Genome-Wide Profiling of Prognostic Alternative Splicing Pattern in Pancreatic Cancer.

Min Yu,Haosheng Jin,Shiye Ruan,Bowen Huang,Baohua Hou,Liheng Ma,Zhixiang Jian,Lei Tu,Weifeng Hong,Renguo Guan

doi:10.3389/fonc.2019.00773

Abstract

Alternative splicing (AS) has a critical role in tumor progression and prognosis. Our study aimed to investigate pancreatic cancer-specific AS events using RNA-seq data, gaining systematic insights into potential prognostic predictors. We downloaded 10,623 genes with 45,313 pancreatic cancer-specific AS events from the Cancer Genome Atlas (TCGA) and SpliceSeq database. Cox univariate analyses of overall survival suggested there was a remarkable association between 6,711 AS events and overall survival in pancreatic cancer patients (P < 0.05). The area under the curves (AUC) of the receiver operator characteristic curves (ROC) of risk score was 0.89 for final prognostic predictor. Results indicated that AS events of DAZAP1, RBM4, ESRP1, QKI, and SF1 were significantly associated with overall survival. The results of FunRich showed that transcription factors KLF7, GABPA, and SP1 were the most highly related to survival-associated AS genes. Furthermore, using DriverDBv2, we identified 13 driver genes associated with survival-associated AS events, including TP53 and CDC27. Thus, we concluded that the aberrant AS patterns in pancreatic cancer patients might serve as prognostic predictors.

Highlights

During the pre-mRNA splicing, introns are removed, and the exons are left to form the final mRNA products
Exon Skip (ES) was the main subtype of alternative splicing (AS) events, while Mutually Exclusive Exons (ME) was relatively rare in the tumor
Emerging data have demonstrated that aberrant AS patterns were identified in various cancers and engaged in multiple carcinogenic processes during cancer development and progression [16]

Summary

Introduction

During the pre-mRNA splicing, introns are removed, and the exons are left to form the final mRNA products. In this process, exons which are left vary, and one single gene may generate multiple mRNA isoforms by alternative splicing (AS). Alternative splicing in pre-mRNA of Epidermal Growth Factor Receptor (EGFR) produces several isoforms, some of which are constitutively active, leading to enhanced tumorigenicity, migration, and invasion [5, 6]. EGFR, Insulin Receptor (INSR), and Vascular Endothelial Growth Factor Receptor (VEGFR), whose alternative splicing features variated, result in promoting tumor progression or reduced response to therapy [7]. Recent evidence found that several tumor suppressor genes undergo aberrant AS in cancer, which leads to

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Results

Conclusion