The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma

The BriTROC Investigators

doi:10.1038/s41467-023-39867-7

The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma

The BriTROC Investigators

Cancer and Genomic Sciences

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Abstract

The drivers of recurrence and resistance in ovarian high grade serous carcinoma remain unclear. We investigate the acquisition of resistance by collecting tumour biopsies from a cohort of 276 women with relapsed ovarian high grade serous carcinoma in the BriTROC-1 study. Panel sequencing shows close concordance between diagnosis and relapse, with only four discordant cases. There is also very strong concordance in copy number between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic copy number alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Copy number signatures are strongly correlated with immune cell infiltration, whilst diagnosis samples from patients with primary platinum resistance have increased rates of CCNE1 and KRAS amplification and copy number signature 1 exposure. Our data show that the ovarian high grade serous carcinoma genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers.

Original language	English
Article number	4387
Number of pages	15
Journal	Nature Communications
Volume	14
Issue number	1
Early online date	20 Jul 2023
DOIs	https://doi.org/10.1038/s41467-023-39867-7
Publication status	Published - Dec 2023

Bibliographical note

Funding Information:
This work was supported by Ovarian Cancer Action (grant number OCA_006 to IAMcN); the National Institute for Healthcare Research (NIHR) Imperial Biomedical Research Centre (grant number P77646 to IAMcN); the Wellcome Trust PhD programme in Mathematical Genomics and Medicine (grant number RG92770 to LMG); Cancer Research UK (grant numbers DRCQQR-Jun22\100005, A22905, A15601 and A26204 to JDB, FM and IAMcN); a European Society of Medical Oncology (ESMO) Translational Fellowship (to G.G.); the Beatson Cancer Charity and Hutchison Whampoa Limited. Infrastructure support was provided by CRUK/NIHR Experimental Cancer Medicine Centres at Imperial, Cambridge, Glasgow and other participating sites. We also thank the Biorepository, Bioinformatics, Histopathology, IT & Scientific Computing and Genomics Core Facilities of the Cancer Research UK Cambridge Institute and the Pathology Core at the Cancer Research UK Beatson Institute for technical support. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper.

Details of the BriTROC-1 study and the first 220 patients were reported previously. Briefly, BriTROC-1 was funded by Ovarian Cancer Action (grant number OCA_006) and sponsored by NHS Greater Glasgow and Clyde. Ethics/IRB approval was given by Cambridge Central Research Ethics Committee (Reference 12/EE/0349) and the trial registration number is ISRCTN09180474. All patients provided written informed consent—this included specific consent to biopsy, access to archival material, use of biopsy and archival material (and ascites if present) for genomic studies, testing of germline DNA for BRCA1/2 and other mutations and the use of clinical data for the research purposes. In addition, patients could optionally consent to a second biopsy upon disease progression and to be informed of germline BRCA1/2 analysis results.

Publisher Copyright:
© 2023, The Author(s).

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Cite this

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title = "The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma",

abstract = "The drivers of recurrence and resistance in ovarian high grade serous carcinoma remain unclear. We investigate the acquisition of resistance by collecting tumour biopsies from a cohort of 276 women with relapsed ovarian high grade serous carcinoma in the BriTROC-1 study. Panel sequencing shows close concordance between diagnosis and relapse, with only four discordant cases. There is also very strong concordance in copy number between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic copy number alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Copy number signatures are strongly correlated with immune cell infiltration, whilst diagnosis samples from patients with primary platinum resistance have increased rates of CCNE1 and KRAS amplification and copy number signature 1 exposure. Our data show that the ovarian high grade serous carcinoma genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers.",

author = "{The BriTROC Investigators} and Philip Smith and Thomas Bradley and Gavarr{\'o}, {Lena Morrill} and Teodora Goranova and Ennis, {Darren P.} and Mirza, {Hasan B.} and {De Silva}, Dilrini and Piskorz, {Anna M.} and Carolyn Sauer and Sarwah Al-Khalidi and Funingana, {Ionat Gabriel} and Reinius, {Marika A.V.} and Gaia Giannone and Lewsley, {Liz Anne} and Jamie Stobo and John McQueen and Gareth Bryson and Matthew Eldridge and Glasspool, {R. M.} and C. Gourley and R. Kennedy and G. Hall and R. Edmondson and A. Clamp and S. Sundar and A. Walter and M. Hall and H. Gabra and C. Fotopoulou and E. Brockbank and A. Montes and M. Lockley and Geoff Macintyre and Florian Markowetz and Brenton, {James D.} and McNeish, {Iain A.}",

