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Cited by 115Epigenetics and DNA MethylationCancer-related gene regulationCancer-related molecular mechanisms research

Elucidating the Landscape of Aberrant DNA Methylation in Hepatocellular Carcinoma

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Song, Min-Ae, Tiirikainen, Maarit, Kwee, Sandi, Okimoto, Gordon, Yu, Herbert, Wong, Linda L.·2013·PLoS ONE
DOI 10.1371/journal.pone.0055761PMC PMC3577824
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Abstract

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers and frequently presents with an advanced disease at diagnosis. There is only limited knowledge of genome-scale methylation changes in HCC. METHODS AND FINDINGS: We performed genome-wide methylation profiling in a total of 47 samples including 27 HCC and 20 adjacent normal liver tissues using the Illumina HumanMethylation450 BeadChip. We focused on differential methylation patterns in the promoter CpG islands as well as in various less studied genomic regions such as those surrounding the CpG islands, i.e. shores and shelves. Of the 485,577 loci studied, significant differential methylation (DM) was observed between HCC and adjacent normal tissues at 62,692 loci or 13% (p<1.03e-07). Of them, 61,058 loci (97%) were hypomethylated and most of these loci were located in the intergenic regions (43%) or gene bodies (33%). Our analysis also identified 10,775 differentially methylated (DM) loci (17% out of 62,692 loci) located in or surrounding the gene promoters, 4% of which reside in known Differentially Methylated Regions (DMRs) including reprogramming specific DMRs and cancer specific DMRs, while the rest (10,315) involving 4,106 genes could be potential new HCC DMR loci. Interestingly, the promoter-related DM loci occurred twice as frequently in the shores than in the actual CpG islands. We further characterized 982 DM loci in the promoter CpG islands to evaluate their potential biological function and found that the methylation changes could have effect on the signaling networks of Cellular development, Gene expression and Cell death (p=1.0e-38), with BMP4, CDKN2A, GSTP1, and NFATC1 on the top of the gene list. CONCLUSION: Substantial changes of DNA methylation at a genome-wide level were observed in HCC. Understanding epigenetic changes in HCC will help to elucidate the pathogenesis and may eventually lead to identification of molecular markers for liver cancer diagnosis, treatment and prognosis.

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  • The role of epigenetic dysregulation in driving the aberrant activity of CREs and retrotransposons in HCC remains incompletely understood.

    “the role of epigenetic dysregulation in driving the aberrant activity of CREs and retrotransposons in HCC remains incompletely understood50–52,93.”

    From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [51]

    The Introduction says HCC methylation studies had been limited in scope, including studies of repetitive elements such as LINE1, and calls for further analysis. This supports the broader point that epigenetic changes in HCC remain incompletely understood, but the paper does not establish a role for epigenetic dysregulation in driving aberrant CRE or retrotransposon activity. (LLM, conf=0.76)

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References 31 · Cited by 115

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Authors
Song, M.-A., Tiirikainen, M., Kwee, S., Okimoto, G., Yu, H., & Wong, L. L.
Affiliations
  • University of Hawaiʻi at Mānoa (US)
  • Cancer Center of Hawaii (US)
Corresponding author
Wong, Linda L.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-02-20
Volume
8
Issue
2
Pages
e55761
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0055761
PMC
PMC3577824
OpenAlex
W2054047930
Cited by
115
References
31
Citations by year
2026: 4 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 10 · 2017: 12 · 2016: 14 · 2015: 15 · 2014: 18 · 2013: 2
FWCI
7.32
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health
  • National Cancer Institute (P30CA071789)
  • National Institute on Minority Health and Health Disparities (U54MD007584)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
Keywords
hepatocellular carcinoma, DNA methylation, genome-wide methylation profiling, differentially methylated regions, promoter CpG islands, hypomethylation, epigenetic reprogramming, BMP4, CDKN2A, GSTP1, NFATc1, signaling networks, liver cancer biomarkers
MeSH terms
Aged, Aged, 80 and over, Enhancer Elements, Genetic, Female, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Middle Aged, Promoter Regions, Genetic, Reproducibility of Results, Genome, Human, Sequence Analysis, DNA, CpG Islands, DNA Methylation, Gene Regulatory Networks, Genetic Loci

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