The landscape of alternative splicing in hepatocellular carcinoma and its association with TP53 mutation

Alternative splicing (AS) is a key mechanism of post-transcriptional regulation and is crucial for the formation of proteomic diversity in eukaryotes. Splicing dysregulation is increasingly recognized as a new hallmark in cancer development and progression. These aberrant splicing events are not only promising biomarkers for diagnosis and prognosis, but also novel targets for drug development. Hepatocellular carcinoma (HCC), which is the most common primary liver tumor, is characterized by significant tumor heterogeneity, which poses a major challenge for effective treatment. Therefore, there is a need to explore post-transcriptional mechanisms, such as AS, as a novel approach to identify new prognostic biomarkers and therapeutic targets. To explore post-transcriptional mechanisms, we uncovered the landscape of AS in HCC, investigated its clinical implications, and explored its association with key driver gene mutations. Differential AS events between HCC and adjacent normal samples were identified, which enabled patient stratification into two subgroups with different prognoses. The poor-prognosis subgroup exhibited a higher TP53 mutation frequency and lower AS values. Through cross-dataset analysis, we identified three consensus differential events that were distinct between TP53 -mutant and wild-type samples. These consensus differential AS events were highly correlated with differentially expressed splicing factors between the TP53 groups. In conclusion, our study demonstrates that alternative splicing is extensively dysregulated in HCC and has significant prognostic implications. We provide evidence that TP53 mutation, a key genetic driver in HCC, is associated with distinct AS patterns, potentially through the transcriptional regulation of specific splicing factors.