Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer

Cancer Research
Hengyu LuKenneth L Scott

Abstract

Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in The Cancer Genome Atlas datasets. In addition to confirming oncogenic activity of the known fusion oncogenes engineered by our construction strategy, we validated five novel fusion genes involving MET, NTRK2, and BRAF kinases that exhibited potent transforming activity and conferred sensitivity to FDA-approved kinase inhibitors. Our fusion construction strategy also enabled domain-function studies of BRAF fusion genes. Our results confirmed other reports that the transforming activity of BRAF fusions results from truncation-mediated loss of inhibitory domains within the N-terminus of the BRAF protein. BRAF mutations residing within this inhibitory region may provide a means for BRAF activation in cancer, therefore we leveraged the modular design of our fusion gene construction methodology to screen N-terminal domain mutations discovered in tumors tha...Continue Reading

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Citations

Nov 4, 2017·Nucleic Acids Research·Xin HuRoel G W Verhaak
Jun 5, 2020·Thyroid : Official Journal of the American Thyroid Association·Barbora PekovaBela Bendlova
Oct 10, 2020·Nature Communications·M Martinez-LageS Rodriguez-Perales
Oct 12, 2020·Journal of Human Genetics·Yena LeeBeom Hee Lee
Jan 9, 2020·Molecular Cancer Research : MCR·Christina StanglW P Kloosterman
Jan 3, 2021·Journal of Cancer Research and Clinical Oncology·Mian LiuShi Chang
Apr 4, 2021·International Journal of Molecular Sciences·Margaret Ottaviano On Behalf Of Scito Youth

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