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Cited by 0Epigenetics and DNA MethylationCancer-related molecular mechanisms researchCancer-related gene regulation

Comprehensive in silico CpG methylation analysis in hepatocellular carcinoma identifies tissue- and tumor-type specific marks disconnected from gene expression

Open access
Bilbao, Idoia, Recalde, Miriam, Daian, Fabrice, Herranz, José Maria, Elizalde, María, Iñarrairaegui, Mercedes, Canale, Matteo, Fernández-Barrena, Maite G. +6 more·2024·Journal of Physiology and Biochemistry
DOI 10.1007/s13105-024-01045-8PMC PMC11682006
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Abstract

DNA methylation is crucial for chromatin structure, transcription regulation and genome stability, defining cellular identity. Aberrant hypermethylation of CpG-rich regions is common in cancer, influencing gene expression. However, the specific contributions of individual epigenetic modifications to tumorigenesis remain under investigation. In hepatocellular carcinoma (HCC), DNA methylation alterations are documented as in other tumor types. We aimed to identify hypermethylated CpGs in HCC, assess their specificity across other tumor types, and investigate their impact on gene expression. To this end, public methylomes from HCC, other liver diseases, and 27 tumor types as well as expression data from TCGA-LIHC and GTEx were analyzed. This study identified 39 CpG sites that were hypermethylated in HCC compared to control liver tissue, and were located within promoter, gene bodies, and intergenic CpG islands. Notably, these CpGs were predominantly unmethylated in healthy liver tissue and other normal tissues. Comparative analysis with 27 other tumors revealed both common and HCC-specific hypermethylated CpGs. Interestingly, the HCC-hypermethylated genes showed minimal expression in the different healthy tissues, with marginal changes in the level of expression in the corresponding tumors. These findings confirm previous evidence on the limited influence of DNA hypermethylation on gene expression regulation in cancer. It also highlights the existence of mechanisms that allow the selection of tissue-specific methylation marks in normally unexpressed genes during carcinogenesis. Overall, our study contributes to demonstrate the complexity of cancer epigenetics, emphasizing the need of better understanding the interplay between DNA methylation, gene expression dynamics, and tumorigenesis. Graphical Abstract

AI snapshot

Written from the paper’s full text.

TL;DR

This in silico study integrates public HM450 methylomes and TCGA/GTEx expression data to identify 39 CpGs hypermethylated in HCC, mostly unmethylated in normal tissues and blood, with some HCC-specific and some shared across many tumor types. It finds hypermethylation largely disconnected from meaningful gene expression changes, supporting passenger/selection hypotheses.

Key findings

  • From 3,862 CpGs hypermethylated in HCC versus controls, the study selected 39 CpGs that were hypermethylated in HCC (β > 0.3) but unmethylated in control liver, cirrhotic tissue, or whole blood (β < 0.2); these were validated in independent datasets and methylated in at least 54% of 977 HCC tissues analyzed (range 54.70–84.25%).
  • Of the 39 CpGs, 32 were unmethylated in all healthy tissues examined; 10 CpGs showed differential methylation exclusively in HCC, while 5 CpGs were hypermethylated in 10 or more tumor types. Cholangiocarcinoma had the most hypermethylated CpGs (23/39), followed by colorectal adenocarcinoma (17), breast carcinoma (16), and pancreatic adenocarcinoma (14); thyroid carcinoma showed none.
  • The 39 CpGs mapped to 32 genes and 2 intergenic regions: 10 genes were not expressed in liver or HCC, 5 showed no expression difference, 9 were downregulated, and 8 were upregulated in HCC. Promoter CGI hypermethylation generally associated with downregulation and gene body CGI hypermethylation with upregulation, with exceptions AMN and SEPT9; most expression changes were small.
  • Genes specifically hypermethylated in HCC (EFNB2, MTHFD2, TSC22D1, CELF6, SH3YL1, RNF135) had markedly lower expression in liver than in other healthy tissues, and genes hypermethylated in ≥10 tumors (MIR129-2, intergenic, MCIDAS, HOXA11, KCNA3) were generally not expressed in healthy tissues.

Methods

  • Discovery used public HM450 methylomes from GSE56588, GSE54503, and TCGA-LIHC (670 HCCs, 135 controls), with whole blood from GSE40279, non-tumor liver disease datasets GSE61258, GSE48325, and GSE60753, validation datasets GSE60753, GSE89852, and GSE157341, and 28 TCGA tumor types (8,706 tumor and 759 non-tumor samples). Expression was analyzed from TCGA-LIHC and GTEx.
  • Differential methylation was assessed across 485,512 CpGs present in all discovery samples; 144,543 CGI CpGs were retained. Hypermethylation required mean β difference > 0.2 and FDR < 0.05 (two-sided t-test with Benjamini–Hochberg correction), followed by filtering for β > 0.3 in HCC and β < 0.2 in control liver, cirrhotic tissue, or blood.
  • Experimental validation used HCC (n = 19), non-tumoral (n = 5), and healthy liver (n = 5) samples; DNA was bisulfite converted, PCR amplified, Sanger sequenced, and quantified with EditR. Hierarchical clustering, UMAP, and GraphPad Prism statistics were also used.

