James P Beirne1, Darragh G McArt2, Aideen Roddy2, Clara McDermott3, Jennifer Ferris3, Niamh E Buckley4, Paula Coulter5, Nuala McCabe3, Sharon L Eddie3, Philip D Dunne6, Paul O'Reilly2, Alan Gilmore2, Laura Feeney7, David Lyons Ewing3, Ronny I Drapkin8, Manuel Salto-Tellez9, Richard D Kennedy7, Ian J G Harley10, W Glenn McCluggage11, Paul B Mullan3. 1. Ovarian Cancer Research Programme, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, United Kingdom of Great Britain and Northern Ireland; Northern Ireland Centre for Gynaecological Cancer, Belfast Health and Social Care Trust, Belfast, United Kingdom of Great Britain and Northern Ireland. Electronic address: j.beirne@qub.ac.uk. 2. Department of Cancer Bioinformatics, Queen's University, Belfast, United Kingdom of Great Britain and Northern Ireland. 3. Ovarian Cancer Research Programme, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, United Kingdom of Great Britain and Northern Ireland. 4. Ovarian Cancer Research Programme, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, United Kingdom of Great Britain and Northern Ireland; School of Pharmacy, Queen's University, Belfast, United Kingdom of Great Britain and Northern Ireland. 5. School of Pharmacy, Queen's University, Belfast, United Kingdom of Great Britain and Northern Ireland. 6. Department of Translational Cancer Genomics, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, United Kingdom of Great Britain and Northern Ireland. 7. Ovarian Cancer Research Programme, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, United Kingdom of Great Britain and Northern Ireland; Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, United Kingdom of Great Britain and Northern Ireland. 8. Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 9. Ovarian Cancer Research Programme, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, United Kingdom of Great Britain and Northern Ireland; Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queens University, Belfast, United Kingdom of Great Britain and Northern Ireland. 10. Ovarian Cancer Research Programme, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, United Kingdom of Great Britain and Northern Ireland; Northern Ireland Centre for Gynaecological Cancer, Belfast Health and Social Care Trust, Belfast, United Kingdom of Great Britain and Northern Ireland. 11. Ovarian Cancer Research Programme, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, United Kingdom of Great Britain and Northern Ireland; Northern Ireland Centre for Gynaecological Cancer, Belfast Health and Social Care Trust, Belfast, United Kingdom of Great Britain and Northern Ireland; Department of Pathology, Belfast Health and Social Care Trust, Belfast, United Kingdom of Great Britain and Northern Ireland.
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.
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.
Authors: James P Beirne; Alan Gilmore; Caitríona E McInerney; Aideen Roddy; W Glenn McCluggage; Ian J G Harley; M Abdullah Alvi; Kevin M Prise; Darragh G McArt; Paul B Mullan Journal: Comput Struct Biotechnol J Date: 2022-06-17 Impact factor: 6.155
Authors: G Tomasch; M Lemmerer; S Oswald; S Uranitsch; C Schauer; A-M Schütz; B Bliem; A Berger; P F J Lang; G Rosanelli; F Ronaghi; J Tschmelitsch; S F Lax; S Uranues; K Tamussino Journal: Br J Surg Date: 2020-03-04 Impact factor: 6.939