An integrative framework identifies alternative splicing events in colorectal cancer development

Area of Science:

• Molecular Biology
• Genomics
• Cancer Research

Background:

• Alternative splicing (AS) generates diverse RNA isoforms from a single gene, potentially expanding protein repertoire.
• AS is increasingly recognized for its significant role in cancer progression.
• Understanding AS in colorectal cancer (CRC) is crucial for identifying novel therapeutic targets.

Purpose of the Study:

• To identify and characterize alternative splicing events during colorectal cancer progression.
• To investigate the role of AS in the transition from normal mucosa to primary tumors and liver metastases.
• To identify specific genes and pathways affected by AS in CRC.

Main Methods:

• Whole transcriptome analysis using GeneChip Human exon 1.0 ST Array on 80 samples (normal colon, primary CRC, liver metastasis).
• Exon-level analysis combined with AltAnalyze algorithms and MMBGX probabilistic method for AS event reconstruction.
• Differential expression analysis of genes and exons to identify AS events.

Main Results:

• The transition from normal to primary tumor showed the highest number of AS genes, which decreased in the transition to liver metastasis.
• Identified 206 genes with probable AS events involved in tumor biology, including cell-cell and cell-matrix interactions.
• Validated AS events in VCL, CALD1, B3GNT6, and CTHRC1 genes at both RNA and protein levels.

Conclusions:

• Cancer-specific alternative splicing is prevalent in the early stages of colorectal cancer.
• AS plays a significant role in the development and progression of colorectal cancer.
• The identified AS events and genes provide insights into CRC pathogenesis and potential biomarkers.