Limitations

  • The paper does not include a dedicated limitations section; the discussion states that the role of differential methylation in some regions remains to be determined and that hypermethylation may be a passenger event rather than a driver.
  • Evident from the text: findings rely heavily on public HM450 array and TCGA/GTEx datasets, experimental validation was limited to three CpGs and small local samples (19 HCC, 5 non-tumoral, 5 healthy liver), and the authors themselves question the biological relevance of the small expression changes observed.
  • Evident from the text: the study is correlative/in silico without functional experiments testing causality, and the authors call for further studies on the mechanisms and functional consequences of these epigenetic alterations.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s13105-024-01045-8

Cites

59 of 59 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

31 of 51 cited sources checked · 21 supported · 0 flagged · accuracy not yet measured

  • Interpretationcitation

    Hypermethylation may be a "passenger" event, reflecting epigenetic dysregulation in cancer rather than contributing to its development.

    “They support the hypothesis that hypermethylation may be a “passenger” event, reflecting epigenetic dysregulation in cancer rather than contributing to its development [48, 49].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [48] Sproul D, Kitchen RR, Nestor CE, Dixon JM, Sims AH, Harrison DJ, Ramsahoye BH, Meehan RR (2012) Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol 13:R84. https://doi.org/10.1186/gb-2012-13-10-r84 source
    • cites [49] Sproul D, Nestor C, Culley J, Dickson JH, Dixon JM, Harrison DJ, Meehan RR, Sims AH, Ramsahoye BH (2011) Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer. Proc Natl Acad Sci 108:4364–4369. https://doi.org/10.1073/pnas.1013224108 source
  • Findingown data

    Hypermethylation across multiple tumor types occurs predominantly in genes that are specifically repressed in the tissue of origin.

    “our results support that hypermethylation across multiple tumor types occurs predominantly in genes that are specifically repressed in the tissue of origin”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [14] Fan S, Tang J, Li N, Zhao Y, Ai R, Zhang K, Wang M, Du W, Wang W (2019) Integrative analysis with expanded DNA methylation data reveals common key regulators and pathways in cancers. npj Genom Med 4:2. https://doi.org/10.1038/s41525-019-0077-8 source

      The Results section ('Identification of triple-evidenced genes'; page unavailable) examines methylation and expression across 13 cancers but says methylation shows no clear trend for the five genes discussed. The Methods compare tumors with corresponding normal samples. Neither passage addresses whether hypermethylation occurs predominantly in genes specifically repressed in the tissue of origin; searches for that relationship found no supporting passage. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [26] Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428. https://doi.org/10.1038/nrg816 source
  • Findingown data

    Focusing on CGIs, global hypermethylation enrichment was observed in HCC patients versus controls (p-value = 4.31E-28).

    “Focusing on CGIs, and consistent with the literature [15], we observed global hypermethylation enrichment in HCC patients versus controls (p-value = 4.31E-28; Supplementary Figure S1D).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [15] Fernández-Barrena MG, Arechederra M, Colyn L, Berasain C, Avila MA (2020) Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg. Jhep Reports 2:100167. https://doi.org/10.1016/j.jhepr.2020.100167 source
  • Findingown data

    The other 17 genes were significantly differentially expressed.

    “However, the other 17 genes were significantly differentially expressed (Fig. 4B-C).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The expression of eight genes (VASH2, MAFA, LRRC10B, PIK3R3, TRIL, CELSR3, IDUA and SEPT9) was increased in HCC compared to control livers.

    “while that of eight genes (VASH2, MAFA, LRRC10B, PIK3R3, TRIL, CELSR3, IDUA and SEPT9) was increased (Fig. 4C) in HCC compared to control livers.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 30
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Methylation of CpG sites is an essential component of cell type-specific gene regulation and a fundamental mark of cell identity.

    “Therefore, methylation of CpG sites is an essential component of cell type-specific gene regulation, a fundamental mark of cell identity [12, 16, 41]”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [12] Dor Y, Cedar H (2018) Principles of DNA methylation and their implications for biology and medicine. Lancet 392:777–786. https://doi.org/10.1016/s0140-6736(18)31268-6 source
    • cites [16] Gifford CA, Ziller MJ, Gu H, Trapnell C, Donaghey J, Tsankov A, Shalek AK, Kelley DR, Shishkin AA, Issner R, Zhang X, Coyne M, Fostel JL, Holmes L, Meldrim J, Guttman M, Epstein C, Park H, Kohlbacher O, Rinn J, Gnirke A, Lander ES, Bernstein BE, Meissner A (2013) Transcriptional and Epigenetic Dynamics during Specification of Human Embryonic Stem Cells. Cell 153:1149–1163. https://doi.org/10.1016/j.cell.2013.04.037 source
    • cites [41] Recalde M, Gárate-Rascón M, Herranz JM, Elizalde M, Azkona M, Unfried JP, Boix L, Reig M, Sangro B, Fernández-Barrena MG, Fortes P, Ávila MA, Berasain C, Arechederra M (2022) DNA Methylation Regulates a Set of Long Non-Coding RNAs Compromising Hepatic Identity during Hepatocarcinogenesis. Cancers 14:2048. https://doi.org/10.3390/cancers14092048 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Approximately half of the annotated CGI are distributed between gene bodies and intergenic regions.

