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Theses and Dissertations

Germline DNA variants as determinants for breast cancer predisposition and prognosis Open Access


Other title
DNA repair
Gene-gene interaction
Association study
Copy number variations
Breast cancer
Low-penetrance variants
Copy neutral-loss of heterozygosity
Logic regression
Logistic regression
Body mass index
Genome-wide association study
Type of item
Degree grantor
University of Alberta
Author or creator
Sapkota, Yadav
Supervisor and department
Damaraju, Sambasivarao (Laboratory Medicine and Pathology)
Lai, Raymond (Laboratory Medicine and Pathology)
Examining committee member and department
Cass, Carol E (Oncology)
Elliott, John (Medical Microbiology and Immunology)
Dumontet, Charles (Université de Lyon, France)
Yasui, Yutaka (Public Health)
Mackey, John R (Oncology)
Medical Sciences- Laboratory Medicine and Pathology

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Breast cancer is the most common cancer among women in the developed world. The disease results from the combined effects of genetic, environmental, reproductive and lifestyle risk factors. Germline DNA variations identified thus far by linkage and genome-wide association studies (GWASs) account for less than one-third of variability in breast cancer predisposition, suggesting that more variants exist. Furthermore, despite advancements in breast cancer therapies guided by tumor-based prognostic and predictive factors, approximately 30% of breast cancer patients who receive standard guideline-based therapies experience disease recurrence within ten years post diagnosis. Consequently, there is a clear need of additional markers for disease risk assessment as well as markers of potential prognostic values to better guide treatment modalities. In this thesis, I adopted a comprehensive approach utilizing single nucleotide polymorphisms (SNPs) and germline copy number aberrations (copy number variations (CNVs) and copy neutral-loss of heterozygosities (CN-LOHs)) to identify markers for breast cancer susceptibility and disease prognosis. I used a multi-stage association study design that included cumulative sample sizes of 2,795 invasive breast cancer cases and 4,505 healthy controls of predominantly Caucasian in origin selected from Alberta, Canada. I identified a novel breast cancer susceptibility locus on chromosome 4q31.22 showing a strong statistical significance for overall breast cancer (per allele odds ratio=1.28 and P=1.5 x 10-7), adjusted for body mass index (BMI). I also independently confirmed one literature reported association on chromosome 8q24.21-rs13281615 (BMI adjusted-P<3.1 x 10-3) with breast cancer prognosis. Since epistatic interactions have been hypothesized to capture additional heritability for breast cancer, I extended my studies and identified interactions involving two SNPs and an interaction involving four SNPs. These interactions were from the single-locus effects with weak statistical significance in GWAS and/or candidate-gene studies. Finally, I identified germline CNAs as potential prognostic markers for the predominant luminal A breast cancers (up to 70% of total cases diagnosed), which recur despite the good prognosis. Germline DNA-based markers for disease predisposition and prognosis is an area in its infancy and clearly more work is warranted to substantiate and extend the reported findings to enable eventual translation of research to clinical applications.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
 Sapkota Y, Mackey JR, Lai R, Franco-Villalobos C, Lupichuk S, Robson PJ, Kopciuk K, Cass CE, Yasui Y, Damaraju S. Assessing SNP-SNP interactions among DNA repair, modification and metabolism related pathway genes in breast cancer susceptibility. PLoS One. 2013 (In Press). Sapkota Y, Yasui Y, Lai R, Sridharan M, Robson PJ, Cass CE, Mackey JR, Damaraju S. Identification of a breast cancer susceptibility locus at 4q31.22 using a genome-wide association paradigm. PLoS One. 2013 (In Press). Sapkota Y, Ghosh S, Lai R, Cass CE, Mackey JR, Yasui Y, Damaraju S. (2013) Germline copy number aberraions identified as potential prognostic factors for breast cancer recurrence. PLoS ONE 8(1): e5385. Sapkota Y, Robson P, Lai R, Cass CE, Mackey JR, Damaraju S. (2012) A two-stage association study identifies methyl-CpG-binding domain protein 2 gene polymorphisms as candidates for breast cancer susceptibility. Eur J Hum Genet 20: 682-689.

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