Transcriptional and epigenomic profiles of ovarian carcinomas: understanding the regulatory landscape across diseases.
Cell Biology
Final Report Abstract
The overall knowledge about the pathophysiology of ovarian cancer has increased over the last decades, however, the survival outcomes have not dramatically changed since the introduction of platinum-based chemotherapy. While we now better understand and differentiate the major histological subtypes, still very little is known about the underlying disease mechanism especially in the less common, non-serous types. The premise of this project was to identify regulatory elements and signatures across ovarian cancer types by evaluating transcriptional and nonhereditary epigenetic differences in the two compartments of the tumor – epithelium and stroma. One of the major findings related to the project is that not only the cell of origin is crucial for the course of tumorigenesis but that also the cell state of origin has an influence. Epigenetic regulation and expression of estrogen receptor alpha (ESR1), and associated signalling and metabolic pathways seem to be essential when evaluating endometrioid and clear cell carcinomas of the ovary. Especially given their common origination from malignant transformation of endometriumlike epithelial cells. Our data support an epigenetically driven state of origin model that leads to clear cell carcinoma in some contexts, and endometrioid ovarian carcinoma in others. An unexpected result also emerged from compartment specific analysis of all tested histological types. This showed little variance in the DNA methylation and associated gene expression patterns in stromal tissue in and around tumors. Stromal tissue can be infiltrated by various immune cells and the importance of tumor-associated fibroblast has long been reported on. However, in our findings the role those stromal cells play, may less rely on changes in epigenetic and transcriptional regulation. This finding may also imply that targeting of essential stromal components may be universally effective across ovarian carcinoma histotypes and is worthy of further investigation.
Publications
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Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8+ TIL infiltration, and provides no independent prognostic value in endometriosis‐associated ovarian carcinomas. The Journal of Pathology, 256(4), 388-401.
Heinze, Karolin; Nazeran, Tayyebeh M.; Lee, Sandra; Krämer, Pauline; Cairns, Evan S.; Chiu, Derek S.; Leung, Samuel C. Y.; Kang, Eun Young; Meagher, Nicola S.; Kennedy, Catherine J.; Boros, Jessica; Kommoss, Friedrich; Vollert, Hans‐Walter; Heitz, Florian; du Bois, Andreas; Harter, Philipp; Grube, Marcel; Kraemer, Bernhard; Staebler, Annette ... & Anglesio, Michael S.
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The Prognostic Effect of Immune Cell Infiltration Depends on Molecular Subtype in Endometrioid Ovarian Carcinomas. Clinical Cancer Research, 29(17), 3471-3483.
Heinze, Karolin; Cairns, Evan S.; Thornton, Shelby; Harris, Bronwyn; Milne, Katy; Grube, Marcel; Meyer, Charlotte; Karnezis, Anthony N.; Fereday, Sian; Garsed, Dale W.; Leung, Samuel C.Y.; Chiu, Derek S.; Moubarak, Malak; Harter, Philipp; Heitz, Florian; McAlpine, Jessica N.; DeFazio, Anna; Bowtell, David D.L.; Goode, Ellen L. ... & Anglesio, Michael S.