    “However approximately half of the annotated CGI are distributed between gene bodies and intergenic regions [24].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [24] Illingworth RS, Gruenewald-Schneider U, Webb S, Kerr ARW, James KD, Turner DJ, Smith C, Harrison DJ, Andrews R, Bird AP (2010) Orphan CpG islands identify numerous conserved promoters in the mammalian genome. Plos Genet 6:e1001134. https://doi.org/10.1371/journal.pgen.1001134 source

  • Classified as probably not a substantial claim.

    Premisecitation

    The unique methylation profile of cells can be used to identify their tissue of origin.

    “and therefore the unique methylation profile of cells can be used to identify their tissue of origin [33, 59].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [33] Loyfer N, Magenheim J, Peretz A, Cann G, Bredno J, Klochendler A, Fox-Fisher I, Shabi-Porat S, Hecht M, Pelet T, Moss J, Drawshy Z, Amini H, Moradi P, Nagaraju S, Bauman D, Shveiky D, Porat S, Dior U, Rivkin G, Or O, Hirshoren N, Carmon E, Pikarsky A, Khalaileh A, Zamir G, Grinbaum R, Gazala MA, Mizrahi I, Shussman N, Korach A, Wald O, Izhar U, Erez E, Yutkin V, Samet Y, Golinkin DR, Spalding KL, Druid H, Arner P, Shapiro AMJ, Grompe M, Aravanis A, Venn O, Jamshidi A, Shemer R, Dor Y, Glaser B, Kaplan T (2023) A DNA methylation atlas of normal human cell types. Nature 613:355–364. https://doi. source
    • cites [59] Zhu T, Liu J, Beck S, Pan S, Capper D, Lechner M, Thirlwell C, Breeze CE, Teschendorff AE (2022) A pan-tissue DNA methylation atlas enables in silico decomposition of human tissue methylomes at cell-type resolution. Nat Methods 19:296–306. https://doi.org/10.1038/s41592-022-01412-7 source

      The Abstract (page unavailable) describes a DNA methylation atlas for 13 tissues and 40 cell types that predicts the cell of origin of diverse cancers. The ‘DNAm-atlas identifies cell of origin in pancreatic cancer’ section (page unavailable) reports distinguishing ductal from endocrine origins of pancreatic tumors. This supports using methylation data to infer cellular origin in that setting, but it does not establish that an individual cell’s unique methylation profile identifies its tissue of origin. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Increased CGI gene body methylation positively correlates with transcriptional activation.

    “Increased CGI gene body methylation positively correlates with transcriptional activation [6, 25, 55]”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [6] Arechederra M, Daian F, Yim A, Bazai SK, Richelme S, Dono R, Saurin AJ, Habermann BH, Maina F (2018) Hypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer. Nat Commun 9:3164. https://doi.org/10.1038/s41467-018-05550-5 source
    • cites [25] Jones PA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 13:484–492. https://doi.org/10.1038/nrg3230 source
    • cites [55] Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G (2014) Gene Body Methylation Can Alter Gene Expression and Is a Therapeutic Target in Cancer. Cancer Cell 26:577–590. https://doi.org/10.1016/j.ccr.2014.07.028 source

      The Results section reports a positive correlation between gene-body methylation and expression for a subset of probes, supporting the general relationship. But most of those positively correlated sites were outside CpG islands, while 62% of a negatively correlated gene-body subset were within CpG islands. The paper therefore does not establish the claim specifically for CGI gene-body methylation; page numbers were not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Alterations of methylation patterns are associated with disease development and allow to distinguish healthy from diseased states, including cancer.

    “Importantly, alterations of methylation patterns are associated with disease development and allow to distinguish healthy from diseased states, including cancer [8, 12, 31].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [8] Bergman Y, Cedar H (2013) DNA methylation dynamics in health and disease. Nat Struct Mol Biol 20:274–281. https://doi.org/10.1038/nsmb.2518 source
    • cites [12] Dor Y, Cedar H (2018) Principles of DNA methylation and their implications for biology and medicine. Lancet 392:777–786. https://doi.org/10.1016/s0140-6736(18)31268-6 source
    • cites [31] Liang W-W, Lu RJ-H, Jayasinghe RG, Foltz SM, Porta-Pardo E, Geffen Y, Wendl MC, Lazcano R, Kolodziejczak I, Song Y, Govindan A, Demicco EG, Li X, Li Y, Sethuraman S, Payne SH, Fenyö D, Rodriguez H, Wiznerowicz M, Shen H, Mani DR, Rodland KD, Lazar AJ, Robles AI, Ding L, Consortium CPTA, Aguet F, Akiyama Y, An E, Anand S, Anurag M, Babur O, Bavarva J, Birger C, Birrer M, Calinawan A, Cantley LC, Cao S, Carr S, Ceccarelli M, Chan D, Chinnaiyan A, Cho H, Chowdhury S, Cieslik M, Clauser K, Colaprico A, Zhou DC, Leprevost F da V, Day C, Dhanasekaran M, Domagalski M, Dou Y, Druker B, Edwards N, Elli source

      The Introduction links aberrant DNA methylation to cancer development and progression. The Results (Aberrant methylation associated with therapeutic vulnerabilities) report pronounced methylation differences between tumors and corresponding normal-adjacent tissues. This supports distinguishing cancer tissue from adjacent non-tumor tissue, but does not establish the broader claim for diseases generally or for healthy individuals. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Genes specifically repressed in one tissue are prone to be hypermethylated in the corresponding tumor, which may help distinguishing the tissue of origin of the tumor.

