Molecular epidemiology studies on risk factors for breast cancer and disease aggressiveness

Abstract

Breast cancer is a heterogeneous disease. Aggressive subtypes are characterized by faster growth rates, increased capability to invade and metastasize, leading to poorer clinical outcomes. In this thesis, we use a molecular epidemiology approach to investigate the association between risk factors and aggressive breast cancer defined by tumor characteristics, intrinsic subtypes, mode of detection, and survival. Using a variety of methods, we analyzed data from well-characterized breast cancer cohorts in Sweden, genome-wide association studies, and gene expression profiling of tumors.

In Paper I, we found that breast cancer genetic load, defined by rare deleterious variants in 31 breast cancer genes, and unlike common variants, is positively associated with unfavorable tumor characteristics, patient survival, and mode of detection. In Paper II, we observed that women with low breast cancer risk defined by the Tyrer-Cuzick risk score were more likely to develop aggressive tumors. We computed a low-risk gene expression profile that was consistently associated with worse prognosis. In addition, our analysis showed that increased proliferation rather than estrogen status underlie this association. In Paper III, we examined gene expression profiles in a subset of aggressive breast cancer tumors, known as interval cancers. By taking mammographic density and intrinsic PAM50 subtypes into account, we found an interval cancer gene expression profile to be associated with immune subtypes in breast cancer, particularly those involving interferon response. In Paper IV, we show that breast cancer has a shared immune-related genetic component with celiac disease, an autoimmune disorder. In consistency with previous epidemiological findings, we found that a higher genetic load for celiac disease was associated with lower breast cancer risk.

Overall, this thesis aims to provide scientific evidence towards a better understanding of the factors underlying the development of aggressive breast cancers that could shed light on the design of better preventative strategies aimed at lowering disease mortality.