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

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 d...

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Autores principales: Hollis, Robert L., Churchman, Michael, Michie, Caroline O., Rye, Tzyvia, Knight, Laura, McCavigan, Andrena, Perren, Timothy, Williams, Alistair R. W., McCluggage, W. Glenn, Kaplan, Richard S., Jayson, Gordon C., Oza, Amit, Harkin, D. Paul, Herrington, C. Simon, Kennedy, Richard, Gourley, Charlie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771827/
https://www.ncbi.nlm.nih.gov/pubmed/31154673
http://dx.doi.org/10.1002/cncr.32079
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author Hollis, Robert L.
Churchman, Michael
Michie, Caroline O.
Rye, Tzyvia
Knight, Laura
McCavigan, Andrena
Perren, Timothy
Williams, Alistair R. W.
McCluggage, W. Glenn
Kaplan, Richard S.
Jayson, Gordon C.
Oza, Amit
Harkin, D. Paul
Herrington, C. Simon
Kennedy, Richard
Gourley, Charlie
author_facet Hollis, Robert L.
Churchman, Michael
Michie, Caroline O.
Rye, Tzyvia
Knight, Laura
McCavigan, Andrena
Perren, Timothy
Williams, Alistair R. W.
McCluggage, W. Glenn
Kaplan, Richard S.
Jayson, Gordon C.
Oza, Amit
Harkin, D. Paul
Herrington, C. Simon
Kennedy, Richard
Gourley, Charlie
author_sort Hollis, Robert L.
collection PubMed
description 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.
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spelling pubmed-67718272019-10-07 High EMSY expression defines a BRCA‐like subgroup of high‐grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum Hollis, Robert L. Churchman, Michael Michie, Caroline O. Rye, Tzyvia Knight, Laura McCavigan, Andrena Perren, Timothy Williams, Alistair R. W. McCluggage, W. Glenn Kaplan, Richard S. Jayson, Gordon C. Oza, Amit Harkin, D. Paul Herrington, C. Simon Kennedy, Richard Gourley, Charlie Cancer Original Articles 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. John Wiley and Sons Inc. 2019-06-02 2019-08-15 /pmc/articles/PMC6771827/ /pubmed/31154673 http://dx.doi.org/10.1002/cncr.32079 Text en © 2019 University of Edinburgh. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Hollis, Robert L.
Churchman, Michael
Michie, Caroline O.
Rye, Tzyvia
Knight, Laura
McCavigan, Andrena
Perren, Timothy
Williams, Alistair R. W.
McCluggage, W. Glenn
Kaplan, Richard S.
Jayson, Gordon C.
Oza, Amit
Harkin, D. Paul
Herrington, C. Simon
Kennedy, Richard
Gourley, Charlie
High EMSY expression defines a BRCA‐like subgroup of high‐grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum
title High EMSY expression defines a BRCA‐like subgroup of high‐grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum
title_full High EMSY expression defines a BRCA‐like subgroup of high‐grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum
title_fullStr High EMSY expression defines a BRCA‐like subgroup of high‐grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum
title_full_unstemmed High EMSY expression defines a BRCA‐like subgroup of high‐grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum
title_short High EMSY expression defines a BRCA‐like subgroup of high‐grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum
title_sort high emsy expression defines a brca‐like subgroup of high‐grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771827/
https://www.ncbi.nlm.nih.gov/pubmed/31154673
http://dx.doi.org/10.1002/cncr.32079
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