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

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Abstract
Alternative splicing is an important mechanism of regulating eukaryotic gene expression. Understanding the most common alternative splicing events in colorectal cancer (CRC) will help developing diagnostic, prognostic or therapeutic tools in CRC. Publicly available RNA-seq data of 31 pairs of CRC and normal tissues and 18 pairs of metastatic and normal tissues were used to identify alternative splicing events using PSI and DEXSeq methods. The highly significant splicing events were used to search a database of The Cancer Genome Atlas (TCGA). We identified alternative splicing events in 10 genes marking the signature of 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 and FBLN2-E9). Except for CHEK1, all other 9 splicing events were confirmed by TCGA data with 382 CRC tumors and 52 normal controls. Two splicing events (COL6A3 and HKDC1) were found to be significantly associated with patient overall survival. The alternative splicing signatures of the 10 genes are highly consistent with previous reports and/or relevant to cancer biology. The 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.
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