Abstract B39: The origins of endometriosis-associated cancers
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".