Differential alternative splicing between hepatocellular carcinoma with normal and elevated serum alpha-fetoprotein

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Serum alpha-fetoprotein (AFP) is a standard biomarker for hepatocellular carcinoma (HCC) screening.
• However, a subset of HCC patients exhibits normal AFP levels, necessitating further investigation into their molecular underpinnings.
• Understanding the biological features of normal AFP HCC is crucial for comprehensive cancer management.

Purpose of the Study:

• To investigate differential alternative splicing (AS) in HCC with normal versus high serum AFP levels.
• To identify specific genes and pathways associated with HCCs that do not elevate AFP.
• To elucidate the molecular mechanisms driving HCCs with normal serum AFP.

Main Methods:

• Genome-wide survey of AS events using RNA-sequencing data from The Cancer Genome Atlas (TCGA).
• Analysis of 249 HCC samples, categorized into normal (n=131) and high (n=118) serum AFP groups.
• Statistical analysis to identify differential AS events (ΔPSI > 0.05, FDR < 0.05) and associated clinical factors.

Main Results:

• 161 differential AS events across 125 genes were identified between normal and high AFP HCC groups.
• Enrichment analysis revealed involvement in cell migration, proliferation, and insulin-like growth factor (IGF) regulation.
• Fibronectin 1 (FN1) showed altered AS, with exon skipping more prevalent in normal AFP HCCs, and these events correlated with gender and vascular invasion.

Conclusions:

• Alternative splicing plays a significant role in the molecular landscape of HCCs with normal serum AFP levels.
• Differential AS events, particularly in genes like FN1, may contribute to HCC development and progression independent of AFP elevation.
• These findings highlight AS as a potential therapeutic target and diagnostic marker in specific HCC subtypes.