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

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.

List of scientific papers

I. Jingmei Li, Emilio Ugalde-Morales, Wei Xiong Wen, Brennan Decker, Mikael Eriksson, Astrid Torstensson, Helene Nordahl Christensen, Alison M. Dunning, Jamie Allen, Craig Luccarini, Karen A. Pooley, Jacques Simard, Leila Dorling, Douglas F. Easton, Soo Hwang Teo, Per Hall, Kamila Czene. Differential burden of rare and common variants on tumor characteristics, survival, and mode of detection in breast cancer. Cancer Research. 2018 Nov 1;78(21):6329-6338.
https://doi.org/10.1158/0008-5472.CAN-18-1018

II. Emilio Ugalde-Morales, Felix Grassmann, Keith Humphreys, Jingmei Li, Mikael Eriksson, Nicholas P. Tobin, Åke Borg, Johan Vallon-Christersson, Per Hall, Kamila Czene. Association between breast cancer risk and disease aggressiveness: characterizing underlying gene expression patterns. [Accepted]
https://doi.org/10.1002/ijc.33270

III. Emilio Ugalde-Morales, Felix Grassmann, Keith Humphreys, Jingmei Li, Nicholas P. Tobin, Jonas Bergh, Åke Borg, Linda Sofie Lindström, Johan Vallon-Christersson, Per Hall, Kamila Czene. Interval breast cancer gene expression profile is associated with immune subtypes. [Manuscript]

IV. Emilio Ugalde-Morales, Jingmei Li, Keith Humphreys, Jonas F. Ludvigsson, Haomin Yang, Per Hall, Kamila Czene. Common shared genetic variation behind decreased risk of breast cancer in celiac disease. Scientific Reports. 2017; 7: 5942.
https://doi.org/10.1038/s41598-017-06287-9