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Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer.
Martins, Filipe Correia; Couturier, Dominique-Laurent; de Santiago, Ines; Sauer, Carolin Margarethe; Vias, Maria; Angelova, Mihaela; Sanders, Deborah; Piskorz, Anna; Hall, James; Hosking, Karen; Amirthanayagam, Anumithra; Cosulich, Sabina; Carnevalli, Larissa; Davies, Barry; Watkins, Thomas B K; Funingana, Ionut G; Bolton, Helen; Haldar, Krishnayan; Latimer, John; Baldwin, Peter; Crawford, Robin; Eldridge, Matthew; Basu, Bristi; Jimenez-Linan, Mercedes; Mcpherson, Andrew W; McGranahan, Nicholas; Litchfield, Kevin; Shah, Sohrab P; McNeish, Iain; Caldas, Carlos; Evan, Gerard; Swanton, Charles; Brenton, James D.
Affiliation
  • Martins FC; Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK. f.correiamartins@nhs.net.
  • Couturier DL; Experimental Medicine Initiative, University of Cambridge, Cambridge, UK. f.correiamartins@nhs.net.
  • de Santiago I; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. f.correiamartins@nhs.net.
  • Sauer CM; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. f.correiamartins@nhs.net.
  • Vias M; Department of Gynaecological Oncology, Cambridge University Hospitals, Cambridge, UK. f.correiamartins@nhs.net.
  • Angelova M; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • Sanders D; Medical Research Council Biostatistics Unit, 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; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • Amirthanayagam A; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
  • Cosulich S; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • Carnevalli L; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • Davies B; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • Watkins TBK; Cambridge University Hospitals, Cambridge, UK.
  • Funingana IG; Department of Gynaecological Oncology, Cambridge University Hospitals, Cambridge, UK.
  • Bolton H; Early Oncology R&D, Astrazeneca, Cambridge, UK.
  • Haldar K; Early Oncology R&D, Astrazeneca, Cambridge, UK.
  • Latimer J; Early Oncology R&D, Astrazeneca, Cambridge, UK.
  • Baldwin P; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
  • Crawford R; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • Eldridge M; Department of Oncology, University of Cambridge, Cambridge, UK.
  • Basu B; Department of Gynaecological Oncology, Cambridge University Hospitals, Cambridge, UK.
  • Jimenez-Linan M; Department of Gynaecological Oncology, Cambridge University Hospitals, Cambridge, UK.
  • Mcpherson AW; Department of Gynaecological Oncology, Cambridge University Hospitals, Cambridge, UK.
  • McGranahan N; Department of Gynaecological Oncology, Cambridge University Hospitals, Cambridge, UK.
  • Litchfield K; Department of Gynaecological Oncology, Cambridge University Hospitals, Cambridge, UK.
  • Shah SP; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • McNeish I; Cambridge University Hospitals, Cambridge, UK.
  • Caldas C; Department of Oncology, University of Cambridge, Cambridge, UK.
  • Evan G; Department of Histopathology, Cambridge University Hospitals, Cambridge, UK.
  • Swanton C; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Centre, NYC, USA.
  • Brenton JD; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
Nat Commun ; 13(1): 6360, 2022 10 26.
Article in En | MEDLINE | ID: mdl-36289203
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ovarian Neoplasms / Cystadenocarcinoma, Serous Type of study: Diagnostic_studies / Risk_factors_studies Limits: Female / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2022 Document type: Article Affiliation country:
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ovarian Neoplasms / Cystadenocarcinoma, Serous Type of study: Diagnostic_studies / Risk_factors_studies Limits: Female / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2022 Document type: Article Affiliation country: