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Aim: Genetic analysis has revealed a subset of recurrently mutated genes and aberrant cellular signaling pathways in hepatocellular carcinoma. To investigate genetic alterations and dysregulated pathways in hepatocellular carcinoma, we performed targeted sequencing and exome analysis using next-generation sequencer., Methods: We analyzed the somatic mutational profiles of 16 genes in primary hepatocellular carcinoma by targeted ultra-deep sequencing using nine pairs of specimens (tumor and peripheral blood) and whole-exome sequencing using one pair of samples., Results: Overall, somatic mutations with high allele fraction were identified in tumor tissues by targeted deep sequencing. Somatic mutations with high allele fraction were observed in TP53 (3/9; 33%) and CTNNB1 (2/9; 22%) genes in five out of nine (55%) specimens. In vitro analysis showed that CTNNB1 H36P mutant protein identified in tumor samples was resistant to protein degradation and promoted cell proliferation. Exome sequencing identified SLIT3 mutation, implying that dysregulation of axon guidance genes is involved in the development of hepatocellular carcinoma. These results showed that TP53 and WNT/β-catenin signaling pathways were commonly mutated in hepatocellular carcinoma., Conclusion: These results suggest that targeted sequencing and exome sequencing enable the identification of putative oncogenic driver mutations during the development of hepatocarcinoma., (© 2016 The Japan Society of Hepatology.)