    “Moreover, it has been shown that genes specifically repressed in one tissue are prone to be hypermethylated in the corresponding tumor, which may help distinguishing the tissue of origin of the tumor [48, 49].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [48] Sproul D, Kitchen RR, Nestor CE, Dixon JM, Sims AH, Harrison DJ, Ramsahoye BH, Meehan RR (2012) Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol 13:R84. https://doi.org/10.1186/gb-2012-13-10-r84 source
    • cites [49] Sproul D, Nestor C, Culley J, Dickson JH, Dixon JM, Harrison DJ, Meehan RR, Sims AH, Ramsahoye BH (2011) Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer. Proc Natl Acad Sci 108:4364–4369. https://doi.org/10.1073/pnas.1013224108 source

      The Results report that genes specifically repressed in normal luminal epithelial cells were more frequently methylated in primary breast tumors than active genes. The paper also says these methylation patterns distinguish epithelial and mesenchymal lineages within breast cancer. It does not establish that the pattern distinguishes tumors by tissue of origin across different organs. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    The level of methylation in CGIs regulates gene expression.

    “it is widely accepted that the level of methylation in the regions known as CGI regulates gene expression”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [6] Arechederra M, Daian F, Yim A, Bazai SK, Richelme S, Dono R, Saurin AJ, Habermann BH, Maina F (2018) Hypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer. Nat Commun 9:3164. https://doi.org/10.1038/s41467-018-05550-5 source
    • cites [43] Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610. https://doi.org/10.1038/nrg1655 source
    • cites [45] Siegfried Z, Eden S, Mendelsohn M, Feng X, Tsuberi B-Z, Cedar H (1999) DNA methylation represses transcription in vivo. Nat Genet 22:203–206. https://doi.org/10.1038/9727 source
    • cites [55] Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G (2014) Gene Body Methylation Can Alter Gene Expression and Is a Therapeutic Target in Cancer. Cancer Cell 26:577–590. https://doi.org/10.1016/j.ccr.2014.07.028 source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Promoter CGI hypermethylation represses transcription, whereas hypermethylation at gene body CGIs activates gene expression.

    “It is well-known that promoter CGI hypermethylation represses transcription [43, 45], whereas hypermethylation at gene body CGIs activates gene expression [6, 55].”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [43] Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610. https://doi.org/10.1038/nrg1655 source
    • cites [45] Siegfried Z, Eden S, Mendelsohn M, Feng X, Tsuberi B-Z, Cedar H (1999) DNA methylation represses transcription in vivo. Nat Genet 22:203–206. https://doi.org/10.1038/9727 source
    • cites [6] Arechederra M, Daian F, Yim A, Bazai SK, Richelme S, Dono R, Saurin AJ, Habermann BH, Maina F (2018) Hypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer. Nat Commun 9:3164. https://doi.org/10.1038/s41467-018-05550-5 source

      The Results section ('CGI hypermethylation correlates with gene upregulation in Alb-R26Met HCC'; page unavailable) reports overexpressed genes with hypermethylated gene-body CGIs. The Discussion describes this as a positive correlation and says the underlying mechanisms remain to be uncovered. Thus, the source supports an association in liver cancer, but not the unqualified claim that gene-body CGI hypermethylation activates expression. The promoter claim is attached to different citations and is not assessed here. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [55] Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G (2014) Gene Body Methylation Can Alter Gene Expression and Is a Therapeutic Target in Cancer. Cancer Cell 26:577–590. https://doi.org/10.1016/j.ccr.2014.07.028 source

      The Discussion says the authors’ experiments show that gene-body DNA methylation increases gene expression. But the Results section on rapid remethylation says most positively correlated gene-body CpGs were outside CpG islands; another Results section reports that many gene-body probes within CpG islands were negatively correlated with expression. The paper therefore supports the gene-body methylation point, but not the claim that hypermethylation at gene-body CGIs generally activates expression. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The location of CGIs determines the direction of this regulation.

    “and that the location of these CGIs determines the direction of this regulation [6, 43, 45, 55]”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [6] Arechederra M, Daian F, Yim A, Bazai SK, Richelme S, Dono R, Saurin AJ, Habermann BH, Maina F (2018) Hypermethylation of gene body CpG islands predicts high dosage of functional oncogenes in liver cancer. Nat Commun 9:3164. https://doi.org/10.1038/s41467-018-05550-5 source

      The Results section reports that hypermethylated CGIs in downregulated genes were located around the ATG, while those in overexpressed genes could also be in the gene body. It describes this as a correlation between CGI location and transcription status, not evidence that location determines the direction of regulation. Page numbers were not supplied. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [43] Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610. https://doi.org/10.1038/nrg1655 source
    • cites [45] Siegfried Z, Eden S, Mendelsohn M, Feng X, Tsuberi B-Z, Cedar H (1999) DNA methylation represses transcription in vivo. Nat Genet 22:203–206. https://doi.org/10.1038/9727 source
    • cites [55] Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G (2014) Gene Body Methylation Can Alter Gene Expression and Is a Therapeutic Target in Cancer. Cancer Cell 26:577–590. https://doi.org/10.1016/j.ccr.2014.07.028 source

