Genetic Drivers and Clonal Heterogeneity of Lethal Breast Cancer

Breast cancer remains the second leading cause of cancer related death in women in the United States. Despite great advances in both early detection and treatment for primary breast cancer, 40,000 women die of breast cancer each year. Metastasis, namely when cancer spreads beyond the original site, is the main cause of breast cancer mortality. A lack of understanding of metastasis continues to thwart prevention and treatment of lethal breast cancer. Genome-wide comparisons of both the genetic composition (DNA) and expression (RNA) of primaries and metastases in multiple patients could help elucidate the underlying mechanisms causing breast cancer metastasis. In this thesis, next-generation sequencing was performed on a dataset of patients with both primary breast cancers and multiple distant metastases. DNA and RNA sequencing were performed on 16 breast cancer patients with 86 matched tumors (primary + multiple metastases). We confirmed previous work that the primary cancer is extremely diverse with multiple distinct populations of cells. Comparisons of these populations in the original tumor and the distant metastases demonstrates that in some instances, it is likely that a clump of cells containing multiple different genetic populations together leave the breast and seed distant sites. Finally, a novel computational method integrating RNA gene expression, somatic copy number alterations, and somatic mutations identifies drivers of breast cancer in matched primaries, metastases, and in the broader context of breast cancer as a whole. We show that a majority of the drivers of breast cancer are established in the original cancer and maintained in metastasis. This work asks clinically impactful questions of the biology of breast cancer metastasis through multiple genomic approaches. The body of knowledge presented here demonstrates that the complex heterogeneity in primary breast cancer is maintained throughout metastasis while also proving that the majority of genetic drivers in metastasis are established in the original breast cancer. Finally, we demonstrate that common mechanisms driving breast cancer are utilized across the previously-described molecular and clinical subgroups of breast cancer, offering novel, tractable therapeutic targets. These findings contribute significantly to our understanding of the genetic diversity and drivers of lethal breast cancer metastasis.Doctor of Philosoph