Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome

John Thomson; Robb Hollis; Juliette van Baal; Narthana Ilenkovan; Michael Churchman; Koen van de Vijver; Alison M Meynert; Clare  Bartos; Tzyvia Rye; Ian Croy; Patricia Diana; Mignon van Gent; Helen Creedon; Rachel Nirsimloo; Fiona Nussey; Christianne Lok; C Simon Herrington; Charlie Gourley

doi:10.1016/j.ygyno.2023.04.011

Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome

John Thomson, Robb Hollis, Juliette van Baal, Narthana Ilenkovan, Michael Churchman, Koen van de Vijver, Alison M Meynert, Clare Bartos, Tzyvia Rye, Ian Croy, Patricia Diana, Mignon van Gent, Helen Creedon, Rachel Nirsimloo, Fiona Nussey, Christianne Lok, C Simon Herrington, Charlie Gourley^*

^*Corresponding author for this work

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

Abstract / Description of output

Objectives
Low-grade serous ovarian carcinoma (LGSOC) is a distinct, rare, ovarian cancer type characterised by younger patient age and intrinsic chemoresistance. Understanding the molecular landscape is crucial for optimising targeted therapy.

Methods
Genomic data from whole exome sequencing of tumour tissue was analysed in a LGSOC cohort with detailed clinical annotation.

Results
63 cases were analysed and three subgroups identified based on single nucleotide variants: canonical MAPK mutant (cMAPKm: 52%, KRAS/BRAF/NRAS), MAPK-associated gene mutation (MAPK-assoc: 27%) and MAPK wild-type (MAPKwt: 21%). NOTCH pathway disruption occurred across all subgroups. Tumour mutational burden (TMB), mutational signatures and recurrent copy number (CN) changes varied across the cohort with co-occurrence of chromosome 1p loss and 1q gain (CN Chr1pq) a recurrent feature. Low TMB and CN Chr1pq were associated with inferior disease-specific survival (HR 6.43; p < 0.001 and HR 3.29, p = 0.011 respectively). Stepwise genomic classification in relation to outcome resulted in four groups (TMB low; CN Chr1pq; MAPKwt/MAPKassoc; cMAPKm). 5 year disease-specific survival was 46%, 55%, 79% and 100% respectively for these groups. The two most favourable genomic subgroups were enriched for the SBS10b mutational signature, particularly the cMAPKm subgroup.

Conclusions
LGSOC comprises multiple genomic subgroups with distinct clinical and molecular features. Chr1pq CN arm disruption and TMB represent promising methods to identify individuals with poorer prognosis. Further investigation of the molecular basis for these observations is required. MAPKwt cases represent around a fifth of patients. NOTCH inhibitors represent a candidate therapeutic strategy worthy of exploration across these cases.

Original language	English
Journal	Gynecologic Oncology
DOIs	https://doi.org/10.1016/j.ygyno.2023.04.011
Publication status	Published - 17 May 2023

Keywords / Materials (for Non-textual outputs)

low grade serous ovarian cancer
Genomics
Exome-sequencing
Molecular Profiling
MAPK

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0090-8258/© 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
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Thomson, J., Hollis, R., van Baal, J., Ilenkovan, N., Churchman, M., van de Vijver, K., Meynert, A. M., Bartos, C., Rye, T., Croy, I., Diana, P., van Gent, M., Creedon, H., Nirsimloo, R., Nussey, F., Lok, C., Herrington, C. S., & Gourley, C. (2023). Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome. Gynecologic Oncology. https://doi.org/10.1016/j.ygyno.2023.04.011

