Functional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR-Cas9 screening

Gabriele Picco, Elisabeth D. Chen, Luz Garcia Alonso, Fiona M. Behan, Emanuel Gonçalves, Graham Bignell, Angela Matchan, Beiyuan Fu, Ruby Banerjee, Elizabeth Anderson, Adam Butler, Cyril H. Benes, Ultan McDermott, David Dow, Francesco Iorio, Euan Stronach, Fengtang Yang, Kosuke Yusa, Julio Saez-Rodriguez and Mathew J. Garnett ()
Additional contact information
Gabriele Picco: Wellcome Sanger Institute
Elisabeth D. Chen: Wellcome Sanger Institute
Luz Garcia Alonso: European Bioinformatics Institute
Fiona M. Behan: Wellcome Sanger Institute
Emanuel Gonçalves: Wellcome Sanger Institute
Graham Bignell: Wellcome Sanger Institute
Angela Matchan: Wellcome Sanger Institute
Beiyuan Fu: Wellcome Sanger Institute
Ruby Banerjee: Wellcome Sanger Institute
Elizabeth Anderson: Wellcome Sanger Institute
Adam Butler: Wellcome Sanger Institute
Cyril H. Benes: Massachusetts General Hospital
Ultan McDermott: Wellcome Sanger Institute
David Dow: Open Targets
Francesco Iorio: Wellcome Sanger Institute
Euan Stronach: Open Targets
Fengtang Yang: Wellcome Sanger Institute
Kosuke Yusa: Wellcome Sanger Institute
Julio Saez-Rodriguez: European Bioinformatics Institute
Mathew J. Garnett: Wellcome Sanger Institute

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Many gene fusions are reported in tumours and for most their role remains unknown. As fusions are used for diagnostic and prognostic purposes, and are targets for treatment, it is crucial to assess their function in cancer. To systematically investigate the role of fusions in tumour cell fitness, we utilized RNA-sequencing data from 1011 human cancer cell lines to functionally link 8354 fusion events with genomic data, sensitivity to >350 anti-cancer drugs and CRISPR-Cas9 loss-of-fitness effects. Established clinically-relevant fusions were identified. Overall, detection of functional fusions was rare, including those involving cancer driver genes, suggesting that many fusions are dispensable for tumour fitness. Therapeutically actionable fusions involving RAF1, BRD4 and ROS1 were verified in new histologies. In addition, recurrent YAP1-MAML2 fusions were identified as activators of Hippo-pathway signaling in multiple cancer types. Our approach discriminates functional fusions, identifying new drivers of carcinogenesis and fusions that could have clinical implications.

Date: 2019
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DOI: 10.1038/s41467-019-09940-1

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