A cell-of-origin epigenetic tracer reveals clinically distinct subtypes of high-grade serous ovarian cancer
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RESEARCH
Open Access
A cell-of-origin epigenetic tracer reveals clinically distinct subtypes of high-grade serous ovarian cancer Pietro Lo Riso1†, Carlo Emanuele Villa1†, Gilles Gasparoni2, Andrea Vingiani3,4, Raffaele Luongo1,5,6, Anna Manfredi7, Annemarie Jungmann2, Alessia Bertolotti4, Francesca Borgo1, Annalisa Garbi8, Michela Lupia9, Pasquale Laise1,10, Vivek Das1,11, Giancarlo Pruneri3,4, Giuseppe Viale3,5, Nicoletta Colombo8, Teresa Manzo1, Luigi Nezi1, Ugo Cavallaro9, Davide Cacchiarelli7,12, Jörn Walter2 and Giuseppe Testa1,5*
Abstract Background: High-grade serous ovarian cancer (HGSOC) is a major unmet need in oncology. The remaining uncertainty on its originating tissue has hampered the discovery of molecular oncogenic pathways and the development of effective therapies. Methods: We used an approach based on the retention in tumors of a DNA methylation trace (OriPrint) that distinguishes the two putative tissues of origin of HGSOC, the fimbrial (FI) and ovarian surface epithelia (OSE), to stratify HGSOC by several clustering methods, both linear and non-linear. The identified tumor subtypes (FI-like and OSE-like HGSOC) were investigated at the RNAseq level to stratify an in-house cohort of macrodissected HGSOC FFPE samples to derive overall and disease-free survival and identify specific transcriptional alterations of the two tumor subtypes, both by classical differential expression and weighted correlation network analysis. We translated our strategy to published datasets and verified the co-occurrence of previously described molecular classification of HGSOC. We performed cytokine analysis coupled to immune phenotyping to verify alterations in the immune compartment associated with HGSOC. We identified genes that are both differentially expressed and methylated in the two tumor subtypes, concentrating on PAX8 as a bona fide marker of FI-like HGSOC. Results: We show that: - OriPrint is a robust DNA methylation tracer that exposes the tissue of origin of HGSOC. - The tissue of origin of HGSOC is the main determinant of DNA methylation variance in HGSOC. - The tissue of origin is a prognostic factor for HGSOC patients. - FI-like and OSE-like HGSOC are endowed with specific transcriptional alterations that impact patients’ prognosis. - OSE-like tumors present a more invasive and immunomodulatory phenotype, compatible with its worse prognostic (Continued on next page)
* Correspondence: [email protected]; [email protected] † Pietro Lo Riso and Carlo Emanuele Villa contributed equally to this work. 1 Department of Experimental Oncology, IEO, European Institute of Oncology IRCSS, Milan, Italy 5 Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to
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