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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalAnnals of Surgical Oncology
DOIs
Publication statusAccepted/In press - Jun 7 2017

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DNA Methylation
Methylation
Folic Acid
Hepatocellular Carcinoma
Survival
Confidence Intervals
Leukocytes
Biomarkers

Keywords

  • Folate
  • Hepatocellular carcinoma
  • LINE-1 methylation
  • Overall survival

ASJC Scopus subject areas

  • Surgery
  • Oncology

Cite this

Global Level of Plasma DNA Methylation is Associated with Overall Survival in Patients with Hepatocellular Carcinoma. / Yeh, Chih Ching; Goyal, Abhishek; Shen, Jing; Wu, Hui chen; Strauss, Joshua A.; Wang, Qiao; Gurvich, Irina; Safyan, Rachael A.; Manji, Gulam A.; Gamble, Mary V.; Siegel, Abby B.; Santella, Regina M.

In: Annals of Surgical Oncology, 07.06.2017, p. 1-8.

Research output: Contribution to journalArticle

Yeh, CC, Goyal, A, Shen, J, Wu, HC, Strauss, JA, Wang, Q, Gurvich, I, Safyan, RA, Manji, GA, Gamble, MV, Siegel, AB & Santella, RM 2017, 'Global Level of Plasma DNA Methylation is Associated with Overall Survival in Patients with Hepatocellular Carcinoma', Annals of Surgical Oncology, pp. 1-8. https://doi.org/10.1245/s10434-017-5913-4
Yeh, Chih Ching ; Goyal, Abhishek ; Shen, Jing ; Wu, Hui chen ; Strauss, Joshua A. ; Wang, Qiao ; Gurvich, Irina ; Safyan, Rachael A. ; Manji, Gulam A. ; Gamble, Mary V. ; Siegel, Abby B. ; Santella, Regina M. / Global Level of Plasma DNA Methylation is Associated with Overall Survival in Patients with Hepatocellular Carcinoma. In: Annals of Surgical Oncology. 2017 ; pp. 1-8.
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title = "Global Level of Plasma DNA Methylation is Associated with Overall Survival in Patients with Hepatocellular Carcinoma",
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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author = "Yeh, {Chih Ching} and Abhishek Goyal and Jing Shen and Wu, {Hui chen} and Strauss, {Joshua A.} and Qiao Wang and Irina Gurvich and Safyan, {Rachael A.} and Manji, {Gulam A.} and Gamble, {Mary V.} and Siegel, {Abby B.} and Santella, {Regina M.}",
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T1 - Global Level of Plasma DNA Methylation is Associated with Overall Survival in Patients with Hepatocellular Carcinoma

AU - Yeh, Chih Ching

AU - Goyal, Abhishek

AU - Shen, Jing

AU - Wu, Hui chen

AU - Strauss, Joshua A.

AU - Wang, Qiao

AU - Gurvich, Irina

AU - Safyan, Rachael A.

AU - Manji, Gulam A.

AU - Gamble, Mary V.

AU - Siegel, Abby B.

AU - Santella, Regina M.

PY - 2017/6/7

Y1 - 2017/6/7

N2 - 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.

AB - 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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KW - Overall survival

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