note = "Funding Information: This work was supported by Ovarian Cancer Action (grant number OCA_006 to IAMcN); the National Institute for Healthcare Research (NIHR) Imperial Biomedical Research Centre (grant number P77646 to IAMcN); the Wellcome Trust PhD programme in Mathematical Genomics and Medicine (grant number RG92770 to LMG); Cancer Research UK (grant numbers DRCQQR-Jun22\100005, A22905, A15601 and A26204 to JDB, FM and IAMcN); a European Society of Medical Oncology (ESMO) Translational Fellowship (to G.G.); the Beatson Cancer Charity and Hutchison Whampoa Limited. Infrastructure support was provided by CRUK/NIHR Experimental Cancer Medicine Centres at Imperial, Cambridge, Glasgow and other participating sites. We also thank the Biorepository, Bioinformatics, Histopathology, IT & Scientific Computing and Genomics Core Facilities of the Cancer Research UK Cambridge Institute and the Pathology Core at the Cancer Research UK Beatson Institute for technical support. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper. Details of the BriTROC-1 study and the first 220 patients were reported previously. Briefly, BriTROC-1 was funded by Ovarian Cancer Action (grant number OCA_006) and sponsored by NHS Greater Glasgow and Clyde. Ethics/IRB approval was given by Cambridge Central Research Ethics Committee (Reference 12/EE/0349) and the trial registration number is ISRCTN09180474. All patients provided written informed consent—this included specific consent to biopsy, access to archival material, use of biopsy and archival material (and ascites if present) for genomic studies, testing of germline DNA for BRCA1/2 and other mutations and the use of clinical data for the research purposes. In addition, patients could optionally consent to a second biopsy upon disease progression and to be informed of germline BRCA1/2 analysis results. Publisher Copyright: {\textcopyright} 2023, The Author(s). ",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-39867-7",

language = "English",

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T1 - The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma

AU - The BriTROC Investigators

AU - Smith, Philip

AU - Bradley, Thomas

AU - Gavarró, Lena Morrill

AU - Goranova, Teodora

AU - Ennis, Darren P.

AU - Mirza, Hasan B.

AU - De Silva, Dilrini

AU - Piskorz, Anna M.

AU - Sauer, Carolyn

AU - Al-Khalidi, Sarwah

AU - Funingana, Ionat Gabriel

AU - Reinius, Marika A.V.

AU - Giannone, Gaia

AU - Lewsley, Liz Anne

AU - Stobo, Jamie

AU - McQueen, John

AU - Bryson, Gareth

AU - Eldridge, Matthew

AU - Glasspool, R. M.

AU - Gourley, C.

AU - Kennedy, R.

AU - Hall, G.

AU - Edmondson, R.

AU - Clamp, A.

AU - Sundar, S.

AU - Walter, A.

AU - Hall, M.

AU - Gabra, H.

AU - Fotopoulou, C.

AU - Brockbank, E.

AU - Montes, A.

AU - Lockley, M.

AU - Macintyre, Geoff

AU - Markowetz, Florian

AU - Brenton, James D.

AU - McNeish, Iain A.

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PY - 2023/12

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N2 - The drivers of recurrence and resistance in ovarian high grade serous carcinoma remain unclear. We investigate the acquisition of resistance by collecting tumour biopsies from a cohort of 276 women with relapsed ovarian high grade serous carcinoma in the BriTROC-1 study. Panel sequencing shows close concordance between diagnosis and relapse, with only four discordant cases. There is also very strong concordance in copy number between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic copy number alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Copy number signatures are strongly correlated with immune cell infiltration, whilst diagnosis samples from patients with primary platinum resistance have increased rates of CCNE1 and KRAS amplification and copy number signature 1 exposure. Our data show that the ovarian high grade serous carcinoma genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers.

AB - The drivers of recurrence and resistance in ovarian high grade serous carcinoma remain unclear. We investigate the acquisition of resistance by collecting tumour biopsies from a cohort of 276 women with relapsed ovarian high grade serous carcinoma in the BriTROC-1 study. Panel sequencing shows close concordance between diagnosis and relapse, with only four discordant cases. There is also very strong concordance in copy number between diagnosis and relapse, with no significant difference in purity, ploidy or focal somatic copy number alterations, even when stratified by platinum sensitivity or prior chemotherapy lines. Copy number signatures are strongly correlated with immune cell infiltration, whilst diagnosis samples from patients with primary platinum resistance have increased rates of CCNE1 and KRAS amplification and copy number signature 1 exposure. Our data show that the ovarian high grade serous carcinoma genome is remarkably stable between diagnosis and relapse and acquired chemotherapy resistance does not select for common copy number drivers.

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The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma

Abstract

Bibliographical note

ASJC Scopus subject areas

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