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Table 1 DNA methylation and HCC

From: Epigenetics of hepatocellular carcinoma

Study objectives Methods Type of sample Genes identified Key findings Implications of study Refs.
Hypo-methylated Hyper-methylated
To investigate the global methylation profile of purified single hepatocytes Illumina Infinium Human Methylation27 BeadChip, COBRA and bisulfite sequencing Single hepatocytes isolated from HBV-positive HCC (HBHC) tissues EMILIN2, WNK2, TM6SF1, TLX3, HIST1H4F, TRIM58, GRASP Hepatocyte methylation profiles can be classified into 3 groups based on hepatocyte origin: HCC, adjacent tissue and normal liver. 7 novel genes were found to be aberrantly methylated in HBHC These genes can be potential novel biomarkers of HBHC once validated in larger clinical cohorts Tao et al. [16]
To identify genes hypermethylated in HCC that can be detected in plasma DNA for early diagnosis Illumina Infinium Human Methylation27 BeadChip 62 paired HCC tumor and NAT CCL20, AKT3, SCGB1D1, WFDC6, PAX4, GCET2, CD300E, CD1B, FLJ00060, MNDA DAB2IP, BMP4, ZFP41, SPDY1, CDKN2A, TSPYL5, CDKL2, ZNF154, ZNF540, CCDC37 684 CpG sites significantly hypermethylated in HCC tissues. 5 of these genes (CDKL2, CDKN2A, HIST1H3G, STEAP4, ZNF154) had detectable hypermethylated DNA in plasma of up to 63% of patients Measuring DNA methylation from patient plasma is feasible. Panel of methylated genes identified can be potential biomarkers for early diagnosis Shen et al. [17]
To study aberrant DNA methylation in HCC using higher resolution genome-wide analysis Illumina HumanMethylation 450 BeadChip 27 HCC and 20 NAT NFATC1 BMP4, CDKN2A, GSTP1 Greater global hypomethylation patterns observed in HCC compared to NAT, with higher frequency of events occurring in promoter CpG islands than CpG shores and shelves Allows deeper understanding of differential methylation patterns in various gene regulatory regions Song et al. [18]
To identify tumor suppressor genes silenced by DNA methylation in HCC Illumina Infinium Human Methylation27 BeadChip, combined with microarray analysis of gene re-expression studies 71 primary HCC tissues, 8 non-diseased normal tissues, 4 HCC cell lines ACTL6B, C19orf30, DGKI, DLX1, ELOVL4, LDHB, LRAT, MLF1, NEFH, PPM1 N, PRPH, SLC8A2, SMPD3 Identified 13 candidate tumor suppressor genes; NEFH and SMPD3 were functionally validated in vitro and in vivo. Low levels of SMPD3 were associated with early HCC recurrence after curative surgery in an independent patient cohort SMPD3 identified to be a potent tumor suppressor gene and could be an independent prognostic factor for early recurrence of HCC Revill et al. [19]
To investigate novel genome-wide aberrant DNA methylation patterns in HCV-related HCC Illumina Infinium HumanMethylation 450 BeadChip 66 pairs of HCC tumor and NAT   Identified 500 significant differentially methylated CpG sites that can distinguish HCC from NAT. Within NAT tissues, 228 CpG sites were identified to be significantly associated with HCV infection Further functional studies would help to identify markers among the large subset of CpG sites/genes found to correlate with HCV infection, liver cirrhosis or HCC to aid in diagnosis and treatment Shen et al. [20]
To investigate the genome-wide DNA methylation profile and identify stochastic epigenetic mutations (SEMs) in HCC Illumina Infinium HumanMethylation 450 BeadChip 69 pairs of HCC tumor and NAT AJAP1, ADARB2, PTPRN2, SDK1 (hypermethylated at promoter level with concomitant hypomethylation at gene body level) HCC tissues showed increased number of SEMs as compared to NAT. From a subset of SEMs unique to tumor tissues, 4 epigenetically-regulated genes that could be involved in HCC tumorigenesis were identified Methylation and SEM profiles of HCC and adjacent non-cancerous liver tissues are highly different, allowing for the identification of important driver epimutations in HCC Gentilini et al. [22]
To examine the effects of epigenetic alterations and features on the HCC genome architecture Whole-genome bisulfite, whole-genome shotgun, long read and virus-capture sequencing approaches 373 HCC cases NA Somatic mutations occur preferentially in both highly methylated as well as hypomethylated regions in the liver cancer genome. HBV integration sites occur more frequently in inactive chromatin regions Epigenetic features greatly influence the mutational processes in HCC. Understanding the mechanisms behind the interdependency between genetic, viral and epigenetic alterations in HCC can help in identifying epigenetic driver events Hama et al. [23]
  1. COBRA combined bisulfite restriction analysis, HBV Hepatitis B virus, HCV hepatitis C virus, NAT normal adjacent tissue