s41467-022-33870-0.pdf (3.88 MB)
Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer.
journal contributionposted on 2022-10-31, 14:13 authored by Filipe Correia Martins, Dominique-Laurent Couturier, Ines de 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 BK 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, James D Brenton
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.
Crick (Grant ID: CC2041, Grant title: Swanton CC2041) European Research Council (Grant ID: 835297 - PROTEUS, Grant title: ERC 835297 - PROTEUS) Novo Nordisk UK Research Foundation (Grant ID: NNF15OC0016584, Grant title: NovoNordisk Foundation 16584)