Abstract
Alternative splicing (AS) is a ubiquitous mechanism in which pre-mRNA can be spliced into divergent variants and involved in carcinogenesis and progression in several cancers. In the present study, we systematically profiled prognostic AS signatures involving both low grade glioma (LGG) and glioblastoma (GBM) and investigated the association of AS signatures with tumor grade and IDH1 status in glioma. Percent spliced in (PSI) values and corresponding clinical data were obtained from TCGA SpliceSeq and TCGA data portal, respectively. Prognostic AS signatures were identified using univariate and stepwise multivariate Cox regression. Heatmap analysis was performed based on prognostic AS signatures. A prognostic signature was established with 69 and 88 AS events, including specific splicing events of MUTYH, STEAP3, and CTNNB1, in LGG and GBM cohorts, respectively. The area under the curve (AUC) of the prediction model was 0.968 at 2000 days of overall survival (OS) in the LGG cohort and 0.966 at 450 days of OS in the GBM cohort. In addition, these prognostic AS signatures could complement current molecular classification, such as IDH1 mutation, 1p/19q codeletion, and ATRX loss, of glioma and further identify potential subgroups of glioma with the same molecular features. In conclusion, our study systematically profiled prognostic AS events involving both low grade glioma and glioblastoma for the first time, which also shed light on the crosstalk between AS signatures and molecular features of glioma.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aldave G, Gonzalez-Huarriz, Rubio A et al (2018) The aberrant splicing of BAF45d links splicing regulation and transcription in glioblastoma. Neuro-oncology 20:930–941. https://doi.org/10.1093/neuonc/noy007
Beqqali A (2018) Alternative splicing in cardiomyopathy. Biophys Rev 10:1061–1071. https://doi.org/10.1007/s12551-018-0439-y
Binder H, Willscher E, Loeffler-Wirth H et al (2019) DNA methylation, transcriptome and genetic copy number signatures of diffuse cerebral WHO grade II/III gliomas resolve cancer heterogeneity and development. Acta Neuropathologica Communications 7:59. https://doi.org/10.1186/s40478-019-0704-8
Castle JC, Zhang C, Shah JK, Kulkarni AV, Kalsotra A, Cooper TA, Johnson JM (2008) Expression of 24,426 human alternative splicing events and predicted cis regulation in 48 tissues and cell lines. Nat Genet 40:1416–1425. https://doi.org/10.1038/ng.264
Chakraborty S, Ghosh Z (2019) A systemic insight into astrocytoma biology across different grades. J Cell Physiol 234:4243–4255. https://doi.org/10.1002/jcp.27193
Chen H, Gao F, He M et al (2019) Long-read RNA sequencing identifies alternative splice variants in hepatocellular carcinoma and tumor-specific isoforms. Hepatology https://doi.org/10.1002/hep.30500
D'Elia G, Caliendo G, Casamassimi A, Cioffi M, Molinari AM, Vietri MT (2018) APC and MUTYH analysis in FAP patients: a novel mutation in APC gene and genotype-phenotype correlation. Genes (Basel) 9:322. https://doi.org/10.3390/genes9070322
Donaldson LF, Beazley-Long N (2016) Alternative RNA splicing: contribution to pain and potential therapeutic strategy. Drug Discov Today 21:1787–1798. https://doi.org/10.1016/j.drudis.2016.06.017
Dussaussois-Montagne A, Jaillet J, Babin L et al (2017) SETMAR isoforms in glioblastoma: a matter of protein stability. Oncotarget 8:9835–9848. https://doi.org/10.18632/oncotarget.14218
Feng H, Qin Z, Zhang X (2013) Opportunities and methods for studying alternative splicing in cancer with RNA-Seq. Cancer Lett 340:179–191. https://doi.org/10.1016/j.canlet.2012.11.010
