Epigenomic profiling of DNA methylation for hepatocellular carcinoma diagnosis and prognosis prediction.
Adult
Aged
Biomarkers, Tumor
/ genetics
Carcinoma, Hepatocellular
/ genetics
Cell Differentiation
Cell Movement
Cell Proliferation
CpG Islands
DNA Methylation
Early Detection of Cancer
/ methods
Epigenesis, Genetic
Female
Genetic Predisposition to Disease
Hep G2 Cells
Humans
Liver Neoplasms
/ genetics
Male
Middle Aged
Molecular Diagnostic Techniques
Phenotype
Predictive Value of Tests
Progression-Free Survival
Promoter Regions, Genetic
Proto-Oncogene Proteins c-fes
/ genetics
Time Factors
Tumor Burden
alpha-Fetoproteins
/ analysis
DNA methylation
genome-wide profiling
hepatocellular carcinoma
hypermethylation
Journal
Journal of gastroenterology and hepatology
ISSN: 1440-1746
Titre abrégé: J Gastroenterol Hepatol
Pays: Australia
ID NLM: 8607909
Informations de publication
Date de publication:
Oct 2019
Oct 2019
Historique:
received:
31
08
2018
revised:
31
03
2019
accepted:
23
04
2019
pubmed:
1
5
2019
medline:
6
5
2020
entrez:
1
5
2019
Statut:
ppublish
Résumé
DNA hypermethylation has emerged as a novel molecular biomarker for the diagnosis and prognosis prediction of many cancers. We aimed to identify clinically useful biomarkers regulated by DNA methylation in hepatocellular carcinoma (HCC). Genome-wide methylation analysis in HCCs and paired noncancerous tissues was performed using an Illumina Infinium HumanMethylation 450K BeadChip array. Methylation-specific polymerase chain reaction and pyrosequencing were used to validate the methylation status of selected genes in 100 paired HCCs and noncancerous samples. A total of 97 027 (20.0%) out of 485 577 CpG sites significantly were differed between HCC and noncancerous tissues. Among all the significant CpG sites, 48.8% are hypermethylated and 51.2% are hypomethylated in HCCs. Multiple signaling pathways (AMP-activated protein kinase, estrogen, and adipocytokine) involved in gene methylation were identified in HCC. FES was selected for further analysis based on its high level of methylation confirmed by polymerase chain reaction and pyrosequencing. The result showed that FES hypermethylation was correlated with tumor size (0.001), serum alpha fetoprotein (0.023), and tumor differentiation (0.006). FES protein was significantly downregulated in 51/100 (51%) HCCs, and 94.12% (48/51) of them were due to promoter hypermethylation. Both FES hypermethylation and protein downregulation were associated with the progression-free survival and overall survival of HCC patients. Overexpressed and knockdown of FES confirmed its inhibitory effect on the proliferation and migration of HCC cells. We identified many new differentially methylated CpGs in HCCs and demonstrate that FES functions as a tumor suppressor gene in HCC and its methylation status could be used as an indicator for prognosis of HCC.
Sections du résumé
BACKGROUND AND AIM
OBJECTIVE
DNA hypermethylation has emerged as a novel molecular biomarker for the diagnosis and prognosis prediction of many cancers. We aimed to identify clinically useful biomarkers regulated by DNA methylation in hepatocellular carcinoma (HCC).
METHODS
METHODS
Genome-wide methylation analysis in HCCs and paired noncancerous tissues was performed using an Illumina Infinium HumanMethylation 450K BeadChip array. Methylation-specific polymerase chain reaction and pyrosequencing were used to validate the methylation status of selected genes in 100 paired HCCs and noncancerous samples.
RESULTS
RESULTS
A total of 97 027 (20.0%) out of 485 577 CpG sites significantly were differed between HCC and noncancerous tissues. Among all the significant CpG sites, 48.8% are hypermethylated and 51.2% are hypomethylated in HCCs. Multiple signaling pathways (AMP-activated protein kinase, estrogen, and adipocytokine) involved in gene methylation were identified in HCC. FES was selected for further analysis based on its high level of methylation confirmed by polymerase chain reaction and pyrosequencing. The result showed that FES hypermethylation was correlated with tumor size (0.001), serum alpha fetoprotein (0.023), and tumor differentiation (0.006). FES protein was significantly downregulated in 51/100 (51%) HCCs, and 94.12% (48/51) of them were due to promoter hypermethylation. Both FES hypermethylation and protein downregulation were associated with the progression-free survival and overall survival of HCC patients. Overexpressed and knockdown of FES confirmed its inhibitory effect on the proliferation and migration of HCC cells.
CONCLUSIONS
CONCLUSIONS
We identified many new differentially methylated CpGs in HCCs and demonstrate that FES functions as a tumor suppressor gene in HCC and its methylation status could be used as an indicator for prognosis of HCC.
Substances chimiques
AFP protein, human
0
Biomarkers, Tumor
0
alpha-Fetoproteins
0
FES protein, human
EC 2.7.10.2
Proto-Oncogene Proteins c-fes
EC 2.7.10.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1869-1877Subventions
Organisme : China Postdoctoral Science Foundation
ID : 2013M540554
Organisme : Science and Technology Program of Shandong Province, China
ID : 2016GSF301031
Informations de copyright
© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.
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