In order to explore the genomic basis for liver cancer metastasis, whole-exome sequencing (WES) was performed on patient-derived hepatocellular carcinoma (HCC) cell lines with differential metastatic potentials and analyzed their clonal evolution relationships. An evolutionary tree based on genomic single nucleotide polymorphism (SNP) was constructed in MegaX software. The WES data showed that the average percentage of heterogeneous mutations in each HCC cell lines was 16.55% (range, 15.38%–18.17%). C: G > T: A and T: A > C: G somatic transitions were the two most frequent substitutions. In these metastatic HCC cell lines, non-silent gene mutations were found in 21.88% of known driver genes and 10 classical signaling pathways. The protein interaction network was constructed by STRING, and hub genes were found in the shared trunk mutation genes and the heterogeneous branch mutations respectively. In cBioPortal database, some of the selected hub genes were found to be associated with poor overall survival (OS) of HCC patients. Among the mutated HCC driver genes, a novel KEAP1 mutation with a homozygous frameshift truncation at the c-terminal Nrf2 binding region was detected and verified in MHCC97-H and HCC97LM3 cells. In conclusion, WES data demonstrate that HCC cell lines from tumor biopsy specimens of the same patient have obtained different metastatic potentials through repeated selection in rodents in vivo, and they do indeed have a genetic relationship at the genomic level.