Functional significance of U2AF1 S34F mutations in lung adenocarcinomas

被引：33

作者：

Esfahani, Mohammad S. ^{[1
,2
,3
]}

Lee, Luke J. ^{[1
]}

Jeon, Young-Jun ^{[1
,3
]}

Flynn, Ryan A. ^{[4
]}

Stehr, Henning ^{[1
,5
]}

Hui, Angela B. ^{[1
,3
]}

Ishisoko, Noriko ^{[6
]}

Kildebeck, Eric ^{[7
]}

Newman, Aaron M. ^{[8
,9
]}

Bratman, Scott V. ^{[3
,8
,12
]}

Porteus, Matthew H. ^{[7
]}

Chang, Howard Y. ^{[10
,11
]}

Alizadeh, Ash A. ^{[1
,2
,11
]}

Diehn, Maximilian ^{[1
,3
,8
]}

机构：

[1] Stanford Univ, Stanford Canc Inst, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Med, Div Oncol, Stanford, CA 94305 USA

[3] Stanford Univ, Dept Radiat Oncol, Stanford, CA 94305 USA

[4] Stanford Univ, Dept Chem, Stanford, CA 94305 USA

[5] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[6] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA

[7] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA

[8] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA

[9] Stanford Univ, Dept Biomed Data Sci, Stanford, CA 94305 USA

[10] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA

[11] Stanford Univ, Dept Med, Div Hematol, Stanford, CA 94305 USA

[12] Univ Toronto, Dept Radiat Oncol, Toronto, ON, Canada

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

美国国家卫生研究院;

关键词：

SPLICING FACTOR MUTATIONS; ROS1; REARRANGEMENTS; CANCER; GENE; DEFINE; SITE; RECOGNITION; MACHINERY; ABERRANT; PLATFORM;

D O I：

10.1038/s41467-019-13392-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

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