Abstract
Both clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (ENOC) are associated with ovarian endometriotic cysts, which is believed to be the precursor lesion of these cancers. Women with endometriotic cysts have up to a 3-fold increased risk of developing CCOC and ENOC. It is perplexing that these two clinically distinct histotypes of ovarian cancer arise from the same precursor lesion. We have performed whole-genome sequencing of ovarian cancer histotypes and found that while some genomic features are more common to one histotype than the other, there is not a single feature that is unique to either histotype. Lacking genomic evidence that could explain the differences between these histotypes, we hypothesized that these cancers arise from distinct cells of origin within endometrial tissue, and the cellular context accounts for their differences. We performed global proteomic analysis of ovarian cancer histotypes and identified CTH as a marker for CCOC. Upon examination of normal Müllerian tissues, we found that CTH is highly expressed in the ciliated cells of endometrium (both ectopic endometrium and endometriosis) and of the fallopian tube, with very little expression in the secretory cells of these tissues. We also find that other ciliated cell markers are expressed in CCOC, whereas endometrial secretory cell markers are expressed in ENOC. We propose a new model of CCOC and ENOC histogenesis wherein ENOC is derived from cells of secretory cell lineage whereas CCOC is derived from, or shares similarities to, cells of ciliated cell lineage. There remain, however, many unanswered questions. For example, while CCOC and ENOC occur at roughly equal prevalence, ciliated cells of the endometrium are rare compared to secretory cells. Cells in the endometriotic cyst are exposed to factors such as inflammation and reactive oxygen species, which could influence differentiation of endometrial progenitor cells into the secretory or ciliated cell lineage. To test factors that promote ciliated cell differentiation in normal endometrium, we treated organoid cultures of normal endometrium with IL-6 and Notch pathway modulators. We propose that ovarian cancer histotypes arise from different cells of origin and that the biology of the normal cells will be partly responsible for determining the phenotype of the cancers.
Citation Format: Dawn Cochrane, Basile Tessier-Cloutier, Katherine Lawrence, Tayyebeh Nazeran, Anthony Karnezis, Clara Salamanca, Timothy Lee, Angela Cheng, Jessica McAlpine, Lien Hoang, Blake Gilks, David Huntsman. The origins of endometriosis-associated cancers. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B39.
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