High EMSY expression defines a BRCA-like subgroup of high-grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum.

Autor: Hollis RL; Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Churchman M; Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Michie CO; Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Rye T; Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Knight L; Almac Diagnostics, Craigavon, United Kingdom., McCavigan A; Almac Diagnostics, Craigavon, United Kingdom., Perren T; St. James's Institute of Oncology, St. James's University Hospital, Leeds, United Kingdom., Williams ARW; Department of Pathology, University of Edinburgh, Edinburgh, United Kingdom., McCluggage WG; Center for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom.; Department of Pathology, Belfast Health and Social Care Trust, Belfast, United Kingdom., Kaplan RS; Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom., Jayson GC; Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester, United Kingdom., Oza A; Cancer Clinical Research Unit, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada., Harkin DP; Almac Diagnostics, Craigavon, United Kingdom.; Center for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom., Herrington CS; Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.; Department of Pathology, University of Edinburgh, Edinburgh, United Kingdom.; Division of Pathology, Centre for Comparative Pathology, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom., Kennedy R; Almac Diagnostics, Craigavon, United Kingdom.; Center for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, United Kingdom., Gourley C; Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Jazyk: angličtina
Zdroj: Cancer [Cancer] 2019 Aug 15; Vol. 125 (16), pp. 2772-2781. Date of Electronic Publication: 2019 Jun 02.
DOI: 10.1002/cncr.32079
Abstrakt: Background: Approximately half of high-grade serous ovarian carcinomas (HGSOCs) demonstrate homologous recombination repair (HR) pathway defects, resulting in a distinct clinical phenotype comprising hypersensitivity to platinum, superior clinical outcome, and greater sensitivity to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. EMSY, which is known to be amplified in breast and ovarian cancers, encodes a protein reported to bind and inactivate BRCA2. Thus, EMSY overexpression may mimic BRCA2 mutation, resulting in HR deficiency. However, to our knowledge, the phenotypic consequences of EMSY overexpression in HGSOC patients has not been explored.
Methods: Here we investigate the impact of EMSY expression on clinical outcome and sensitivity to platinum-based chemotherapy using available data from transcriptomically characterized HGSOC cohorts.
Results: High EMSY expression was associated with better clinical outcome in a cohort of 265 patients with HGSOC from Edinburgh (overall survival multivariable hazard ratio, 0.58 [95% CI, 0.38-0.88; P = .011] and progression-free survival multivariable hazard ratio, 0.62 [95% CI, 0.40-0.96; P = .030]). Superior outcome also was demonstrated in the Medical Research Council ICON7 clinical trial and multiple publicly available data sets. Patients within the Edinburgh cohort who had high EMSY expression were found to demonstrate greater rates of complete response to multiple platinum-containing chemotherapy regimens (radiological complete response rate of 44.4% vs 12.5% at second exposure; P = .035) and corresponding prolonged time to disease progression (median, 151.5 days vs 60.5 days after third platinum exposure; P = .004).
Conclusions: Patients with HGSOCs demonstrating high EMSY expression appear to experience prolonged survival and greater platinum sensitivity, reminiscent of BRCA-mutant cases. These data are consistent with the notion that EMSY overexpression may render HGSOCs HR deficient.
(© 2019 University of Edinburgh. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)
Databáze: MEDLINE
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