Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences Across 33 Cancer Types

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2018 Apr 5

PMID 29617667

Citations 233

Authors

Michael Seiler

Shouyong Peng

Anant A Agrawal

James Palacino

Teng Teng

Ping Zhu

Peter G Smith

Silvia Buonamici

Lihua Yu

Affiliations

Soon will be listed here.

Abstract

Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis.

Citing Articles

SUGP1 loss is the sole driver of SF3B1 hotspot mutant missplicing in cancer.

Xing P, Bak-Gordon P, Xie J, Zhang J, Liu Z, Manley J bioRxiv. 2025; .

PMID: 40027711 PMC: 11870612. DOI: 10.1101/2025.02.17.638713.

OBSCN undergoes extensive alternative splicing during human cardiac and skeletal muscle development.

Oghabian A, Jonson P, Gayathri S, Johari M, Nippala E, Andres D Skelet Muscle. 2025; 15(1):5.

PMID: 40025502 PMC: 11871629. DOI: 10.1186/s13395-025-00374-6.

Establishment of an alternative splicing prognostic risk model and identification of FN1 as a potential biomarker in glioblastoma multiforme.

Liu X, Song J, Zhou Z, He Y, Wu S, Yang J Sci Rep. 2025; 15(1):6716.

PMID: 40000711 PMC: 11862013. DOI: 10.1038/s41598-025-91038-4.

RBM10 loss promotes metastases by aberrant splicing of cytoskeletal and extracellular matrix mRNAs.

Krishnamoorthy G, Glover A, Untch B, Sigcha-Coello N, Xu B, Vukel D J Exp Med. 2025; 222(5).

PMID: 39992626 PMC: 11849553. DOI: 10.1084/jem.20241029.

Tumour-wide RNA splicing aberrations generate actionable public neoantigens.

Kwok D, Stevers N, Etxeberria I, Nejo T, Colton Cove M, Chen L Nature. 2025; 639(8054):463-473.

PMID: 39972144 PMC: 11903331. DOI: 10.1038/s41586-024-08552-0.

References

Lawrence M, Stojanov P, Polak P, Kryukov G, Cibulskis K, Sivachenko A . Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499(7457):214-218. PMC: 3919509. DOI: 10.1038/nature12213. View

Kim E, Ilagan J, Liang Y, Daubner G, Lee S, Ramakrishnan A . SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition. Cancer Cell. 2015; 27(5):617-30. PMC: 4429920. DOI: 10.1016/j.ccell.2015.04.006. View

Neelamraju Y, Gonzalez-Perez A, Bhat-Nakshatri P, Nakshatri H, Janga S . Mutational landscape of RNA-binding proteins in human cancers. RNA Biol. 2017; 15(1):115-129. PMC: 5786023. DOI: 10.1080/15476286.2017.1391436. View

. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014; 511(7511):543-50. PMC: 4231481. DOI: 10.1038/nature13385. View

Zhao J, Sun Y, Huang Y, Song F, Huang Z, Bao Y . Functional analysis reveals that RBM10 mutations contribute to lung adenocarcinoma pathogenesis by deregulating splicing. Sci Rep. 2017; 7:40488. PMC: 5238425. DOI: 10.1038/srep40488. View

He L, Liu J, Collins I, Sanford S, OConnell B, Benham C . Loss of FBP function arrests cellular proliferation and extinguishes c-myc expression. EMBO J. 2000; 19(5):1034-44. PMC: 305642. DOI: 10.1093/emboj/19.5.1034. View

Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P . Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013; 122(22):3616-27. PMC: 3837510. DOI: 10.1182/blood-2013-08-518886. View

Hintzsche J, Gorden N, Amato C, Kim J, Wuensch K, Robinson S . Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma. Melanoma Res. 2017; 27(3):189-199. PMC: 5470740. DOI: 10.1097/CMR.0000000000000345. View

Desmedt C, Zoppoli G, Gundem G, Pruneri G, Larsimont D, Fornili M . Genomic Characterization of Primary Invasive Lobular Breast Cancer. J Clin Oncol. 2016; 34(16):1872-81. DOI: 10.1200/JCO.2015.64.0334. View

10.

Patnaik M, Lasho T, Finke C, Hanson C, Hodnefield J, Knudson R . Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: prevalence, clinical correlates, and prognostic relevance. Am J Hematol. 2013; 88(3):201-6. DOI: 10.1002/ajh.23373. View

11.

Obeng E, Chappell R, Seiler M, Chen M, Campagna D, Schmidt P . Physiologic Expression of Sf3b1(K700E) Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation. Cancer Cell. 2016; 30(3):404-417. PMC: 5023069. DOI: 10.1016/j.ccell.2016.08.006. View

12.

Johnston J, Teer J, Cherukuri P, Hansen N, Loftus S, Chong K . Massively parallel sequencing of exons on the X chromosome identifies RBM10 as the gene that causes a syndromic form of cleft palate. Am J Hum Genet. 2010; 86(5):743-8. PMC: 2868995. DOI: 10.1016/j.ajhg.2010.04.007. View

13.

Lindsley R, Mar B, Mazzola E, Grauman P, Shareef S, Allen S . Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015; 125(9):1367-76. PMC: 4342352. DOI: 10.1182/blood-2014-11-610543. View

14.

Brooks A, Choi P, de Waal L, Sharifnia T, Imielinski M, Saksena G . A pan-cancer analysis of transcriptome changes associated with somatic mutations in U2AF1 reveals commonly altered splicing events. PLoS One. 2014; 9(1):e87361. PMC: 3909098. DOI: 10.1371/journal.pone.0087361. View

15.

Duncan R, Bazar L, Michelotti G, Tomonaga T, Krutzsch H, Avigan M . A sequence-specific, single-strand binding protein activates the far upstream element of c-myc and defines a new DNA-binding motif. Genes Dev. 1994; 8(4):465-80. DOI: 10.1101/gad.8.4.465. View

16.

Jiang L, Huang J, Higgs B, Hu Z, Xiao Z, Yao X . Genomic Landscape Survey Identifies SRSF1 as a Key Oncodriver in Small Cell Lung Cancer. PLoS Genet. 2016; 12(4):e1005895. PMC: 4836692. DOI: 10.1371/journal.pgen.1005895. View

17.

Zhang J, Lieu Y, Ali A, Penson A, Reggio K, Rabadan R . Disease-associated mutation in SRSF2 misregulates splicing by altering RNA-binding affinities. Proc Natl Acad Sci U S A. 2015; 112(34):E4726-34. PMC: 4553800. DOI: 10.1073/pnas.1514105112. View

18.

Bray N, Pimentel H, Melsted P, Pachter L . Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol. 2016; 34(5):525-7. DOI: 10.1038/nbt.3519. View

19.

Zhou Q, Derti A, Ruddy D, Rakiec D, Kao I, Lira M . A chemical genetics approach for the functional assessment of novel cancer genes. Cancer Res. 2015; 75(10):1949-58. DOI: 10.1158/0008-5472.CAN-14-2930. View

20.

Papasaikas P, Valcarcel J . The Spliceosome: The Ultimate RNA Chaperone and Sculptor. Trends Biochem Sci. 2015; 41(1):33-45. DOI: 10.1016/j.tibs.2015.11.003. View