ABSTRACT
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.
ABSTRACT
BACKGROUND: Because of the heterogeneity of hepatitis C virus (HCV) distribution of different genotypes, large-scale clinical trials on direct-acting antiviral (DAA) mainly included patients with genotype 1 and genotype 3 infection. Data on the efficacy of direct-acting antiviral agents in patients with chronic genotype 6 HCV infection are limited. METHODS: The PubMed, Embase, and the Cochrane Libraries were searched comprehensively. All published clinical trials assessing the efficacy of DAA therapy for patients with chronic genotype 6 HCV infection were included. Sustained virological response (SVR) and rapid virological response (RVR) were pooled. Additional meta-analyses were also performed to compare the efficacy of DAA therapy in HCV-6 versus HCV-1 or HCV-3 patients. RESULTS: Seventeen studies met the inclusion criteria and were included in our meta-analysis. The pooled SVR of all single arms was 95% [95% confidence interval (CI): 0.90-0.97]. The pooled RVR of all single arms was 97% (95% CI: 0.95-0.99). The SVR and RVR were both similar between HCV-6 and HCV-1 or HCV-3. Adverse events were common but rarely caused treatment interruption. CONCLUSION: Based on the available data, our results indicate that DAA treatment is effective and safe for patients with genotype 6 HCV infection, and the efficacy was similar compared to patients with genotype 1 HCV or genotype 3 HCV infection.
