Identification of novel alternative splicing isoform biomarkers and their association with overall survival in colorectal cancer

Haifeng Lian,Aili Wang,Zhenru Zhou,Qian Wang,Hongtao Jia,Chengxia Liu,Kun Li,Yuanyuan Shen,Ranran Zhang

doi:10.1186/s12876-020-01288-x

Haifeng Lian, Aili Wang + Show 7 more

Open Access

https://doi.org/10.1186/s12876-020-01288-x

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Abstract

BackgroundAlternative splicing (AS) is an important mechanism of regulating eukaryotic gene expression. Understanding the most common AS events in colorectal cancer (CRC) will help developing diagnostic, prognostic or therapeutic tools in CRC.MethodsPublicly available RNA-seq data of 28 pairs of CRC and normal tissues and 18 pairs of metastatic and normal tissues were used to identify AS events using PSI and DEXSeq methods.ResultThe highly significant splicing events were used to search a database of The Cancer Genome Atlas (TCGA). We identified AS events in 9 genes in CRC (more inclusion of CLK1-E4, COL6A3-E6, CD44v8–10, alternative first exon regulation of ARHGEF9, CHEK1, HKDC1 and HNF4A) or metastasis (decrease of SERPINA1-E1a, CALD-E5b, E6). Except for CHEK1, all other 8 splicing events were confirmed by TCGA data with 382 CRC tumors and 51 normal controls. The combination of three splicing events was used to build a logistic regression model that can predict sample type (CRC or normal) with near perfect performance (AUC = 1). Two splicing events (COL6A3 and HKDC1) were found to be significantly associated with patient overall survival. The AS features of the 9 genes are highly consistent with previous reports and/or relevant to cancer biology.ConclusionsThe significant association of higher expression of the COL6A3 E5-E6 junction and HKDC1 E1-E2 with better overall survival was firstly reported. This study might be of significant value in the future biomarker, prognosis marker and therapeutics development of CRC.

Highlights

Alternative splicing (AS) is an important mechanism of regulating eukaryotic gene expression
We applied percent-spliced-in (PSI) analysis (Fig. 1a, see Methods for details) to identify splicing events, which are different in Colorectal cancer (CRC) compared to normal colon (NC) tissues with PSI change> 20% and P < 0.05
In summary, we have identified significant AS of 7 genes in CRC and its metastasis tissue, and 3 genes with the stronger effect in metastatic tissue compared to normal tissue

Summary

Introduction

Alternative splicing (AS) is an important mechanism of regulating eukaryotic gene expression. Understanding the most common AS events in colorectal cancer (CRC) will help developing diagnostic, prognostic or therapeutic tools in CRC. Colorectal cancer (CRC) is the third and second most common cancer in men and women worldwide [1] and it’s the second and third leading cause of death in men and women in developed countries [1]. AS is an important mechanism of regulating eukaryotic gene expression. Different protein isoforms produced by the same gene through AS may have related, distinct or even opposing functions [2]. Regulation of AS plays an important role in both normal and disease states of biological processes [3, 4]. Defects of AS or mutation, misregulation of splicing

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