      The Results sections report that promoter methylation can be negatively correlated with gene expression, while some gene-body methylation is positively correlated. But the paper also reports gene-body probes with a negative correlation, including probes within CpG islands. Location is therefore relevant, but the source does not support the unqualified claim that CGI location determines the direction of regulation. Page numbers were not provided in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Study design and conductcitation

    None of these 1061 CpGs were part of the 353 CpG sites constituting the aging clock, ruling out the possibility of an age-related methylation effect in the identified CpGs.

    “Moreover, none of these 1061 CpGs were part of the 353 CpG sites constituting the aging clock [21], ruling out the possibility of an age-related methylation effect in the identified CpGs.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [21] Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol 14:3156. https://doi.org/10.1186/gb-2013-14-10-r115 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Genes repressed in a specific tissue are prone to hypermethylation in cancers derived from that tissue.

    “that genes repressed in a specific tissue are prone to hypermethylation in cancers derived from that tissue [48, 49]”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [48] Sproul D, Kitchen RR, Nestor CE, Dixon JM, Sims AH, Harrison DJ, Ramsahoye BH, Meehan RR (2012) Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol 13:R84. https://doi.org/10.1186/gb-2012-13-10-r84 source
    • cites [49] Sproul D, Nestor C, Culley J, Dickson JH, Dixon JM, Harrison DJ, Meehan RR, Sims AH, Ramsahoye BH (2011) Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer. Proc Natl Acad Sci 108:4364–4369. https://doi.org/10.1073/pnas.1013224108 source

      The Results report that genes repressed in normal luminal epithelial cells were significantly more frequently methylated in primary breast tumors than active genes. The Discussion proposes that aberrant methylation in breast cancer affects genes already repressed through normal lineage commitment. The claim extends this breast-cancer finding to cancers derived from any tissue, which this paper does not establish. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S1 (asserted).

    Premisecitation

    It has been proposed that the majority of hypermethylated genes in cancer are genes already transcriptionally repressed in the pre-cancerous tissue.

    “it has also been proposed that the majority of hypermethylated genes in cancer are genes already transcriptionally repressed in the pre-cancerous tissue [48, 49].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [48] Sproul D, Kitchen RR, Nestor CE, Dixon JM, Sims AH, Harrison DJ, Ramsahoye BH, Meehan RR (2012) Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol 13:R84. https://doi.org/10.1186/gb-2012-13-10-r84 source
    • cites [49] Sproul D, Nestor C, Culley J, Dickson JH, Dixon JM, Harrison DJ, Meehan RR, Sims AH, Ramsahoye BH (2011) Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer. Proc Natl Acad Sci 108:4364–4369. https://doi.org/10.1073/pnas.1013224108 source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Some DNA methylation patterns are associated with specific types of cancers and can be used to differentiate between various tumor types.

    “it has also been described that some DNA methylation patterns are associated with specific types of cancers and therefore can be used to differentiate between various tumor types [56, 59].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [56] Zhang S, He S, Zhu X, Wang Y, Xie Q, Song X, Xu C, Wang W, Xing L, Xia C, Wang Q, Li W, Zhang X, Yu J, Ma S, Shi J, Gu H (2023) DNA methylation profiling to determine the primary sites of metastatic cancers using formalin-fixed paraffin-embedded tissues. Nat Commun 14:5686. https://doi.org/10.1038/s41467-023-41015-0 source
    • cites [59] Zhu T, Liu J, Beck S, Pan S, Capper D, Lechner M, Thirlwell C, Breeze CE, Teschendorff AE (2022) A pan-tissue DNA methylation atlas enables in silico decomposition of human tissue methylomes at cell-type resolution. Nat Methods 19:296–306. https://doi.org/10.1038/s41592-022-01412-7 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Aberrant DNA methylation in cancer occurs in genes normally repressed in the corresponding normal tissues.

    “it has been described that aberrant DNA methylation in cancer occurs in genes normally repressed in the corresponding normal tissues [48, 49]”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [48] Sproul D, Kitchen RR, Nestor CE, Dixon JM, Sims AH, Harrison DJ, Ramsahoye BH, Meehan RR (2012) Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol 13:R84. https://doi.org/10.1186/gb-2012-13-10-r84 source
    • cites [49] Sproul D, Nestor C, Culley J, Dickson JH, Dixon JM, Harrison DJ, Meehan RR, Sims AH, Ramsahoye BH (2011) Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer. Proc Natl Acad Sci 108:4364–4369. https://doi.org/10.1073/pnas.1013224108 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    HCC development and progression consists in a multistep and complex process with sequential genetic and epigenetic alterations.

