété du droit d'auteur ownership and moral rights in this et des droits moraux qui protège cette thèse. Ni thesis. Neither the thesis nor la thèse ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent être imprimés ou autrement printed or otherwise reproduced reproduits sans son autorisation. without the author's permission. In compliance with the Canadian Conformément à la loi canadienne sur la Privacy Act some supporting forms protection de la vie privée, quelques may have been removed from this formulaires secondaires ont été enlevés de thesis. cette thèse. While these forms may be included Bien que ces formulaires aient inclus dans in the document page count, their la pagination, il n'y aura aucun contenu removal does not represent any loss manquant. of content from the thesis. ¦+¦ Canada Abstract Gene-environment and gene-gene interactions lie at the root of many human diseases. This thesis evaluated the risk of bias in the case-only design applied to studies of genetic interaction by way of a systematic review and meta-regression analysis. The case-only design was then used to investigate interactions between BRCA gene mutations and alcohol consumption among breast cancer patients, and the results were compared to a case-control analysis of BRCA mutation carriers with and without breast cancer. The systematic review suggests that the case-only design is unbiased when applied to studies of genetic interaction. The case-control analysis found that increasing wine consumption may reduce the risk of breast cancer among BRCAl mutation carriers, and the results of case-only analysis may be compatible with this. Among BRCA2 mutation carriers, consumption of alcohol other than wine increased breast cancer risk in the case-only analysis while no association was observed in the case-control analysis. ii Acknowledgements Thank you to my supervisors, Dr. Krewski and Dr. Little, for their guidance, support, and encouragement. I am very grateful to my thesis committee members, Dr. Ghadirian and Dr. Narod, for the use of their data and for their input on this thesis. Thanks also to those who contributed to the systematic review, Mihaela Gheorghe and Julia Frei, for their help with database searching and data extraction, and Steven Hawken, whose willingness to discuss statistical problems was always appreciated. To those who helped me access and navigate the data in Montreal and Toronto, Frédérique-Sophie Côté, Eve Fafard, and Marcia Llacuachaqui, your kindness was appreciated. To my family, friends, and colleagues in the MSc program, thank you for your support and advice throughout my studies. Lastly, thanks to the faculty and staff in the Department of Epidemiology and Community Medicine for their mentorship and support. m Table of Contents Abstract ü Acknowledgements iü List of Tables vi List of Figures vii 1. Introduction 1 1.1. Background and Rationale 1 1.1.1. Breast Cancer Epidemiology 1 1.1.1.1. Alcohol Consumption and Breast Cancer Risk 2 1.1.2. Mutations in the BRCA 1 and BRCA2 Genes 3 1.1.3. The Case-Only Study Design 6 1.2. Objectives and Scope of Thesis 6 2. Bias in the Case-Only Design Applied to Studies of Gene-Environment and Gene-Gene Interaction; a Systematic Review and Meta-Analysis 12 2.1. Abstract 13 2.2. Introduction 15 2.3. Methods 16 2.3.1. Search Strategy 16 2.3.2. Inclusion and Exclusion Criteria 17 2.3.3. Study Selection 17 2.3.4. Qualitative Synthesis 17 2.3.5. Quantitative Synthesis 18 2.3.6. Statistical Methods 19 2.4. Results 20 2.4.1. Qualitative Comments 22 2.4.2. Meta-Regression Analysis 25 2.5. Discussion 33 3. Breast Cancer Risk in Relation to Alcohol Consumption and BRCA Gene Mutations - A Case-Only Study of Gene-Environment Interaction 46 3.1. Abstract 47 3.2. Introduction 48 3.3. Methods 49 3.3.1. Study Population 49 3.3.2. Genetic Testing 50 3.3.3. Assessment of Alcohol Consumption 51 3.3.4. Assessment of Other Lifestyle Factors 51 3.3.5. Statistical Methods 52 3.4. Results 52 3.5. Discussion 57 IV 4. Alcohol Consumption and the Risk of Breast Cancer Among BRCAl and BRCA2 Mutation Carriers 66 4.1. Abstract 68 4.2. Introduction 69 4.3. Materials and Methods 69 4.3.1. Study Population and Design 69 4.3.2. Data Collection and Definition of Variables 71 4.3.3. Statistical Methods 71 4.4. Results 72 4.5. Discussion 78 5. Discussion and Conclusions 86 5.1. Summary of Principal Findings 86 5.2. Interpretation and Comparison with Other Related Studies in the Literature 87 5.3. Strengths and Limitations of the Thesis 96 5.4. Unanswered Questions and Future Research 98 5.5. Conclusions 99 Appendix A 106 Appendix B 109 Appendix C 110 Appendix D 144 Appendix E 145 Appendix F 146 Appendix G 147 Appendix H 148 Appendix I 149 Appendix J 150 Appendix K 151 Appendix L 152 Appendix M 153 ? List of Tables Table 2-1. Types of studies included in the systematic review 22 Table 2-2. Characteristics of studies included in the meta-regression analysis 28 Table 2-3. Univariable meta-regression analysis of study design parameters on the IORcc/IORco ratio 32 Table 3-1 . Characteristics of study participants with and without BRCA gene mutations 54 Table 3-2. Alcohol consumption patterns in the year prior to breast cancer diagnosis in non- mutation carriers, BRCAl mutation carriers, and BRCA2 mutation carriers 56 Table 3-3. Interaction between alcohol consumption in drinks/week (dichotomized at the median of all cases) and BRCAl and BRCA2 gene mutations 56 Table 4-1. Characteristics of study participants 73 Table 4-2. Frequency of alcohol consumption and types of alcohol regularly consumed among cases and controls 74 Table 4-3. Association between breast cancer risk and the number of alcoholic drinks consumed per week among BRCAl and BRCA2 mutation carriers 76 Table 4-4. Association between breast cancer risk and the number of alcoholic drinks consumed per week by the type(s) of alcohol typically consumed among BRCAl and BRCA2 mutation carriers 78 vi List of Figures Figure 2-1. Flow of information through different phases of the systematic review 21 Figure 2-2. Forrest plot of the mean IORcc/IORco ratio calculated from studies included in the meta-regression analysis under a random effect model 31 Figure 4-1 . Variation in the number of drinks consumed per week by country of study site 75 Figure 4-2. Prevalence of exclusive wine consumers among those who reported consuming alcohol by country 77 VIl 1. Introduction 1.1. Background and Rationale 1.1.1. Breast Cancer Epidemiology Breast cancer is the most commonly diagnosed cancer among women worldwide.(l) It is more commonly diagnosed in developed regions (67.8 per 100,000 persons per year) than in developing regions (23.8 per 100,000 persons per year),(l) but is increasing in the latter.(2) In Canada, a woman's lifetime risks of developing and dying from breast cancer are 11.1% and 3.6% respectively.(3) This means that approximately 1 in 9 Canadian women will develop breast cancer in her lifetime and 1 in 28 will die from the disease. Breast tissue is composed of fat, glandular tissue (arranged in lobes), ducts, and connective tissue, with the relative composition depending on life stage.(2) Breast cancers are most often derived from the epithelial cells lining the ducts (2) and arise as a result of genetic mutations in these cells and proliferation of these cells.(l) Hormones in particular are associated with this process.
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