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(Title of the Thesis)* THE IDENTIFICATION OF BRCA1 AND BRCA2 MUTATION CARRIERS USING FUNCTIONAL GENOMIC ASSAYS by Claire S. Michel A thesis submitted to the Department of Pathology & Molecular Medicine In conformity with the requirements for the degree of Master of Science Queen’s University Kingston, Ontario, Canada March, 2008 Copyright © Claire S. Michel, 2008 Abstract An estimated 5-10% of breast cancers are hereditary in nature and are due to the presence of a mutation in a breast cancer predisposition gene; approximately half of these cases possess a mutation in BRCA1 or BRCA2. Many BRCA1/BRCA2 mutations result in a truncated protein and hence are unequivocally disease-causing. However another class of mutations, the Variants of Unknown Significance (VUS), are more problematic as the effect of these mutations on protein function is unclear. The inability to classify these mutations as disease causing generates significant problems in risk evaluation, counseling and preventive care. Accordingly we sought to determine whether carriers of either a BRCA1 or BRCA2 mutation could be identified from non- carriers based on the gene expression patterns of non-cancerous cells. EBV-transformed lymphoblastoid cell lines established from BRCA1/BRCA2 mutation carriers and normal individuals were obtained through the NIH Breast Cancer Family Registries. Cell lines were mock-irradiated or treated with ionizing radiation (2 Gy). Following a recovery period of 6 hours total RNA was extracted and whole genome gene expression profiling was carried out. Molecular classifiers comparing the baseline expression profiles and the radiation- dependent expression profiles of BRCA1/BRCA2 mutation carriers to control individuals were created using a Support Vector Machine (SVM) coupled with a recursive feature removal (RFR) algorithm. Our results suggest that cell populations derived from BRCA1/BRCA2 mutation carriers display unique expression phenotypes from those of control individuals in both the basal and radiation-induced cases. In the task of classification using baseline expression, the BRCA1- classifier correctly classified 15/18 test samples using feature selection based on the training set only, while feature selection using the entire dataset (AD) improved classification to 16/18 samples. The BRCA2-baseline classifier correctly classified 13/17 and 14/17 (AD) samples, ii respectively. In the task of radiation-dependent classification, the BRCA1-IR classifier correctly classified 12/18 and 16/18 (AD) test samples respectively while the BRCA2-IR classifier correctly classified 13/17 and 16/17 (AD) test samples respectively. These results suggest the possibility of development of this assay into a novel hereditary breast cancer screening diagnostic able to accurately identify the presence of BRCA1 or BRCA2 mutations via a functional assay thereby improving patient outcomes. iii Acknowledgements Firstly I would like to thank my supervisors, Dr. Scott Davey and Dr. Harriet Feilotter for continually challenging and supporting me over the course of my work. To the members of the Davey lab past and present: it is always a pleasure. I would like to thank my family; Jane, Dave and Alex for always encouraging me to strive to do well in whatever I pursue, and for letting me believe the sky is the limit. Mum, thank you for always thinking of us: I dedicate this work to you. I would like to thank ―The Family‖: Jenny, Rob, Catriona, Pou and especially Larbi, you guys mean to world to me and I would be only a shadow of the person I am today without your constant love, encouragement and understanding. To be surrounded by such loving and caring people is a truly wonderful gift. Larbi, thank you for always encouraging me in my endeavors—to know that I can always count on you is beyond words. To the Science Geeks: Matt, Cheryl, Joe, Jess, Shawna, Andrea, Jalna, Mia, Morgan, Dr. C & The Crudden Lab: thank you for many hours of entertainment, enrichment-ridiculousness, white board races and much, much, more. Lastly, to the Queen’s Triathlon & Cycling Teams: to have been fortunate enough to spend so many hours around such hard-working, motivated, kind people was truly my honour. iv Table of Contents Abstract ............................................................................................................................................ ii Acknowledgements ......................................................................................................................... iv Table of Contents ............................................................................................................................. v List of Figures ............................................................................................................................... viii List of Tables .................................................................................................................................. ix List of Abbreviations ....................................................................................................................... x Chapter 1 Introduction & Literature Review 1.1 Breast Cancer 1.1.1 The Disease At Large .................................................................................... 1 1.1.2 Hereditary Breast Cancer .............................................................................. 1 1.1.3 BRCA1 Structure & Its Relationship to Breast Cancer ................................ 3 1.1.4 BRCA2 Structure & Its Relationship to Breast Cancer ................................ 5 1.1.5 Classical Tumor Suppressor Genes or Otherwise? ....................................... 5 1.2 The Cell Cycle & Control via Checkpoint Activation 1.2.1 The Cell Cycle .............................................................................................. 6 1.2.2 Cell Cycle Checkpoints Maintain Genomic Integrity ................................... 7 1.2.3 The Checkpoint Proteins ............................................................................... 7 1.3 The Cell Cycle Checkpoints 1.3.1 The G1/S-Phase Checkpoint ....................................................................... 11 1.3.2 The G2/M-Phase Checkpoint ...................................................................... 12 1.3.3. The Functions of BRCA1 in the Cell Cycle Checkpoints.......................... 12 1.4 DNA Damage Response 1.4.1 DNA Damaging Agents ............................................................................. 13 1.4.2 DNA Double Stranded Breaks (DSBs) ....................................................... 14 1.4.3 DNA Damage Repair .................................................................................. 15 1.5 DNA DSB Repair Pathways 1.5.1 NHEJ ........................................................................................................... 15 1.5.2 HR ............................................................................................................... 17 1.5.3 SSA ............................................................................................................. 20 v 1.6 BRCA1 & BRCA2 Function in the DNA Damage Response .................................... 20 1.6.1 BRCA1 in DNA Damage Repair ................................................................ 21 1.6.2 BRCA2 in DNA Damage Repair ................................................................ 22 1.7 Microarrays ................................................................................................................. 23 1.7.1 The Components Of A Microarray ............................................................. 23 1.7.2 Normalization ............................................................................................. 25 1.7.3 Hypothesis Testing...................................................................................... 25 1.8 Classification Methods 1.8.1 Unsupervised Classification ........................................................................ 26 1.8.2 Supervised Classification ............................................................................ 27 1.8.3 Recursive Feature Removal ........................................................................ 28 1.9 Hypothesis & Objectives ............................................................................................ 30 Chapter 2 Materials & Methods 2.1 Cell Culture ................................................................................................................. 31 2.2 DNA Damage Induction ............................................................................................. 31 2.3 Cell Cycle Experiments 2.3.1 Determination of IR treatment dose and Recovery Time ........................... 31 2.3.2 G1/S-Phase Checkpoint Activation: Visualization via Flow Cytometry .... 33 2.4 Gene Expression Profiling .......................................................................................... 34 2.5 Data Analysis 2.5.1 Filtering & Normalization ........................................................................... 35 2.5.2 Classification Algorithms ........................................................................... 36 2.5.3 Visual Representation of Data .................................................................... 40 Chapter 3 Results 3.1 Cell Cycle Checkpoint Activation is Present in all Genotypes ................................... 41 3.1.1 Determination of Optimal IR Treatment Dose ........................................... 41 3.1.2 Elucidation of Optimal DNA Damage Recovery Period ...........................
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