    “HCC development and progression consists in a multistep and complex process with sequential genetic and epigenetic alterations [15, 32].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [15] Fernández-Barrena MG, Arechederra M, Colyn L, Berasain C, Avila MA (2020) Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg. Jhep Reports 2:100167. https://doi.org/10.1016/j.jhepr.2020.100167 source
    • cites [32] Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS (2021) Hepatocellular carcinoma Nat Rev Dis Primers 7:6. https://doi.org/10.1038/s41572-020-00240-3 source

  • May combine two claims.

    Findingown data

    Comparative analysis with 27 other tumors revealed both common and HCC-specific hypermethylated CpGs.

    “Comparative analysis with 27 other tumors revealed both common and HCC-specific hypermethylated CpGs.”
    • Also stated in: § Differential methylation of the CpGs hypermethylated in HCC in other tumors · plain
      “Additionally, we identified a subset of CpGs specifically hypermethylated in HCC, while many others are hypermethylated across multiple tumor types.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Focusing on the six genes specifically hypermethylated in HCC, one (CELF6) is not expressed in either liver or HCC, two (EFNB2 and MTHFD2) are not associated with changes in expression, and the remaining three (TSC22D1, SH3YL1 and RNF135) are slightly downregulated in HCC.

    “focusing on the six genes that are specifically hypermethylated in HCC (Fig. 5A-right), and noting that one of them is not expressed in either liver or HCC (CELF6), two others are not associated with changes in expression (EFNB2 and MTHFD2), and the remaining three are slightly downregulated in HCC (TSC22D1, SH3YL1 and RNF135)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The HCC-hypermethylated genes showed minimal expression in different healthy tissues, with marginal changes in expression in corresponding tumors.

    “Interestingly, the HCC-hypermethylated genes showed minimal expression in the different healthy tissues, with marginal changes in the level of expression in the corresponding tumors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Each of the 39 CpGs was methylated in at least 54% of the 977 HCC tissues analyzed, ranging from 54.70% to 84.25%.

    “Indeed, each CpGs was methylated in at least 54% of the 977 HCC tissues analyzed, ranging from 54.70% to 84.25% (Supplementary Figure S2B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Genes whose expression was downregulated in HCC had the hypermethylated CpGs located in promoter CGIs, whereas the upregulated genes had hypermethylated CpGs located in gene body CGIs.

    “In agreement with the literature, genes whose expression was downregulated in HCC had the hypermethylated CpGs located in promoter CGIs, whereas the upregulated genes had hypermethylated CpGs located in gene body CGIs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In addition to the two CpGs located in intergenic regions, 21 CpGs were located within promoter CGIs, while the remaining 16 were within gene body CGIs.

    “We found that in addition to the two CpGs located in intergenic regions, 21 CpGs were located within promoter CGIs, while the remaining 16 were within gene body CGIs (Fig. 4D, Supplementary Table S3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Uterine carcinosarcoma, sarcoma, ovarian serous cystadenocarcinoma, and acute myeloid leukemia exhibited methylation in only two CpG sites, while testicular germ cell tumors and thymoma did not display methylation in any of the CpG sites analyzed.

    “Conversely, uterine carcinosarcoma, sarcoma, ovarian serous cystadenocarcinoma, and acute myeloid leukemia exhibited methylation in only two CpG sites, while testicular germ cell tumors and thymoma did not display methylation in any of the CpG sites analyzed (Fig. 3B).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    CpG#26 is located in an intergenic region.

    “CpG#26 was located in an intergenic region”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In our analysis, MCIDAS is hypermethylated in HCC, cholangiocarcinoma, and colorectal, breast, prostate, pancreas, lung, esophagus or head and neck carcinomas, among others.

    “In our analysis, we found hypermethylation of MCIDAS in HCC, cholangiocarcinoma, and colorectal, breast, prostate, pancreas, lung, esophagus or head and neck carcinomas, among others.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Two exceptions were observed: AMN and SEPT9, whose CpGs were located in the gene body and the promoter CGIs respectively but their expression was reduced and induced.

    “We observed two exceptions, AMN and SEPT9, whose CpGs were located in the gene body and the promoter CGIs respectively but their expression was reduced and induced (Fig. 4B-C, Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among the 39 CpGs, some methylation sites are common to many tumor types while others are specific to HCC.

    “we identified a group of methylation sites that were common to many tumor types, while others were specific to HCC”
    • Also stated in: § Discussion · plain
      “our analysis identified common and tumor-specific epigenetic events”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The 39 CpG sites were located in 32 distinct genes and two intergenic regions not uniformly distributed across the genome, predominantly on larger chromosomes, with six on chromosome 1.

    “The 39 CpG sites were located in 32 distinct genes and two intergenic regions not uniformly distributed across the genome (Supplementary Table S3), as they were predominantly found on the larger chromosomes, with six of them in chromosome 1 (Supplementary Figure S3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Eight CpGs are specifically hypermethylated in HCC and located in six genes: EFNB2 (CpG#2, CpG#17, CpG#21), MTHFD2 (CpG#3), TSC22D1 (CpG#8), CELF6 (CpG#24), SH3YL1 (CpG#29) and RNF135 (CpG#32).

    “our study reveals eight CpGs specifically hypermethylated in HCC and located in six genes, EFNB2 (CpG#2, CpG#17, CpG#21), MTHFD2 (CpG#3), TSC22D1 (CpG#8), CELF6 (CpG#24), SH3YL1 (CpG#29) and RNF135 (CpG#32).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The study identified 39 CpG sites that were hypermethylated in HCC compared to control liver tissue and located within promoter, gene bodies, and intergenic CpG islands.

