Whole-exome mutational landscape of metastasis in patient-derived hepatocellular carcinoma cells

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.

Association of FOXO3 Expression with Tumor Pathogenesis, Prognosis and Clinicopathological Features in Hepatocellular Carcinoma: A Systematic Review with Meta-Analysis

“…Therefore, these 112 papers were also removed from our study. Finally, five articles [ 12 , 15 , 16 , 19 , 20 ] were assessed for quality and data extraction. All these studies reached the quality threshold according to NOS score ( Table 2 ) and were included for quantitative meta-analysis ( Figure 1 ).…”

“…A total of 1059 HCC cases were included. Zhou et al [ 15 ] did not directly report sample collection procedure or patient information. The rest of the samples were obtained by surgical resection, and the enrolled patients did not receive any pre- or post-operative treatment.…”

“…The number of tumor samples across studies ranged from 91 to 365, and 537 of the totals (50.71%) exhibited FOXO3 overexpression. All included studies [ 12 , 15 , 16 , 19 , 20 ] provided data relating FOXO3 expression with OS, four articles [ 12 , 16 , 19 , 20 ] with clinicopathological features and two investigations [ 12 , 16 ] also compared FOXO3 levels between tumoral and healthy liver tissues. Only one study [ 16 ] evaluated disease-free survival (DFS).…”

“…Although FOXO3 is ubiquitously expressed [ 8 , 10 ], hepatocytes usually exhibit high levels [ 7 ], and this transcription factor seems to be implicated in the pathogenesis of liver disease [ 12 ]. Regarding liver cancer, several studies sustain that abnormal FOXO3 overexpression could represent an unfavorable hallmark in HCC, being linked to multidrug resistance [ 13 , 14 ], more aggressive phenotypes and a worse long-term prognosis [ 12 , 15 , 16 , 17 ]. Conversely, other investigations defend the correlation of low levels of FOXO3 with the development of chemoresistance [ 18 ] and poorer HCC patient outcomes [ 19 , 20 ].…”

Transcriptomic heterogeneity of driver gene mutations reveals novel mutual exclusivity and improves exploration of functional associations

“…In this study, the mutation profile, gene expression profile, and corresponding clinical metadata (including clinicopathological factors, overall survival [OS], disease‐specific survival [DSS]) of LUAD patients were accessed through The Cancer Genome Atlas (TCGA) portal ( https://portal.gdc.cancer.gov ). Non‐silent mutations are of great significance for the functional analysis of mutated genes, 39 so subsequent analysis focused on non‐silent mutations. For the mutation profile, non‐silent somatic mutations (missense mutation, nonsense mutation, translation start site, in‐frame deletion, in‐frame insert, frame‐shift deletion, frame‐shift insert, splice site, and nonstop mutation) remained according to UCSC Genome Browser ( http://genome.ucsc.edu ).…”