Functional significance of U2AF1 S34F mutations in lung adenocarcinomas

• Published in: Nature communications Vol. 10; no. 1; pp. 5712 - 13
• Main Authors: Esfahani, Mohammad S., Lee, Luke J., Jeon, Young-Jun, Flynn, Ryan A., Stehr, Henning, Hui, Angela B., Ishisoko, Noriko, Kildebeck, Eric, Newman, Aaron M., Bratman, Scott V., Porteus, Matthew H., Chang, Howard Y., Alizadeh, Ash A., Diehn, Maximilian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.12.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 38; 38/91; 631/67; 631/67/1612; 631/67/68; 692/4028; 82/80; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - pathology; Alternative Splicing - genetics; Animals; Biopsy; Epithelial-Mesenchymal Transition - genetics; Exons; Gene expression; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Humans; Lung - pathology; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lungs; Mice; multidisciplinary; Mutation; Neoplasm Invasiveness - genetics; NIH 3T3 Cells; Oncogene Proteins, Fusion - genetics; Protein Isoforms - genetics; Protein-Tyrosine Kinases - genetics; Proto-Oncogene Proteins - genetics; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Sodium-Phosphate Cotransporter Proteins, Type IIb - genetics; Splicing; Splicing Factor U2AF - genetics; Splicing Factor U2AF - metabolism; Splicing factors; Translocation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13392-y

The functional role of U2AF1 mutations in lung adenocarcinomas (LUADs) remains incompletely understood. Here, we report a significant co-occurrence of U2AF1 S34F mutations with ROS1 translocations in LUADs. To characterize this interaction, we profiled effects of S34F on the transcriptome-wide distribution of RNA binding and alternative splicing in cells harboring the ROS1 translocation. Compared to its wild-type counterpart, U2AF1 S34F preferentially binds and modulates splicing of introns containing CAG trinucleotides at their 3′ splice junctions. The presence of S34F caused a shift in cross-linking at 3′ splice sites, which was significantly associated with alternative splicing of skipped exons. U2AF1 S34F induced expression of genes involved in the epithelial-mesenchymal transition (EMT) and increased tumor cell invasion. Finally, S34F increased splicing of the long over the short SLC34A2-ROS1 isoform, which was also associated with enhanced invasiveness. Taken together, our results suggest a mechanistic interaction between mutant U2AF1 and ROS1 in LUAD. The authors report a co-occurrence of the U2AF1 S34F splicing factor mutation and ROS1 translocations in lung adenocarcinomas and profile effects of S34F on transcriptome-wide RNA binding. They further show that U2AF1 S34F enhances invasive potential and alters splicing of ROS1 fusion transcripts