Ferrarese R, Harsh GR. Yadav AK et al (2014) Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression, J Clin Invest 124:2861–2876. https://doi.org/10.1172/JCI68836
Gerard X, Perrault I, Munnich A, Kaplan J, Rozet JM (2015) Intravitreal injection of splice-switching oligonucleotides to manipulate splicing in retinal cells. Mol Ther Nucleic Acids 4:e250. https://doi.org/10.1038/mtna.2015.24
Ghigna C, Giordano S, Shen H et al (2005) Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Mol Cell 20:881–890. https://doi.org/10.1016/j.molcel.2005.10.026
Gokmen-Polar Y, Neelamraju Y, Goswami CP et al (2019) Splicing factor ESRP1 controls ER-positive breast cancer by altering metabolic pathways EMBO Reports 20 https://doi.org/10.15252/embr.201846078
Han M, Xu R, Wang S et al (2018) Six-transmembrane epithelial antigen of prostate 3 predicts poor prognosis and promotes glioblastoma growth and invasion. Neoplasia 20:543–554. https://doi.org/10.1016/j.neo.2018.04.002
Havens MA, Hastings ML (2016) Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res 44:6549–6563. https://doi.org/10.1093/nar/gkw533
Kahles A, Lehmann KV, Toussaint NC et al (2018) Comprehensive analysis of alternative splicing across Tumors from 8,705 patients. Cancer Cell 34:211–224 e216. https://doi.org/10.1016/j.ccell.2018.07.001
Katz Y, Wang ET, Airoldi EM, Burge CB (2010) Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat Methods 7:1009–1015. https://doi.org/10.1038/nmeth.1528
Kline CN, Joseph NM, Grenert JP et al (2016) Inactivating MUTYH germline mutations in pediatric patients with high-grade midline gliomas. Neuro-oncology 18:752–753. https://doi.org/10.1093/neuonc/now013
Lapointe S, Perry A, Butowski NA (2018) Primary brain tumours in adults. Lancet 392:432–446. https://doi.org/10.1016/S0140-6736(18)30990-5
Louis DN, Perry A, Reifenberger G et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820. https://doi.org/10.1007/s00401-016-1545-1
Lu J, Li H, Chen Z, Fan L, Feng S, Cai X, Wang H (2019) Identification of 3 subpopulations of tumor-infiltrating immune cells for malignant transformation of low-grade glioma. Cancer Cell Int 19:265. https://doi.org/10.1186/s12935-019-0972-1
Ma L, Lin K, Chang G et al (2019) Aberrant activation of beta-catenin Signaling drives glioma tumorigenesis via USP1-mediated stabilization of EZH2. Cancer Res 79:72–85. https://doi.org/10.1158/0008-5472.CAN-18-1304
Mao S, Li Y, Lu Z et al (2018) Survival-associated alternative splicing signatures in esophageal carcinoma. Carcinogenesis. https://doi.org/10.1093/carcin/bgy123
Mogilevsky M, Shimshon, Kumar S et al (2018) Modulation of MKNK2 alternative splicing by splice-switching oligonucleotides as a novel approach for glioblastoma treatment. Nucleic Acids Res 46:11396–11404. https://doi.org/10.1093/nar/gky921
Pal S, Bi Y, Macyszyn L, Showe LC, O'Rourke DM, Davuluri RV (2014) Isoform-level gene signature improves prognostic stratification and accurately classifies glioblastoma subtypes. Nucleic Acids Res 42:e64. https://doi.org/10.1093/nar/gku121
Paul Y, Mondal B, Patil V, Somasundaram K (2017) DNA methylation signatures for 2016 WHO classification subtypes of diffuse gliomas. Clin Epigenetics 9:32. https://doi.org/10.1186/s13148-017-0331-9
Paronetto MP, Passacantilli I, Sette C (2016) Alternative splicing and cell survival: from tissue homeostasis to disease. Cell Death Differ 23:1919–1929. https://doi.org/10.1038/cdd.2016.91
Plotz G, Casper M, Raedle J et al (2012) MUTYH gene expression and alternative splicing in controls and polyposis patients. Hum Mutat 33:1067–1074. https://doi.org/10.1002/humu.22059
Poulikakos PI, Persaud Y, Janakiraman M et al (2011) RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480:387–390. https://doi.org/10.1038/nature10662
