Functional significance of U2AF1 S34F mutations in lung adenocarcinomas

Mohammad S Esfahani; Luke J Lee; Young-Jun Jeon; Ryan A Flynn; Henning Stehr; Angela B Hui; Noriko Ishisoko; Eric Kildebeck; Aaron M Newman; Scott V Bratman; Matthew H Porteus; Howard Y Chang; Ash A Alizadeh; Maximilian Diehn

doi:10.1038/s41467-019-13392-y

Functional significance of U2AF1 S34F mutations in lung adenocarcinomas

Nat Commun. 2019 Dec 13;10(1):5712. doi: 10.1038/s41467-019-13392-y.

Authors

Mohammad S Esfahani^{1

2

3}, Luke J Lee¹, Young-Jun Jeon^{1

3}, Ryan A Flynn⁴, Henning Stehr^{1

5}, Angela B Hui^{1

3}, Noriko Ishisoko⁶, Eric Kildebeck⁷, Aaron M Newman^{8

9}, Scott V Bratman^{3

8

10}, Matthew H Porteus⁷, Howard Y Chang^{11

12}, Ash A Alizadeh^{13

14

15}, Maximilian Diehn^{16

17

18}

Affiliations

¹ Stanford Cancer Institute, Stanford University, Stanford, USA.
² Division of Oncology, Department of Medicine, Stanford University, Stanford, USA.
³ Department of Radiation Oncology, Stanford University, Stanford, USA.
⁴ Department of Chemistry, Stanford University, Stanford, USA.
⁵ Department of Pathology, Stanford University, Stanford, CA, USA.
⁶ Department of Bioengineering, Stanford University, Stanford, USA.
⁷ Department of Pediatrics, Stanford University, Stanford, USA.
⁸ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, USA.
⁹ Department of Biomedical Data Science, Stanford University, Stanford, USA.
¹⁰ Department of Radiation Oncology, University of Toronto, Toronto, CA, USA.
¹¹ Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
¹² Division of Hematology, Department of Medicine, Stanford University, Stanford, USA.
¹³ Stanford Cancer Institute, Stanford University, Stanford, USA. [email protected].
¹⁴ Division of Oncology, Department of Medicine, Stanford University, Stanford, USA. [email protected].
¹⁵ Division of Hematology, Department of Medicine, Stanford University, Stanford, USA. [email protected].
¹⁶ Stanford Cancer Institute, Stanford University, Stanford, USA. [email protected].
¹⁷ Department of Radiation Oncology, Stanford University, Stanford, USA. [email protected].
¹⁸ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, USA. [email protected].

Abstract

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adenocarcinoma of Lung / genetics*
Adenocarcinoma of Lung / pathology
Alternative Splicing / genetics*
Animals
Biopsy
Epithelial-Mesenchymal Transition / genetics
Exons
Gene Expression Regulation, Neoplastic
Humans
Lung / pathology
Lung Neoplasms / genetics*
Lung Neoplasms / pathology
Mice
Mutation
NIH 3T3 Cells
Neoplasm Invasiveness / genetics
Oncogene Proteins, Fusion / genetics*
Protein Isoforms / genetics
Protein-Tyrosine Kinases / genetics
Proto-Oncogene Proteins / genetics
Sodium-Phosphate Cotransporter Proteins, Type IIb / genetics
Splicing Factor U2AF / genetics*
Splicing Factor U2AF / metabolism

Substances

Oncogene Proteins, Fusion
Protein Isoforms
Proto-Oncogene Proteins
SLC34A2 protein, human
Sodium-Phosphate Cotransporter Proteins, Type IIb
Splicing Factor U2AF
U2AF1 protein, human
Protein-Tyrosine Kinases
ROS1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding