Journal article

Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer

Stefano Annunziato, Julian R de Ruiter, Linda Henneman, Chiara S Brambillasca, Catrin Lutz, Francois Vaillant, Federica Ferrante, Anne Paulien Drenth, Eline van der Burg, Bjorn Siteur, Bas van Gerwen, Roebi de Bruijn, Martine H van Miltenburg, Ivo J Huijbers, Marieke van de Ven, Jane E Visvader, Geoffrey J Lindeman, Lodewyk FA Wessels, Jos Jonkers



BRCA1-mutated breast cancer is primarily driven by DNA copy-number alterations (CNAs) containing large numbers of candidate driver genes. Validation of these candidates requires novel approaches for high-throughput in vivo perturbation of gene function. Here we develop genetically engineered mouse models (GEMMs) of BRCA1-deficient breast cancer that permit rapid introduction of putative drivers by either retargeting of GEMM-derived embryonic stem cells, lentivirus-mediated somatic overexpression or in situ CRISPR/Cas9-mediated gene disruption. We use these approaches to validate Myc, Met, Pten and Rb1 as bona fide drivers in BRCA1-associated mammary tumorigenesis. Iterative mouse modeling an..

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Awarded by SURF Cooperative

Awarded by Netherlands Organization for Scientific Research (NWO: Netherlands Genomics Initiative (NGI))

Awarded by National Health and Medical Research Council (Australia)

Funding Acknowledgements

We thank Sjors Kas, Eva Schut, Bastiaan Evers, Ben Morris, Renske de Korte-Grimmerink, Natalie Proost and Rebecca Theeuwsen for providing reagents, technical suggestions, and/or help with the experiments. We are grateful for excellent support from the NKI animal facility, RHPC computing facility, flow cytometry facility, animal pathology facility, transgenic facility, preclinical intervention unit, core facility molecular pathology and biobanking (CFMPB), and genomics core facility. PDX-110 was derived from a primary breast tumor provided by the Victorian Cancer Biobank (supported by the Victorian Government, Australia). This work was carried out on the Dutch national e-infrastructure with the support of SURF Cooperative (e-infra160136). Financial support was provided by the Oncode Institute, the Netherlands Organization for Scientific Research (NWO: Cancer Genomics Netherlands (CGCNL), Cancer Systems Biology Center (CSBC), Netherlands Genomics Initiative (NGI) Zenith 93512009 (J.J.), VICI 91814643 (J.J.)), the European Research Council (ERC Synergy project CombatCancer), a National Roadmap grant for Large-Scale Research Facilities from NWO (J.J.) and National Health and Medical Research Council (Australia) grants 1113133 (J.E.V. and G.J.L.), 1078730 (G.J.L.) and 1102742 (J.E.V.).