@article{e9553f8134b54183865650952158391f,

title = "Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome",

abstract = "ObjectivesLow-grade serous ovarian carcinoma (LGSOC) is a distinct, rare, ovarian cancer type characterised by younger patient age and intrinsic chemoresistance. Understanding the molecular landscape is crucial for optimising targeted therapy.MethodsGenomic data from whole exome sequencing of tumour tissue was analysed in a LGSOC cohort with detailed clinical annotation.Results63 cases were analysed and three subgroups identified based on single nucleotide variants: canonical MAPK mutant (cMAPKm: 52%, KRAS/BRAF/NRAS), MAPK-associated gene mutation (MAPK-assoc: 27%) and MAPK wild-type (MAPKwt: 21%). NOTCH pathway disruption occurred across all subgroups. Tumour mutational burden (TMB), mutational signatures and recurrent copy number (CN) changes varied across the cohort with co-occurrence of chromosome 1p loss and 1q gain (CN Chr1pq) a recurrent feature. Low TMB and CN Chr1pq were associated with inferior disease-specific survival (HR 6.43; p < 0.001 and HR 3.29, p = 0.011 respectively). Stepwise genomic classification in relation to outcome resulted in four groups (TMB low; CN Chr1pq; MAPKwt/MAPKassoc; cMAPKm). 5 year disease-specific survival was 46%, 55%, 79% and 100% respectively for these groups. The two most favourable genomic subgroups were enriched for the SBS10b mutational signature, particularly the cMAPKm subgroup.ConclusionsLGSOC comprises multiple genomic subgroups with distinct clinical and molecular features. Chr1pq CN arm disruption and TMB represent promising methods to identify individuals with poorer prognosis. Further investigation of the molecular basis for these observations is required. MAPKwt cases represent around a fifth of patients. NOTCH inhibitors represent a candidate therapeutic strategy worthy of exploration across these cases.",

keywords = "low grade serous ovarian cancer, Genomics, Exome-sequencing, Molecular Profiling, MAPK",

author = "John Thomson and Robb Hollis and {van Baal}, Juliette and Narthana Ilenkovan and Michael Churchman and {van de Vijver}, Koen and Meynert, {Alison M} and Clare Bartos and Tzyvia Rye and Ian Croy and Patricia Diana and {van Gent}, Mignon and Helen Creedon and Rachel Nirsimloo and Fiona Nussey and Christianne Lok and Herrington, {C Simon} and Charlie Gourley",

note = "Funding Information: JT and CB were supported by core funding from the CRUK Scotland Centre . RLH was supported by Target Ovarian Cancer and by an IGC Langmuir Talent Fellowship . This work was funded in part by a HANARTH Foundation grant. AMM was supported by core funding awarded to the MRC Human Genetics Unit . We extend our thanks to The Nicola Murray Foundation for their generous support of The Nicola Murray Centre for Ovarian Cancer Research. Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = may,

day = "17",

doi = "10.1016/j.ygyno.2023.04.011",

language = "English",

journal = "Gynecologic Oncology",

issn = "0090-8258",

publisher = "Academic Press Inc.",

}

Thomson, J , Hollis, R, van Baal, J, Ilenkovan, N, Churchman, M, van de Vijver, K, Meynert, AM, Bartos, C, Rye, T, Croy, I, Diana, P, van Gent, M, Creedon, H, Nirsimloo, R, Nussey, F, Lok, C, Herrington, CS & Gourley, C 2023, 'Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome', Gynecologic Oncology. https://doi.org/10.1016/j.ygyno.2023.04.011

TY - JOUR

T1 - Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome

AU - Thomson, John

AU - Hollis, Robb

AU - van Baal, Juliette

AU - Ilenkovan, Narthana

AU - Churchman, Michael

AU - van de Vijver, Koen

AU - Meynert, Alison M

AU - Bartos, Clare

AU - Rye, Tzyvia

AU - Croy, Ian

AU - Diana, Patricia

AU - van Gent, Mignon

AU - Creedon, Helen

AU - Nirsimloo, Rachel

AU - Nussey, Fiona

AU - Lok, Christianne

AU - Herrington, C Simon

AU - Gourley, Charlie

N1 - Funding Information: JT and CB were supported by core funding from the CRUK Scotland Centre . RLH was supported by Target Ovarian Cancer and by an IGC Langmuir Talent Fellowship . This work was funded in part by a HANARTH Foundation grant. AMM was supported by core funding awarded to the MRC Human Genetics Unit . We extend our thanks to The Nicola Murray Foundation for their generous support of The Nicola Murray Centre for Ovarian Cancer Research. Publisher Copyright: © 2023

