Molecular characterization of high grade serous ovarian cancer with a focus on peritoneal tumor spread aimed to identify prognostic markers

Ovarian cancer is one the most deadly malignancies in women with a five year survival of only 40%. Despite the fact that ovarian cancer, even the most common subtype of high grade serous ovarian cancer (HGSC), is a very heterogeneous disease most patients are treated with standard therapy consisting of cytoreductive surgery and platinum-based chemotherapy. Molecular characteristics are usually not considered. In this PhD thesis I evaluated potential molecular prognostic markers. Since in ovarian cancer peritoneal tumor dissemination is more frequent and important than distant metastases, the focus of this thesis was the characterization of two macroscopically distinct types of peritoneal spread, miliary (i.e. many small seeds) versus non-miliary (i.e. no/few larger implants), which we introduced in a publication arising from this thesis. In the first study of this thesis comprising 200 epithelial ovarian cancer patients, tumor infiltration of cytotoxic T cells (CD8) was associated with prolonged overall survival; this effect seemed more important in patients with residual tumor. Patients with very low tumor cell proliferation (less than 5% of Ki67+ tumor cells) had a shorter overall survival, presumably due to worse response to chemotherapy. In another project of this thesis we performed a comprehensive analysis of tumor cells from different peritoneal and ovarian sites and ascites from 25 HGSC patients and determined differences between the miliary and non-miliary tumor spread. Integrative analyses of RNA-sequencing of large and small (