    “This study identified 39 CpG sites that were hypermethylated in HCC compared to control liver tissue, and were located within promoter, gene bodies, and intergenic CpG islands.”
    • Also stated in: § Introduction · plain
      “Here, using publicly available methylomes, we identified a set of 39 CpGs hypermethylated in HCC compared to control liver that were located not only in promoter but also in gene bodies and intergenic CGIs.”
    • Also stated in: § In silico identification of CpGs hypermethylated in HCC · plain
      “Finally, we selected a set of 39 CpGs that were hypermethylated (β-value > 0.3) in HCC but unmethylated (β-value < 0.2) in control liver, cirrhotic tissue or whole blood (Fig. 1B, Supplementary Table S3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Six CpGs exhibited methylation (mean β-value > 0.2) in only one of the analyzed tissues, while one CpG was methylated in five tissues.

    “Additionally, six CpGs (CpG#20, CpG#26, CpG#28, CpG#31, CpG#33, and CpG#39) exhibited methylation (mean β-value > 0.2) in only one of the analyzed tissues, while one CpG (CpG#27) was methylated (mean β-value > 0.2) in five tissues (Fig. 3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    These three genes are not hypermethylated in thyroid carcinoma and at least two of them are expressed in the normal thyroid tissue.

    “Interestingly, as mentioned above these three genes are not hypermethylated in thyroid carcinoma (THCA) and at least two of them are expressed in the normal thyroid tissue.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The remaining two CpGs (CpG#9 and CpG#22) were methylated (mean β-value > 0.2) in two and three tumors, respectively.

    “The remaining two CpGs (CpG#9 and CpG#22) were methylated (mean β-value > 0.2) in two and three tumors, respectively (Fig. 3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Two CpGs (cg04321866 and cg04281464) were hypermethylated in HCC compared to both healthy liver and non-tumoral tissue, while the third CpG (cg04823311) was hypermethylated in both HCC and non-tumoral tissue but not in healthy liver samples.

    “Consistent with our criteria, two CpGs (cg04321866 and cg04281464) were hypermethylated in HCC compared to both healthy liver and non-tumoral tissue, while the third CpG (cg04823311) was hypermethylated in both HCC and non-tumoral tissue but not in healthy liver samples (Fig. 2).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Promoter-CGI methylation is associated with gene silencing.

    “promoter-CGI methylation is associated with gene silencing [26, 43].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428. https://doi.org/10.1038/nrg816 source
    • cites [43] Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610. https://doi.org/10.1038/nrg1655 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DNA methylation is an essential epigenetic mechanism influencing chromatin structure, regulation of transcription and genome stability.

    “DNA methylation, which consists on the addition of a methyl group at carbon 5 of cytosine in cytosine-guanine dinucleotides (CpG), is an essential epigenetic mechanism influencing chromatin structure, regulation of transcription and genome stability [26, 43].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428. https://doi.org/10.1038/nrg816 source
    • cites [43] Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610. https://doi.org/10.1038/nrg1655 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study was approved by the Human Research Review Committee of the University of Navarra (CEI 47/2015).

    “The study was approved by the Human Research Review Committee of the University of Navarra (CEI 47/2015).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Interpretationown data

    These small differences question their biological relevance.

    “questioning their biological relevance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationown data

    This result highlights a complex interplay between DNA methylation, gene expression, and tumorigenesis in HCC, suggesting that other regulatory mechanisms may influence the expression of these genes and that the role of differential methylation in these regions remains to be determined.

    “This result highlights a complex interplay between DNA methylation, gene expression, and tumorigenesis in HCC, suggesting that other regulatory mechanisms may influence the expression of these genes and that the role of differential methylation in these regions remains to be determined.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Tumor hypermethylation marks may provide insights into their tissue of origin and have implications for the development of tissue-specific biomarkers, liquid biopsy approaches and targeted therapies.

    “tumor hypermethylation marks may provide insights into their tissue of origin, and therefore have implications for the development of tissue-specific biomarkers, liquid biopsy approaches and targeted therapies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    During carcinogenesis, global hypomethylation of DNA occurs in parallel with hypermethylation of CGIs in the promoter regions.

    “It has been widely described that during the process of carcinogenesis a global hypomethylation of DNA occurs in parallel with the hypermethylation of CGIs in the promoter regions [26, 43].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428. https://doi.org/10.1038/nrg816 source
    • cites [43] Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610. https://doi.org/10.1038/nrg1655 source

  • May combine two claims.

    Study design and conductown data

    UMAP dimensionality reduction clustered HCC and control liver samples together, indicating minimal batch effect.

    “UMAP dimensionality reduction similarly clustered HCC and control liver samples together (Supplementary Figure S1C), indicating minimal batch effect.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DNA methylation is a key epigenetic modification that regulates gene expression and plays an essential role in cancer development.

