Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer

Filipe Correia Martins (), Dominique-Laurent Couturier, Ines Santiago, Carolin Margarethe Sauer, Maria Vias, Mihaela Angelova, Deborah Sanders, Anna Piskorz, James Hall, Karen Hosking, Anumithra Amirthanayagam, Sabina Cosulich, Larissa Carnevalli, Barry Davies, Thomas B. K. Watkins, Ionut G. Funingana, Helen Bolton, Krishnayan Haldar, John Latimer, Peter Baldwin, Robin Crawford, Matthew Eldridge, Bristi Basu, Mercedes Jimenez-Linan, Andrew W. Mcpherson, Nicholas McGranahan, Kevin Litchfield, Sohrab P. Shah, Iain McNeish, Carlos Caldas, Gerard Evan, Charles Swanton () and James D. Brenton ()
Additional contact information
Filipe Correia Martins: University of Cambridge
Dominique-Laurent Couturier: University of Cambridge
Ines Santiago: University of Cambridge
Carolin Margarethe Sauer: University of Cambridge
Maria Vias: University of Cambridge
Mihaela Angelova: The Francis Crick Institute
Deborah Sanders: University of Cambridge
Anna Piskorz: University of Cambridge
James Hall: University of Cambridge
Karen Hosking: Cambridge University Hospitals
Anumithra Amirthanayagam: Cambridge University Hospitals
Sabina Cosulich: Astrazeneca
Larissa Carnevalli: Astrazeneca
Barry Davies: Astrazeneca
Thomas B. K. Watkins: The Francis Crick Institute
Ionut G. Funingana: University of Cambridge
Helen Bolton: Cambridge University Hospitals
Krishnayan Haldar: Cambridge University Hospitals
John Latimer: Cambridge University Hospitals
Peter Baldwin: Cambridge University Hospitals
Robin Crawford: Cambridge University Hospitals
Matthew Eldridge: University of Cambridge
Bristi Basu: Cambridge University Hospitals
Mercedes Jimenez-Linan: Cambridge University Hospitals
Andrew W. Mcpherson: Memorial Sloan Kettering Cancer Centre
Nicholas McGranahan: University College London Cancer Institute
Kevin Litchfield: The Francis Crick Institute
Sohrab P. Shah: Memorial Sloan Kettering Cancer Centre
Iain McNeish: Imperial College of London
Carlos Caldas: University of Cambridge
Gerard Evan: University of Cambridge
Charles Swanton: The Francis Crick Institute
James D. Brenton: University of Cambridge

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and methylation status. We identify five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reason that their strong selection should prioritise them as key biomarkers for targeted therapies. We use primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number is associated with in-vitro and clinical response to paclitaxel and in-vitro response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context of MYC-amplified HGSOC is statistically associated with increased prevalence of SCNAs in genes from the PI3K pathway. Co-occurrence of amplifications in MYC and genes from the PI3K pathway is independently observed in squamous lung cancer and triple negative breast cancer. In this work, we show that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine.

Date: 2022
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DOI: 10.1038/s41467-022-33870-0

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