The developmental origins of high grade serous ovarian cancer.

Abstract

e17063 Background: The still persistent uncertainty in the identification of the cell of origin of high grade serous ovarian cancer (HGSOC), with two candidate originating tissues identified in the distal tract of the fallopian tube (FI) and the surface epithelium of the ovary (OSE), has hampered the identification of clinically relevant molecular features for this disease to be targeted for therapy. This resulted in only a negligible improvement in patient’s care since the introduction of carboplatin-based treatments. Methods: To solve this issue, here we show an innovative method based on the identification of a cell of origin-specific DNA methylation print (OriPrint) that allows the reliable stratification of human primary HGSOC in FI and OSE-originated tumors. Results: We show that this approach is robust to alternative clustering methods and can discriminate tumors derived from each of the two origins across different datasets. Also, we translated these findings on a well-characterized retrospective cohort, showing that the cell of origin significantly impacts patient’s prognosis. Finally, through RNAseq, we unveil origin-specific transcriptional networks compatible with the differential impact on patient’s survival, mainly involved in inflammatory response and cell survival, movement and signaling. Conclusions: Our approach proves for the first time in human primary samples that both origins can give rise to HGSOC, paving the way to a finer molecular characterization of this disease and to the development of more effective therapeutic regimens for improved care for patients.