Recurrent hepatocellular carcinoma is associated with the enrichment of MYC targets gene sets, elevated high confidence deleterious mutations and alternative splicing of DDB2 and BRCA1 transcripts

Purpose

Recurrence is the main cause of hepatocellular carcinoma (HCC) related deaths. Underlying recurrence biology can be better understood by comparative analysis of the complete set of transcripts between recurrent and non-recurrent HCC. In this study, transcriptomic data (GSE56545) from 21 male patients diagnosed with either recurrent or non-recurrent HCC were reanalyzed to identify deregulated pathways, somatic mutations, fusion transcripts, alternative splicing events, and the immune context in recurrent HCC.

Materials and methods

DESeq2 was used for differential expression analysis, Mutect2 for somatic mutation analysis, Arriba and STAR-Fusion for fusion transcript analysis, and rMATs for alternative splicing analysis.

Results

The results revealed that MYC targets gene sets (Hallmark_MYC_targets_V1 and Hallmark_MYC_targets_V2) were significantly enriched in recurrent HCC. Among the MYC targets, CBX3, NOP56, CDK4, NPM1, MCM5, MCM4 and PA2G4 upregulation was significantly associated with poor survival. Somatic mutation analysis demonstrated that the numbers of high confidence deleterious mutations were significantly increased in recurrent HCC. Alternative splicing-mediated production of non-functional DDB2 and oncogenic BRCA1 D11q were discovered in recurrent HCC. Finally, CD8⁺ T-cells were significantly decreased in recurrent HCC.

Conclusions

These results indicated that the enrichment of MYC targets gene sets is one of the most critical factors that leads to the development of recurrent HCC. In addition, elevated deleterious mutation numbers and alternative spliced DDB2 and BRCA1 isoforms have been identified as prominent contributors to increasing genomic instability in male patients with recurrent HCC.