Ryan M, Wong WG, Brown R et al (2016) TCGASpliceSeq a compendium of alternative mRNA splicing in cancer nucleic acids. Research 44:D1018–D1022. https://doi.org/10.1093/nar/gkv1288
Salton M, Kasprzak WK, Voss T, Shapiro BA, Poulikakos PI, Misteli T (2015) Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing. Nat Commun 6:7103. https://doi.org/10.1038/ncomms8103
Scotti MM, Swanson MS (2016) RNA mis-splicing in disease. Nat Rev Genet 17:19–32. https://doi.org/10.1038/nrg.2015.3
Siegel RL, Miller KD, Jemal A (2018) Cancer statistics. CA Cancer J Clin 68:7–30. https://doi.org/10.3322/caac.21442
Skubal M, Gielen GH, Waha A et al (2016) Altered splicing leads to reduced activation of CPEB3 in high-grade gliomas. Oncotarget 7:41898–41912. https://doi.org/10.18632/oncotarget.9735
Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. https://doi.org/10.1056/NEJMoa043330
Stupp R, Taillibert S, Kanner AA et al (2015) Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. Jama 314:2535–2543. https://doi.org/10.1001/jama.2015.16669
Stupp R, Taillibert S, Kanner AA et al (2017) Effect of tumor-treating fields plus maintenance Temozolomide vs maintenance Temozolomide alone on survival in patients with Glioblastoma: a randomized clinical trial. Jama 318:2306–2316. https://doi.org/10.1001/jama.2017.18718
Su CH, Dhananjaya D, Tarn WY (2018) Alternative splicing in neurogenesis and brain development frontiers in molecular. Biosciences. https://doi.org/10.3389/fmolb.2018.00012
Tesileanu CMS, Dirven L, Wijnenga MMJ et al (2020) Survival of diffuse astrocytic glioma, IDH1/2 wildtype, with molecular features of glioblastoma, WHO grade IV: a confirmation of the cIMPACT-NOW criteria. Neuro-oncology 22:515–523. https://doi.org/10.1093/neuonc/noz200
Tian J, Wang Z, Mei S et al (2019) CancerSplicingQTL: a database for genome-wide identification of splicing QTLs in human cancer. Nucleic Acids Res 47:D909–D916. https://doi.org/10.1093/nar/gky954
Vashishtha V, Jinghan N, Yadav AK (2018) Antagonistic role of GSK3 isoforms in glioma survival. J Cancer 9:1846–1855. https://doi.org/10.7150/jca.21248
Wang ET, Sandberg R, Luo S et al (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456:470–476. https://doi.org/10.1038/nature07509
Xiong Y, Deng Y, Wang K, Zhou H, Zheng X, Si L, Fu Z (2018) Profiles of alternative splicing in colorectal cancer and their clinical significance: a study based on large-scale sequencing data. EBioMedicine 36:183–195. https://doi.org/10.1016/j.ebiom.2018.09.021
Zhang Y, Yan L, Zeng J et al (2019) Pan-cancer analysis of clinical relevance of alternative splicing events in 31 human cancers. Oncogene. https://doi.org/10.1038/s41388-019-0910-7
Zhou X, Wang R, Li X et al (2019) Splicing factor SRSF1 promotes gliomagenesis via oncogenic splice-switching of MYO1B. J Clin Invest 129:676–693. https://doi.org/10.1172/JCI120279
Funding
This study was supported by the National Nature Science Fund of China (No. 81872064), Natural Science Fund of Guangdong Province, China (No. 2016A030313549), Natural Science Fund of Tibet Autonomous Region (No.XZ2017ZR-ZYZ27), Science and Technology Program of Guangzhou, China (No.201607010350), Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University (No.2016 J008).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of Interest
The authors declare that they have no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zeng, Y., Zhang, P., Wang, X. et al. Identification of Prognostic Signatures of Alternative Splicing in Glioma. J Mol Neurosci 70, 1484–1492 (2020). https://doi.org/10.1007/s12031-020-01581-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-020-01581-0