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

Autor:	Martins FC; Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK. f.correiamartins@nhs.net.; Experimental Medicine Initiative, University of Cambridge, Cambridge, UK. f.correiamartins@nhs.net.; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. f.correiamartins@nhs.net.; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. f.correiamartins@nhs.net.; Department of Gynaecological Oncology, Cambridge University Hospitals, Cambridge, UK. f.correiamartins@nhs.net., Couturier DL; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.; Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK., de Santiago I; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Sauer CM; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Vias M; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Angelova M; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK., Sanders D; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Piskorz A; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Hall J; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Hosking K; Cambridge University Hospitals, Cambridge, UK., Amirthanayagam A; Department of Gynaecological Oncology, Cambridge University Hospitals, Cambridge, UK., Cosulich S; Early Oncology R&D, Astrazeneca, Cambridge, UK., Carnevalli L; Early Oncology R&D, Astrazeneca, Cambridge, UK., Davies B; Early Oncology R&D, Astrazeneca, Cambridge, UK., Watkins TBK; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK., Funingana IG; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.; Department of Oncology, University of Cambridge, Cambridge, UK., Bolton H; Department of Gynaecological Oncology, Cambridge University Hospitals, Cambridge, UK., Haldar K; Department of Gynaecological Oncology, Cambridge University Hospitals, Cambridge, UK., Latimer J; Department of Gynaecological Oncology, Cambridge University Hospitals, Cambridge, UK., Baldwin P; Department of Gynaecological Oncology, Cambridge University Hospitals, Cambridge, UK., Crawford R; Department of Gynaecological Oncology, Cambridge University Hospitals, Cambridge, UK., Eldridge M; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Basu B; Cambridge University Hospitals, Cambridge, UK.; Department of Oncology, University of Cambridge, Cambridge, UK., Jimenez-Linan M; Department of Histopathology, Cambridge University Hospitals, Cambridge, UK., Mcpherson AW; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Centre, NYC, USA., McGranahan N; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK., Litchfield K; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK., Shah SP; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Centre, NYC, USA., McNeish I; Department of Surgery and Cancer, Imperial College of London, London, UK., Caldas C; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.; Department of Oncology, University of Cambridge, Cambridge, UK., Evan G; Department of Biochemistry, University of Cambridge, Cambridge, UK., Swanton C; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. Charles.swanton@crick.ac.uk.; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Charles.swanton@crick.ac.uk., Brenton JD; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. james.brenton@cruk.cam.ac.uk.; Department of Oncology, University of Cambridge, Cambridge, UK. james.brenton@cruk.cam.ac.uk.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2022 Oct 26; Vol. 13 (1), pp. 6360. Date of Electronic Publication: 2022 Oct 26.
DOI:	10.1038/s41467-022-33870-0
Abstrakt:	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. (© 2022. The Author(s).)
Databáze:	MEDLINE
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