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Associations Between Genetic Polymorphisms in Dna Bypass Polymerases and Base Excision Repair Genes with the Risk of Breast Cancer

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Associations Between Genetic Polymorphisms in Dna Bypass Polymerases and Base Excision Repair Genes with the Risk of Breast Cancer ASSOCIATIONS BETWEEN GENETIC POLYMORPHISMS IN DNA BYPASS POLYMERASES AND BASE EXCISION REPAIR GENES WITH THE RISK OF BREAST CANCER Leila Family A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Epidemiology. Chapel Hill 2014 Approved by: Andrew F. Olshan Jeanette T. Bensen Melissa A. Troester Michael C. Wu Carey K. Anders ©2014 Leila Family ALL RIGHTS RESERVED ii ABSTRACT LEILA FAMILY: Associations between genetic polymorphisms in DNA bypass polymerases and base excision repair genes with the risk of breast cancer (Under the direction of Andrew F. Olshan) Mutations in BRCA1, a DNA repair gene, have been associated with a lifetime increased risk of breast cancer (1). Therefore, researchers hypothesized there may be other DNA repair genes associated with breast cancer risk. However thus far, studies of common low-penetrant DNA repair SNPs have not yielded consistent results. In this proposed study, we hypothesized one or more of the following mechanisms may explain the lack of main SNP effects: combined SNP effects, modification by race or breast cancer subtype, and functional redundancy. To evaluate these hypotheses, we used genotype data from the Carolina Breast Cancer Study (1,972 cases and 1,776 controls) to investigate race-specific, subtype-specific, and combined SNP associations using unconditional logistic regression in two DNA damage pathways, base excision repair (BER) and translesion synthesis (TLS). For BER, we evaluated the association between 31 single-nucleotide polymorphisms (SNPs) in 15 genes and breast cancer risk. SKAT, a pathway-based analytic method, was used to evaluate the combined SNP effects within the BER pathway. Among Whites, our results showed a significant positive association for NEIL2 rs1534862 and a significant inverse association for PCNA rs17352. Among African Americans, we found a suggestive positive association for UNG rs3219275 and an inverse association for NEIL2 rs8191613. Tumor subtype analysis showed that NEIL2 rs1534862 was associated with luminal and HER2+/ER- subtypes. SKAT analysis showed no significant combined effects between SNPs. For DNA bypass polymerases, we evaluated the association between 22 single- iii nucleotide polymorphisms (SNPs) in 7 bypass polymerase genes and breast cancer risk. We found similar increased odds ratios for breast cancer with three POLQ SNPs (rs487848, rs532411, rs3218634), which were also in high LD in both races. Furthermore, analysis by specific tumor subtypes showed all three SNPs were associated with increased risk of luminal breast cancer. These significant findings need to be replicated independently in other studies. Overall, our results did not indicate associations with breast cancer, which may concur with the theory that our cells possess an intricate system of functionally redundant DNA repair mechanisms in order to avoid the catastrophic effects of genomic instability. iv To Dr. Robert C. Millikan Who always believed in me “The thing always happens that you really believe in, and the belief in a thing makes it happen.” -Frank Lloyd Wright v ACKNOWLEDGEMENTS First, I would like to thank God for giving the strength and endurance to continue and finish my dissertation work. Also, I would like to thank my dissertation committee members, Dr. Andrew Olshan, Dr. Jeannette Bensen, Dr. Melissa Troester, Dr. Michael Wu, and Dr. Carey Anders, for providing me with their expertise and valuable feedback. I would like to extend a special thanks to my chair, Dr. Andrew Olshan, for his continuous guidance and support and for navigating me through the dissertation process and dealing with unforeseen circumstances. I would also like to thank everyone who has contributed their time and energy to the Carolina Breast Cancer Study. Without their hard work and dedication, this work would not be possible. I would especially like to thank Mary Beth Bell, CBCS Project Manager, for her strong commitment to the study. Of course, I would also like to acknowledge the selfless contributions of all the women that participated in the Carolina Breast Cancer Study. I would also like to thank my vast circle of support, including the helpful staff in the Epidemiology Department. I especially want to thank Nancy Colvin for her unwavering support and dedication to my success. I would also like to thank my awesome friends and family. In particular, I would like to give special thanks to Katie O’Brien and Lauren McCullough. These ladies went out of their way to make sure I was successful, including volunteering countless hours of their time to provide advice and feedback. I would also like to take a moment to acknowledge and honor the work of Dr. Robert Millikan and Dr. Keith Amos, whose impact in the field of breast cancer will be felt for years to come. vi Last, but certainly not least, I would like to thank my amazing parents, Gity and Siamak Family, for their unwavering support and unconditional love throughout my whole life, and the many selfless sacrifices they have made for me. I am truly blessed and honored to know such wonderful and genuinely humble people. I would also like to acknowledge the sources of financial support that enabled me to complete this research: the University Cancer Research Fund of North Carolina, the National Cancer Institute Specialized Program of Research Excellence (SPORE) in Breast Cancer (NIH/ NCI P50-CA58223) and NRSA Pre Doctoral Training Grant (2007-2009), University of North Carolina at Chapel Hill Grant # 2-T32-CA09330. vii TABLE OF CONTENTS LIST OF FIGURES .................................................................................................................. xvii LIST OF ABBREVIATIONS ................................................................................................. xviii CHAPTER 1. REVIEW OF THE LITERATURE .................................................................... 1 1.1 Introduction ........................................................................................................................... 1 1.2 Definition of breast cancer .................................................................................................... 1 1.3 Epidemiology of breast cancer.............................................................................................. 2 1.3.1 Breast cancer incidence .................................................................................................. 2 1.3.2 Breast cancer mortality .................................................................................................. 3 1.3.3 Non-genetic risk factors of breast cancer ....................................................................... 3 1.3.3.1 Non-genetic risk factors of breast cancer by race ................................................... 4 1.3.4 Genetic risk factors of breast cancer .............................................................................. 5 1.3.4.1 Genetic risk factors of breast cancer by race .......................................................... 7 1.4 Heterogeneity of breast cancer.............................................................................................. 7 1.4.1 Non-genetic risk factors of breast cancer by subtype .................................................... 9 1.4.2 Genetic risk factors of breast cancer by subtype.......................................................... 10 1.4.3 Summary of breast cancer risk factors ......................................................................... 12 1.5 Variation in DNA repair capacity ....................................................................................... 12 viii 1.5.1 Low-penetrant common DNA repair variation in breast cancer .................................. 13 1.6 DNA damage responses ...................................................................................................... 13 1.6.1 Overview of DNA repair.............................................................................................. 14 1.6.2 Overview of base excision repair (BER) ..................................................................... 14 1.6.2.1 Base excision repair and breast cancer ................................................................. 16 1.6.2.1.1 UNG ............................................................................................................................. 16 1.6.2.1.2 SMUG1 ....................................................................................................................... 16 1.6.2.1.3 MBD ............................................................................................................................. 17 1.6.2.1.4 MPG ............................................................................................................................. 17 1.6.2.1.5 MYH/MUYTH .............................................................................................................. 17 1.6.2.1.6 TDG .............................................................................................................................. 18 1.6.2.1.7 OGG1 ........................................................................................................................... 18 1.6.2.1.8 NEIL1 ........................................................................................................................... 19 1.6.2.1.9 NEIL2 ..........................................................................................................................
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