    “DNA methylation is a key epigenetic modification that regulates gene expression and plays an essential role in cancer development [17, 26].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Hanahan D (2022) Hallmarks of Cancer: New Dimensions. Cancer Discov 12:31–46. https://doi.org/10.1158/2159-8290.cd-21-1059 source
    • cites [26] Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428. https://doi.org/10.1038/nrg816 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Epigenetic reprogramming, including abnormal DNA methylation patterns, is a common alteration in the tumorigenic process, independently of the cell of origin.

    “In fact, an epigenetic reprogramming, including abnormal DNA methylation patterns, is a common alteration in the tumorigenic process, independently of the cell of origin [17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Hanahan D (2022) Hallmarks of Cancer: New Dimensions. Cancer Discov 12:31–46. https://doi.org/10.1158/2159-8290.cd-21-1059 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Informed consent was obtained from each patient and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki.

    “Informed consent was obtained from each patient and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Altogether, these findings are in line with the emerging notion that genes normally repressed in a healthy tissue become hypermethylated in the corresponding tumor, a situation that would be at odds with the commonly recognized role of DNA hypermethylation in gene expression regulation.

    “Altogether, these findings are in line with the emerging notion that genes normally repressed in a healthy tissue become hypermethylated in the corresponding tumor, a situation that would be at odds with the commonly recognized role of DNA hypermethylation in gene expression regulation.”
    Quote in the paperSubstantial claim
45 of 45

  • The paper relies on this without support.

    The 39 CpGs identified as hypermethylated in HCC are methylated in HCC cells rather than in non-blood non-tumoral cells within the tumor.

    “To identify those CpGs methylated mainly in HCC cells we eliminated marks potentially originating from circulating blood cells.”

  • The paper relies on this without support.

    The methylation status of the 39 CpGs in tumor tissues from the 13 TCGA tumor types without non-tumor methylation data is sufficient to infer whether these CpGs are hypermethylated in those tumor types.

    “Additionally, the methylation status of these 39 CpGs was assessed across 13 tumor types from TCGA database where non-tumor sample methylation data were unavailable (Supplementary Table S4). While differential methylation compared to controls could not be confirmed, their methylation status in tumor tissues was established.”

  • The paper relies on this without support.

    The TCGA-LIHC and GTEx expression data are comparable and reflect gene expression in the same tissues.

    “The expression of the genes was analyzed in HCC and non-tumoral liver samples from the TCGA-LIHC dataset (raw RNA-Seq data downloaded from the GDC Data Portal) and in normal tissues from GTEx.”

  • The paper relies on this without support.

    In general, studies are focused on events within a particular tumor type, leaving uncertainty about whether these changes are specific to that tumor or associated with the general carcinogenesis process.

    “However, in general, studies are focused on events within a particular tumor type, leaving uncertainty about whether these changes are specific to that tumor or associated with the general carcinogenesis process.”

  • The paper relies on this without support.

    DNA methylation changes have been typically studied in gene promoters in association with gene expression alterations, rather than considering a broader view of differential DNA methylation at any CpG site across the genome.

    “Additionally, DNA methylation changes have been typically studied in gene promoters in association with gene expression alterations, rather than considering a broader view of differential DNA methylation at any CpG site across the genome.”
5 of 5

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Five frequently hypermethylated CpGs are called five genes

    Minor

    The paper calls this group five genes, but elsewhere identifies it as five CpGs: one intergenic and four in gene loci. Thus the five CpGs do not correspond to five genes.

1 of 1

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Authors
Bilbao, I., Recalde, M., Daian, F., Herranz, J. M., Elizalde, M., Iñarrairaegui, M., Canale, M., Fernández-Barrena, M. G., Casadei-Gardini, A., Sangro, B., Ávila, M. A., Landecho Acha, M. F., Berasain, C., & Arechederra, M.
Affiliations
  • Clinica Universidad de Navarra (ES)
  • Universidad de Navarra (ES)
  • Centre National de la Recherche Scientifique (FR)
  • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
  • Navarre Institute of Health Research (ES)
  • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT)
Corresponding author
  • Berasain, Carmen
  • Arechederra, María
ORCID
Venue
Journal of Physiology and Biochemistry
Publisher
Springer Science and Business Media LLC
Published
2024-09-21
Volume
80
Issue
4
Pages
865-879
ISSN
  • 1138-7548 (ISSN-L)
  • 1877-8755
DOI
10.1007/s13105-024-01045-8
PMC
PMC11682006
OpenAlex
W4402707896
Semantic Scholar
e2207bbb78c90c1fba74db3d2690f42cbe557852
Cited by
0
References
59
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Physiology and Biochemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • Ministerio de Ciencia e Innovación (BES-2017-079883, RYC2018-024475-1)
  • Instituto de Salud Carlos III (SCIII) cofinanced by ‘Fondo Europeo de Desarrollo Regional’ (FEDER) ‘Una Manera de Hacer Europa’ (PI19/00613)
  • Fundación Científica Asociación Española Contra el Cáncer (INVES223049AREC)
  • Universidad de Navarra
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
Keywords
hepatocellular carcinoma, DNA methylation, CpG hypermethylation, gene expression regulation, epigenetics, liver tissue, carcinogenesis, promoter methylation
MeSH terms
Computer Simulation, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Promoter Regions, Genetic, Gene Expression Regulation, Neoplastic, CpG Islands, DNA Methylation, Epigenesis, Genetic

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