PY - 2023/5/17

Y1 - 2023/5/17

N2 - ObjectivesLow-grade serous ovarian carcinoma (LGSOC) is a distinct, rare, ovarian cancer type characterised by younger patient age and intrinsic chemoresistance. Understanding the molecular landscape is crucial for optimising targeted therapy.MethodsGenomic data from whole exome sequencing of tumour tissue was analysed in a LGSOC cohort with detailed clinical annotation.Results63 cases were analysed and three subgroups identified based on single nucleotide variants: canonical MAPK mutant (cMAPKm: 52%, KRAS/BRAF/NRAS), MAPK-associated gene mutation (MAPK-assoc: 27%) and MAPK wild-type (MAPKwt: 21%). NOTCH pathway disruption occurred across all subgroups. Tumour mutational burden (TMB), mutational signatures and recurrent copy number (CN) changes varied across the cohort with co-occurrence of chromosome 1p loss and 1q gain (CN Chr1pq) a recurrent feature. Low TMB and CN Chr1pq were associated with inferior disease-specific survival (HR 6.43; p < 0.001 and HR 3.29, p = 0.011 respectively). Stepwise genomic classification in relation to outcome resulted in four groups (TMB low; CN Chr1pq; MAPKwt/MAPKassoc; cMAPKm). 5 year disease-specific survival was 46%, 55%, 79% and 100% respectively for these groups. The two most favourable genomic subgroups were enriched for the SBS10b mutational signature, particularly the cMAPKm subgroup.ConclusionsLGSOC comprises multiple genomic subgroups with distinct clinical and molecular features. Chr1pq CN arm disruption and TMB represent promising methods to identify individuals with poorer prognosis. Further investigation of the molecular basis for these observations is required. MAPKwt cases represent around a fifth of patients. NOTCH inhibitors represent a candidate therapeutic strategy worthy of exploration across these cases.

AB - ObjectivesLow-grade serous ovarian carcinoma (LGSOC) is a distinct, rare, ovarian cancer type characterised by younger patient age and intrinsic chemoresistance. Understanding the molecular landscape is crucial for optimising targeted therapy.MethodsGenomic data from whole exome sequencing of tumour tissue was analysed in a LGSOC cohort with detailed clinical annotation.Results63 cases were analysed and three subgroups identified based on single nucleotide variants: canonical MAPK mutant (cMAPKm: 52%, KRAS/BRAF/NRAS), MAPK-associated gene mutation (MAPK-assoc: 27%) and MAPK wild-type (MAPKwt: 21%). NOTCH pathway disruption occurred across all subgroups. Tumour mutational burden (TMB), mutational signatures and recurrent copy number (CN) changes varied across the cohort with co-occurrence of chromosome 1p loss and 1q gain (CN Chr1pq) a recurrent feature. Low TMB and CN Chr1pq were associated with inferior disease-specific survival (HR 6.43; p < 0.001 and HR 3.29, p = 0.011 respectively). Stepwise genomic classification in relation to outcome resulted in four groups (TMB low; CN Chr1pq; MAPKwt/MAPKassoc; cMAPKm). 5 year disease-specific survival was 46%, 55%, 79% and 100% respectively for these groups. The two most favourable genomic subgroups were enriched for the SBS10b mutational signature, particularly the cMAPKm subgroup.ConclusionsLGSOC comprises multiple genomic subgroups with distinct clinical and molecular features. Chr1pq CN arm disruption and TMB represent promising methods to identify individuals with poorer prognosis. Further investigation of the molecular basis for these observations is required. MAPKwt cases represent around a fifth of patients. NOTCH inhibitors represent a candidate therapeutic strategy worthy of exploration across these cases.

KW - low grade serous ovarian cancer

KW - Genomics

KW - Exome-sequencing

KW - Molecular Profiling

KW - MAPK

U2 - 10.1016/j.ygyno.2023.04.011

DO - 10.1016/j.ygyno.2023.04.011

M3 - Article

SN - 0090-8258

JO - Gynecologic Oncology

JF - Gynecologic Oncology

ER -

Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

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