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

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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

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Acknowledgement

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.

Author information

Author notes

  1. Abhishek Goyal MD

    Present address: Internal Medicine Resident at Westchester Medical Center, Valhalla, NY, USA

  2. Joshua A. Strauss MD

    Present address: Advanced Care Oncology and Hematology Associates, Springfield, NJ, USA

  3. Abby B. Siegel MD, MS

    Present address: Merck & Co, Kenilworth, NJ, USA

Authors and Affiliations

  1. Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, New York, NY, USA

    Chih-Ching Yeh PhD, Jing Shen PhD, Hui-chen Wu PhD, Qiao Wang, Irina Gurvich MS, Mary V. Gamble PhD & Regina M. Santella PhD

  2. School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan

    Chih-Ching Yeh PhD

  3. Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan

    Chih-Ching Yeh PhD

  4. Department of Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA

    Abhishek Goyal MD, Joshua A. Strauss MD, Rachael A. Safyan MD, Gulam A. Manji MD, PhD, Abby B. Siegel MD, MS & Regina M. Santella PhD

  5. Internal Medicine Resident at Westchester Medical Center, Valhalla, NY, USA

    Rachael A. Safyan MD & Gulam A. Manji MD, PhD

  6. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA

    Abby B. Siegel MD, MS & Regina M. Santella PhD

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  1. Chih-Ching Yeh PhD
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Corresponding author

Correspondence to Regina M. Santella PhD.

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Yeh, CC., Goyal, A., Shen, J. et al. Global Level of Plasma DNA Methylation is Associated with Overall Survival in Patients with Hepatocellular Carcinoma. Ann Surg Oncol 24, 3788–3795 (2017). https://doi.org/10.1245/s10434-017-5913-4

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  • DOI: https://doi.org/10.1245/s10434-017-5913-4

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