RT Journal Article
SR Electronic
T1 Functional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR/Cas9 screening
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 559690
DO 10.1101/559690
A1 Gabriele Picco
A1 Elisabeth D Chen
A1 Luz Garcia Alonso
A1 Fiona M Behan
A1 Emanuel Gonçalves
A1 Graham Bignell
A1 Angela Matchan
A1 Beiyuan Fu
A1 Ruby Banerjee
A1 Elizabeth Anderson
A1 Adam Butler
A1 Cyril H Benes
A1 Ultan McDermott
A1 David Dow
A1 Francesco Iorio
A1 Euan Stronach
A1 Fengtang Yang
A1 Kosuke Yusa
A1 Julio Saez-Rodriguez
A1 Mathew J Garnett
YR 2019
UL http://biorxiv.org/content/early/2019/02/24/559690.abstract
AB Many gene fusions have been reported in tumours and for most their role remains unknown. As fusions can be used clinically for diagnostic and prognostic purposes, and are targets for treatment, it is crucial to assess their functional implications in cancer. To investigate the role of fusions in tumor cell fitness, we developed a systematic analysis utilising RNA-sequencing data from 1,011 human cancer cell lines to functionally link 8,354 gene fusion events with genomic data, sensitivity to >350 anti-cancer drugs and CRISPR-Cas9 loss-of-fitness information. Established clinically-relevant fusions were readily identified. Overall, functional fusions were rare, including those involving cancer driver genes, suggesting that many fusions are dispensable for tumor cell fitness. Novel 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, supporting therapeutic targeting of Hippo signalling. Our approach discriminates functional fusions, identifying new drivers of carcinogenesis and fusions that could have important clinical implications.Significance We identify fusions as new potential candidates for drug repurposing and drivers of carcinogenesis. These results support histology agnostic marker-driven precision cancer medicine. Most fusions are not functional with implications for interpreting cancer fusions reported from clinical sequencing studies.