Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

Robb Hollis; Barbara Stanley; John P. Thomson; Michael Churchman; Ian Croy; Tzyvia Rye; Clare  Bartos; Fiona Nussey; Melanie J Mackean; Alison M Meynert; Colin A Semple; Charlie Gourley; C Simon Herrington

doi:.org/10.1038/s41698-021-00187

Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

Robb Hollis, Barbara Stanley, John P. Thomson, Michael Churchman, Ian Croy, Tzyvia Rye, Clare Bartos, Fiona Nussey, Melanie J Mackean, Alison M Meynert, Colin A Semple, Charlie Gourley, C Simon Herrington

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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 estrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathology 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 tumors (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 tumors – 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.

Original language	English
Journal	npj Precision Oncology
Early online date	2 Jun 2021
DOIs	https://doi.org/.org/10.1038/s41698-021-00187
Publication status	E-pub ahead of print - 2 Jun 2021

Keywords / Materials (for Non-textual outputs)

ovarian cancer
endometrioid
genomics
progesterone receptor
estrogen receptor
stratification

Access to Document

.org/10.1038/s41698-021-00187

Integrated molecular characterisation of endometrioid ovarian_publishers pdfFinal published version, 1.41 MB

Bioinformatics Analysis Core
Alison Meynert (Manager), Murray Wham (Other), Kevin Donnelly (Other), Mihail Halachev (Other), Hannes Becher (Other), Philippe Gautier (Other) & Graeme Grimes (Other)
Deanery of Molecular, Genetic and Population Health Sciences
Facility/equipment: Facility

Cite this

Hollis, R., Stanley, B., Thomson, J. P., Churchman, M., Croy, I., Rye, T., Bartos, C., Nussey, F., Mackean, M. J., Meynert, A. M., Semple, C. A., Gourley, C., & Herrington, C. S. (2021). Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification. npj Precision Oncology . Advance online publication. https://doi.org/.org/10.1038/s41698-021-00187

@article{61a52830992b4c99989e20acfd423263,

title = "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 landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and estrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathology 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 tumors (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 tumors – 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.",

keywords = "ovarian cancer, endometrioid, genomics, progesterone receptor, estrogen receptor, stratification",

author = "Robb Hollis and Barbara Stanley and Thomson, {John P.} and Michael Churchman and Ian Croy and Tzyvia Rye and Clare Bartos and Fiona Nussey and Mackean, {Melanie J} and Meynert, {Alison M} and Semple, {Colin A} and Charlie Gourley and Herrington, {C Simon}",

year = "2021",

month = jun,

day = "2",

doi = ".org/10.1038/s41698-021-00187",

language = "English",

journal = "npj Precision Oncology ",

issn = "2397-768X",

publisher = "Springer Nature",

}

TY - JOUR

T1 - Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

AU - Hollis, Robb

AU - Stanley, Barbara

AU - Thomson, John P.

AU - Churchman, Michael

AU - Croy, Ian

AU - Rye, Tzyvia

AU - Bartos, Clare

AU - Nussey, Fiona

AU - Mackean, Melanie J

AU - Meynert, Alison M

AU - Semple, Colin A

AU - Gourley, Charlie

AU - Herrington, C Simon

PY - 2021/6/2

Y1 - 2021/6/2

N2 - 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 estrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathology 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 tumors (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 tumors – 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.

AB - 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 estrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathology 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 tumors (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 tumors – 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.

KW - ovarian cancer

KW - endometrioid

KW - genomics

KW - progesterone receptor

KW - estrogen receptor

KW - stratification

U2 - .org/10.1038/s41698-021-00187

DO - .org/10.1038/s41698-021-00187

M3 - Article

SN - 2397-768X

JO - npj Precision Oncology

JF - npj Precision Oncology

ER -

Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Equipment

Bioinformatics Analysis Core

Cite this