Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer.
Watkins, Thomas BK
Mcpherson, Andrew W
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Martins, F. C., Couturier, D., de Santiago, I., Sauer, C. M., Vias, M., Angelova, M., Sanders, D., et al. (2022). Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer.. Nat Commun https://doi.org/10.1038/s41467-022-33870-0
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.
F.C.M. is funded by the Experimental Medicine Initiative from the University of Cambridge, by the Academy of Medical Sciences (SGL016_1084), Cancer Research UK (C53876/A24267) and by the Addenbrooke’s Charitable Trust (REF 13/17). This research was also supported by a pump-priming award from the Cancer Research UK Cambridge Centre Early detection Programme (CRUK grant ref: A25117). This research was supported by the NIHR Cambridge Biomedical Research Centre. The OVO4 study is supported by the CRUK Cambridge Cancer Centre and the Mark Foundation Institute for Integrated Cancer Medicine. We would like to acknowledge the support of The University of Cambridge, the National Institute for Health Research Cambridge, National Cancer Research Network, the Cambridge Experimental Cancer Medicine Centres, Hutchison Whampoa Limited and Cancer Research UK (CRUK grant numbers A22905 (JDB), A15601 (JDB), A25177 (CRUK Cancer Centre Cambridge)). C.S. is Royal Society Napier Research Professor. His team and work is supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). C.S. is funded by Cancer Research UK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK Lung Cancer Centre of Excellence, the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Professorship Enhancement Award (RP/EA/180007), the National Institute for Health Research (NIHR) Biomedical Research Centre at University College London Hospitals, the CRUK-UCL Centre, Experimental Cancer Medicine Centre, and the Breast Cancer Research Foundation (BCRF, USA). His research is supported by a Stand Up To Cancer‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT23-17). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. CS receives funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007-2013) Consolidator Grant (FP7-THESEUS-617844), European Commission ITN (FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 835297), and Chromavision from the European Union’s Horizon 2020 research and innovation programme (grant agreement 665233).
Cancer Research UK (24267)
Cancer Research UK (A25117)
Cancer Research UK (A22905)
Cancer Research UK (A15601)
External DOI: https://doi.org/10.1038/s41467-022-33870-0
This record's URL: https://www.repository.cam.ac.uk/handle/1810/343071
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/
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