Functional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR-Cas9 screening
| Autor: | Julio Saez-Rodriguez, Graham R. Bignell, Euan A. Stronach, Beiyuan Fu, Angela Matchan, Fiona M. Behan, Emanuel Gonçalves, Ruby Banerjee, Elisabeth Chen, Ultan McDermott, Gabriele Picco, Fengtang Yang, Kosuke Yusa, Luz Garcia Alonso, Cyril H. Benes, David J. Dow, Adam Butler, Elizabeth Anderson, Francesco Iorio, Mathew J. Garnett |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
BRD4 CRISPR-Cas systems Carcinogenesis Science General Physics and Astronomy Datasets as Topic Antineoplastic Agents 02 engineering and technology Computational biology Biology medicine.disease_cause General Biochemistry Genetics and Molecular Biology Article Fusion gene 03 medical and health sciences Targeted therapies Cell Line Tumor Neoplasms ROS1 medicine Biomarkers Tumor Cancer genomics CRISPR Humans lcsh:Science Gene Early Detection of Cancer Regulation of gene expression Multidisciplinary Sequence Analysis RNA Gene Expression Profiling Cancer High-Throughput Nucleotide Sequencing Functional genomics General Chemistry Genomics 021001 nanoscience & nanotechnology medicine.disease Gene Expression Regulation Neoplastic 030104 developmental biology Drug Resistance Neoplasm Cancer cell lcsh:Q Gene Fusion 0210 nano-technology |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-12 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. Gene fusions are observed in many cancers but their link to tumour fitness is largely unknown. Here, transcriptomic analysis combined with pharmacological and CRISPR-Cas9 screening of cancer cell lines was used to evaluate the functional linkage between fusions and tumour fitness. |
| Databáze: | OpenAIRE |
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