Defining the molecular evolution of extrauterine high grade serous carcinoma

James P Beirne, Darragh G McArt, Aideen Roddy, Clara McDermott, Jennifer Ferris, Niamh E Buckley, Paula Coulter, Nuala McCabe, Sharon L Eddie, Philip D Dunne, Paul O'Reilly, Alan Gilmore, Laura Feeney, David Lyons Ewing, Ronny I Drapkin, Manuel Salto-Tellez, Richard D Kennedy, Ian J G Harley, W Glenn McCluggage, Paul B Mullan

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE: High grade serous carcinoma (HGSC) is the most common and most aggressive, subtype of epithelial ovarian cancer. It presents as advanced stage disease with poor prognosis. Recent pathological evidence strongly suggests HGSC arises from the fallopian tube via the precursor lesion; serous tubal intraepithelial carcinoma (STIC). However, further definition of the molecular evolution of HGSC has major implications for both clinical management and research. This study aims to more clearly define the molecular pathogenesis of HGSC.

METHODS: Six cases of HGSC were identified at the Northern Ireland Gynaecological Cancer Centre (NIGCC) that each contained ovarian HGSC (HGSC), omental HGSC (OMT), STIC, normal fallopian tube epithelium (FTE) and normal ovarian surface epithelium (OSE). The relevant formalin-fixed paraffin embedded (FFPE) tissue samples were retrieved from the pathology archive via the Northern Ireland Biobank following attaining ethical approval (NIB11:005). Full microarray-based gene expression profiling was performed on the cohort. The resulting data was analysed bioinformatically and the results were validated in a HGSC-specific in-vitro model.

RESULTS: The carcinogenesis of HGSC was investigated and showed the molecular profile of HGSC to be more closely related to normal FTE than OSE. STIC lesions also clustered closely with HGSC, indicating a common molecular origin.

CONCLUSION: This study provides strong evidence suggesting that extrauterine HGSC arises from the fimbria of the distal fallopian tube. Furthermore, several potential pathways were identified which could be targeted by novel therapies for HGSC. These findings have significant translational relevance for both primary prevention and clinical management of the disease.

Original languageEnglish
Pages (from-to)305-317
Number of pages13
JournalGynecologic Oncology
Volume155
Issue number2
Early online date04 Sep 2019
DOIs
Publication statusPublished - 04 Sep 2019

Bibliographical note

Copyright © 2019 Elsevier Inc. All rights reserved.

Keywords

  • Molecular profiling; Ovarian cancer; Pathogenesis

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  • Student Theses

    The development of a blood-based test of DNA methylation for the earlier detection of high-grade serous tubo-ovarian cancer

    Author: Feeney, L., Jul 2020

    Supervisor: Mullan, P. (Supervisor), Salto-Tellez, M. (Supervisor) & Beirne, J. P. (Supervisor)

    Student thesis: Doctoral ThesisDoctor of Philosophy

    Cite this

    Beirne, J. P., McArt, D. G., Roddy, A., McDermott, C., Ferris, J., Buckley, N. E., Coulter, P., McCabe, N., Eddie, S. L., Dunne, P. D., O'Reilly, P., Gilmore, A., Feeney, L., Ewing, D. L., Drapkin, R. I., Salto-Tellez, M., Kennedy, R. D., Harley, I. J. G., McCluggage, W. G., & Mullan, P. B. (2019). Defining the molecular evolution of extrauterine high grade serous carcinoma. Gynecologic Oncology, 155(2), 305-317. https://doi.org/10.1016/j.ygyno.2019.08.029