Annals of Surgical Oncology

, Volume 24, Issue 12, pp 3788–3795 | Cite as

Global Level of Plasma DNA Methylation is Associated with Overall Survival in Patients with Hepatocellular Carcinoma

  • Chih-Ching Yeh
  • Abhishek Goyal
  • Jing Shen
  • Hui-chen Wu
  • Joshua A. Strauss
  • Qiao Wang
  • Irina Gurvich
  • Rachael A. Safyan
  • Gulam A. Manji
  • Mary V. Gamble
  • Abby B. Siegel
  • Regina M. Santella
Translational Research and Biomarkers



The impact of folate deficiency on global DNA methylation is uncertain. It also is unclear whether global DNA methylation is associated with outcome in HCC. LINE-1 methylation levels, as a surrogate marker of global methylation, may be influenced by folate deficiency. However, the interaction between LINE-1 methylation and folate level on overall survival (OS) in hepatocellular carcinoma (HCC) patients is unknown. We evaluated whether LINE-1 hypomethylation and folate deficiency are associated with HCC prognosis.


We prospectively recruited 172 HCC patients between 2008 and 2012. LINE-1 methylation levels in plasma and white blood cells (WBC) were measured by pyrosequencing, and plasma folate levels by a radioprotein-binding assay.


Patients with plasma LINE-1 methylation <70.0% (hypomethylation) had significantly worse OS compared with those with ≥70.0% methylation (hypermethylation) [hazard ratio (HR) = 1.77; 95% confidence interval (CI) 1.12–2.79; P = 0.015]. HCC patients with lower plasma folate levels also had worse survival (<27.7 vs. ≥27.7 nmol/L; HR = 1.96; 95% CI, 1.24–3.09; P = 0.004). Furthermore, survival was poor in patients in whom both plasma LINE-1 methylation and folate levels were low compared with those patients in whom both levels were high (HR = 3.36; 95%CI, 1.77-6.40; P < 0.001). This interaction neared statistical significance (P = 0.057). No significant association was found between WBC LINE-1 methylation levels and survival.


These findings suggest that both lower plasma levels of LINE-1 methylation and folate are associated with worse survival in HCC patients.


LINE-1 methylation Folate Hepatocellular carcinoma Overall survival 



This work is supported by NIH Grants R01 ES005116 (RMS), P30 ES009089 (RMS) and by the Ministry of Science and Technology, Taiwan MOST 104-2918-I-038-001 (CCY).

Conflict of interest

There is no interest confliction involved for this submission.

Supplementary material

10434_2017_5913_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 13 kb)
10434_2017_5913_MOESM2_ESM.docx (22 kb)
Supplementary material 2 (DOCX 22 kb)


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Copyright information

© Society of Surgical Oncology 2017

Authors and Affiliations

  • Chih-Ching Yeh
    • 1
    • 2
    • 3
  • Abhishek Goyal
    • 4
    • 5
  • Jing Shen
    • 1
  • Hui-chen Wu
    • 1
  • Joshua A. Strauss
    • 4
    • 6
  • Qiao Wang
    • 1
  • Irina Gurvich
    • 1
  • Rachael A. Safyan
    • 4
    • 5
  • Gulam A. Manji
    • 4
    • 5
  • Mary V. Gamble
    • 1
  • Abby B. Siegel
    • 4
    • 7
    • 8
  • Regina M. Santella
    • 1
    • 4
    • 7
  1. 1.Department of Environmental Health Sciences, Mailman School of Public HealthColumbia University Medical CenterNew YorkUSA
  2. 2.School of Public Health, College of Public HealthTaipei Medical UniversityTaipeiTaiwan
  3. 3.Department of Public Health, College of Public HealthChina Medical UniversityTaichungTaiwan
  4. 4.Department of Medicine, College of Physicians and SurgeonsColumbia University Medical CenterNew YorkUSA
  5. 5.Internal Medicine Resident at Westchester Medical CenterValhallaUSA
  6. 6.Advanced Care Oncology and Hematology AssociatesSpringfieldUSA
  7. 7.Herbert Irving Comprehensive Cancer CenterColumbia University Medical CenterNew YorkUSA
  8. 8.Merck & CoKenilworthUSA

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