Defining the molecular evolution of extrauterine high grade serous carcinoma

AbstractObjectiveHigh 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; se...

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Published in:	Gynecologic oncology Vol. 155; no. 2; pp. 305 - 317
Main Authors:	Beirne, James P, McArt, Darragh G, Roddy, Aideen, McDermott, Clara, Ferris, Jennifer, Buckley, Niamh E, Coulter, Paula, McCabe, Nuala, Eddie, Sharon L, Dunne, Philip D, O'Reilly, Paul, Gilmore, Alan, Feeney, Laura, Ewing, David Lyons, Drapkin, Ronny I, Salto-Tellez, Manuel, Kennedy, Richard D, Harley, Ian J.G, McCluggage, W. Glenn, Mullan, Paul B
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-11-2019
Subjects:	Cell Line, Tumor Cell Transformation, Neoplastic - pathology Cystadenocarcinoma, Serous - genetics Cystadenocarcinoma, Serous - mortality Cystadenocarcinoma, Serous - pathology Disease-Free Survival Fallopian Tubes - pathology Female Gene Expression Profiling Genes, Neoplasm - genetics Hematology, Oncology, and Palliative Medicine Humans Molecular profiling Obstetrics and Gynecology Ovarian cancer Ovarian Neoplasms - genetics Ovarian Neoplasms - mortality Ovarian Neoplasms - pathology Pathogenesis Up-Regulation - physiology Pathogenesis Molecular profiling Ovarian cancer
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Summary:	AbstractObjectiveHigh 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. MethodsSix 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. ResultsThe 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. ConclusionThis 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.
ISSN:	0090-8258 1095-6859
DOI:	10.1016/j.ygyno.2019.08.029