Functional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR-Cas9 screening.
Antineoplastic Agents
/ pharmacology
Biomarkers, Tumor
/ genetics
CRISPR-Cas Systems
/ genetics
Carcinogenesis
/ genetics
Cell Line, Tumor
Datasets as Topic
Drug Resistance, Neoplasm
/ genetics
Early Detection of Cancer
/ methods
Gene Expression Profiling
/ methods
Gene Expression Regulation, Neoplastic
/ drug effects
Gene Fusion
/ genetics
Genomics
/ methods
High-Throughput Nucleotide Sequencing
Humans
Neoplasms
/ diagnosis
Sequence Analysis, RNA
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
16 05 2019
16 05 2019
Historique:
received:
09
08
2018
accepted:
09
04
2019
entrez:
18
5
2019
pubmed:
18
5
2019
medline:
8
6
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31097696
doi: 10.1038/s41467-019-09940-1
pii: 10.1038/s41467-019-09940-1
pmc: PMC6522557
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers, Tumor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2198Références
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