Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

Abstract Endometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landsca...

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Autores principales:	Robert L. Hollis, Barbara Stanley, John P. Thomson, Michael Churchman, Ian Croy, Tzyvia Rye, Clare Bartos, Fiona Nussey, Melanie Mackean, Alison M. Meynert, Colin A. Semple, Charlie Gourley, C. Simon Herrington
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/4527ed8d1b464da188a3bb4b385ac1a6
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spelling	oai:doaj.org-article:4527ed8d1b464da188a3bb4b385ac1a62021-12-02T15:56:39ZIntegrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification10.1038/s41698-021-00187-y2397-768Xhttps://doaj.org/article/4527ed8d1b464da188a3bb4b385ac1a62021-06-01T00:00:00Zhttps://doi.org/10.1038/s41698-021-00187-yhttps://doaj.org/toc/2397-768XAbstract Endometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and oestrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathological assessment, revealing dominant clinical and molecular features in the resulting integrated subtypes. We demonstrate significant correlation between subtyping approaches: PR-high (PR + /ER + , PR + /ER−) cases were predominantly CTNNB1-mutant (73.2% vs 18.4%, P < 0.001), while PR-low (PR−/ER + , PR−/ER−) cases displayed higher TP53 mutation frequency (38.8% vs 7.3%, P = 0.001), greater genomic complexity (P = 0.007) and more frequent copy number alterations (P = 0.001). PR-high EnOC patients experience favourable disease-specific survival independent of clinicopathological and genomic features (HR = 0.16, 95% CI 0.04–0.71). TP53 mutation further delineates the outcome of patients with PR-low tumours (HR = 2.56, 95% CI 1.14–5.75). A simple, routinely applicable, classification algorithm utilising immunohistochemistry for PR and p53 recapitulated these subtypes and their survival profiles. The genomic profile of high-risk EnOC subtypes suggests that inhibitors of the MAPK and PI3K-AKT pathways, alongside PARP inhibitors, represent promising candidate agents for improving patient survival. Patients with PR-low TP53-mutant EnOC have the greatest unmet clinical need, while PR-high tumours—which are typically CTNNB1-mutant and TP53 wild-type—experience excellent survival and may represent candidates for trials investigating de-escalation of adjuvant chemotherapy to agents such as endocrine therapy.Robert L. HollisBarbara StanleyJohn P. ThomsonMichael ChurchmanIan CroyTzyvia RyeClare BartosFiona NusseyMelanie MackeanAlison M. MeynertColin A. SempleCharlie GourleyC. Simon HerringtonNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Robert L. Hollis Barbara Stanley John P. Thomson Michael Churchman Ian Croy Tzyvia Rye Clare Bartos Fiona Nussey Melanie Mackean Alison M. Meynert Colin A. Semple Charlie Gourley C. Simon Herrington Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification
description	Abstract Endometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and oestrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathological assessment, revealing dominant clinical and molecular features in the resulting integrated subtypes. We demonstrate significant correlation between subtyping approaches: PR-high (PR + /ER + , PR + /ER−) cases were predominantly CTNNB1-mutant (73.2% vs 18.4%, P < 0.001), while PR-low (PR−/ER + , PR−/ER−) cases displayed higher TP53 mutation frequency (38.8% vs 7.3%, P = 0.001), greater genomic complexity (P = 0.007) and more frequent copy number alterations (P = 0.001). PR-high EnOC patients experience favourable disease-specific survival independent of clinicopathological and genomic features (HR = 0.16, 95% CI 0.04–0.71). TP53 mutation further delineates the outcome of patients with PR-low tumours (HR = 2.56, 95% CI 1.14–5.75). A simple, routinely applicable, classification algorithm utilising immunohistochemistry for PR and p53 recapitulated these subtypes and their survival profiles. The genomic profile of high-risk EnOC subtypes suggests that inhibitors of the MAPK and PI3K-AKT pathways, alongside PARP inhibitors, represent promising candidate agents for improving patient survival. Patients with PR-low TP53-mutant EnOC have the greatest unmet clinical need, while PR-high tumours—which are typically CTNNB1-mutant and TP53 wild-type—experience excellent survival and may represent candidates for trials investigating de-escalation of adjuvant chemotherapy to agents such as endocrine therapy.
format	article
author	Robert L. Hollis Barbara Stanley John P. Thomson Michael Churchman Ian Croy Tzyvia Rye Clare Bartos Fiona Nussey Melanie Mackean Alison M. Meynert Colin A. Semple Charlie Gourley C. Simon Herrington
author_facet	Robert L. Hollis Barbara Stanley John P. Thomson Michael Churchman Ian Croy Tzyvia Rye Clare Bartos Fiona Nussey Melanie Mackean Alison M. Meynert Colin A. Semple Charlie Gourley C. Simon Herrington
author_sort	Robert L. Hollis
title	Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification
title_short	Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification
title_full	Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification
title_fullStr	Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification
title_full_unstemmed	Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification
title_sort	integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4527ed8d1b464da188a3bb4b385ac1a6
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Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

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