A Systems Biology Approach to Characterizing Gene Fusion Pathways in Cancer

Thesis (Master's)--University of Washington, 2017-08Gene fusions have long been known to drive cancer. Initial discovery of gene fusions was opportunistic, and functional assessment was done individually and experimentally. There is no comprehensive systems biology approach to understanding the impact of gene fusions on the signaling networks within tumor cells. An integrative computational approach was taken to achieve a better understanding of gene fusions and their complex influence on pathways and interaction networks in the context of lung cancer. Using well-studied fusions and publicly available gene expression data, the effect of fusion events on the expression pattern of gene networks revealed unique differences in tumors with gene fusions, tumors without gene fusions, and normal samples. This approach identifies gene expression signatures associated with specific fusions, and provides a model for integrating experimental and pathway data to better understand the biology of a fusion genes and their roles in oncogenesis

The Prosigna gene expression assay and responsiveness to adjuvant cyclophosphamide-based chemotherapy in premenopausal high-risk patients with breast cancer

Background: The PAM50-based (Prosigna) risk of recurrence (ROR) score and intrinsic subtypes are prognostic for women with high-risk breast cancer. We investigate the predictive ability of Prosigna regarding the effectiveness of cyclophosphamide-based adjuvant chemotherapy in premenopausal patients with high-risk breast cancer. Methods: Prosigna assays were performed on the NanoString platform in tumors from participants in Danish Breast Cancer Group (DBCG) 77B, a four-arm trial that randomized premenopausal women with high-risk early breast cancer to no systemic treatment, levamisole, oral cyclophosphamide (C) or cyclophosphamide, methotrexate and fluorouracil (CMF). Results: In total, this retrospective analysis included 460 women (40% of the 1146 randomized patients). The continuous Prosigna ROR score was prognostic in the no systemic treatment group (unadjusted P < 0.001 for disease-free survival (DFS), P = 0.001 for overall survival (OS)). No statistically significant interaction of continuous ROR score and treatment on DFS and OS was found. A highly significant association was observed between intrinsic subtypes and C/CMF treatment for DFS (Pinteraction = 0.003 unadjusted, P = 0.001 adjusted) and OS (Pinteraction = 0.04). In the adjusted analysis treatment with C/CMF was associated with a reduced risk of DFS events in patients with basal-like (hazard ratio (HR) 0.14; 95% CI 0.06; 0.32) and luminal B (HR 0.48; 95% CI 0.27; 0.84) subtypes but not in patients with Human epidermal growth factor receptor-enriched (HR 1.05; 95% CI 0.56; 1.95) or luminal A (HR 0.61; 95% CI 0.32; 1.16) subtypes. Conclusion: The Prosigna ROR score and intrinsic subtypes were prognostic in high-risk premenopausal patients with breast cancer, and intrinsic subtypes identify high-risk patients with or without major benefit from adjuvant C/CMF treatment.Medicine, Faculty ofNon UBCPathology and Laboratory Medicine, Department ofReviewedFacult

Additional file 1: of The Prosigna gene expression assay and responsiveness to adjuvant cyclophosphamide-based chemotherapy in premenopausal high-risk patients with breast cancer

Figure S1. Consort flow diagram. (PDF 234 kb