Computational analysis of DNA repair pathways in breast cancer

Abstract

The integrity of the human genome is constantly challenged by a variety of endogenous and exogenous factors such as ultraviolet radiation and cigarette smoke. To deal with these threats, five major DNA repair pathways, which are principally defined by the type of lesions they repair, have evolved. Defects in these repair pathways predispose individuals to a wide variety of cancers, and at the same time can be therapeutically exploited to target tumours with defective DNA repair.Dysregulation of these repair pathways are also frequently observed in cancer, presenting both opportunities and challenges for cancer therapy: downregulated repair pathways sensitise tumours to DNA-damaging therapies, while upregulated repair pathways cause resistance to these therapies.The primary aim of this thesis is to obtain a comprehensive and in-depth understanding of the mechanisms and roles of these major DNA repair pathways in the context of breast cancer. This will be beneficial for predicting response to radiation and chemotherapy, and for developing novel targeted therapies in this common type of malignancy.By careful literature search and consulting a domain expert, the research presented in this thesis started with a manual curation of six DNA repair pathways, including the five major repair pathways and the Fanconi anaemia pathway that is closely associated with breast cancer susceptibility. Six comprehensive pathway figures were generated, each for one repair pathway, describing in total 195 genes and 138 reactions with direct relevance to DNA repair. Moreover, to facilitate a deep understanding of the repair mechanisms, a detailed description for each reaction was given, importantly including the literature references used for curating the reaction. This curation work enables a mechanistic understanding of how cells respond to DNA damage, and provides a solid foundation for the subsequent computational analyses.In the second study of this PhD research, I performed a personalised pathway analysis to investigate the status of homologous recombination (HR) pathway dysregulation in individual sporadic breast tumours, its association with HR repair deficiency and its impact on tumour characteristics.Specifically, using the expression values of the HR genes curated in the previous study, I calculated an HR score for each tumour that quantifies the extent of HR pathway dysregulation in that tumour.Based on that score, I observed a great diversity in HR dysregulation between and within gene expression-based breast cancer subtypes. And by comparing to two published HR-defect signatures, I found HR pathway dysregulation reflects HR repair deficiency. Furthermore, I uncovered a novel association between HR pathway dysregulation and chromosomal instability (CIN): tumours with more-dysregulated HR tend to have higher CIN. Although CIN has long been considered to be a iii hallmark of most solid tumours, with recent studies highlighting its importance in tumour evolution and drug resistance, the molecular basis of CIN in spora...