Prognostic significance of LINE-1 hypomethylation in oropharyngeal squamous cell carcinoma

Carlo Furlan, Jerry Polesel, Luigi Barzan, Giovanni Franchin, Sandro Sulfaro, Salvatore Romeo, Francesca Colizzi, Aurora Rizzo, Vittorio Baggio, Vittorio Giacomarra, Angelo Paolo Dei Tos, Paolo Boscolo-Rizzo, Emanuela Vaccher, Riccardo Dolcetti, Luca Sigalotti, Elisabetta Fratta

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Inclusion of new biomarkers to improve a personalized treatment approach for oropharyngeal squamous cell carcinoma (OPSCC) is urgently needed. Hypomethylation of the Long interspersed nucleotide element-1 (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was found to be associated with a poor prognosis in several cancers. At present, no studies have investigated the influence of LINE-1 methylation levels on OPSCC relapse. The main goal of this study was the evaluation of the prognostic value of LINE-1 methylation status in predicting early tumor relapse in locally advanced OPSCC. Methods: We retrospectively reviewed a cohort of 77 patients with stage III–IVB OPSCC. Methylation of LINE-1 repetitive sequences was evaluated by real-time quantitative methylation-specific PCR in formalin-fixed paraffin-embedded tissues. The prognostic relevance of LINE-1 methylation was assessed by comparing patients who relapsed within 2 years from the end of treatment (cases) with those who did not (controls). Results were validated in an independent cohort of 33 patients with OPSCC. Results: With respect to early OPSCC relapse, the mean LINE-1 methylation level was significantly lower in relapsed cases than in control group (p < 0.01). Interestingly, LINE-1 methylation was lower in relapsed cases than in controls in both HPV16-negative and HPV16-positive OPSCC patients, even if statistical significance was reached only for the former group (p = 0.01). LINE-1 methylation levels were also significantly reduced in relapsed cases with respect to the controls in OPSCC current smokers (p = 0.02). Consistently, in HPV16-negative current smokers, OPSCC relapse was significantly associated with decreased levels of LINE-1 methylation (p = 0.02). Using logistic regression model, we found that patients with hypomethylated LINE-1 were associated with a 3.5 higher risk of early relapse than hypermethylated ones (OR = 3.51; 95% CI 1.03–12.00). Adjustment for potential confounders did not substantially change the risk magnitude. Results from the validation cohort confirmed the lower LINE-1 methylation in patients who early relapsed compared to relapse-free patients. Conclusions: LINE-1 hypomethylation is associated with higher risk of early relapse in stage III–IVB OPSCC. Further validation in a prospective study is needed for its application in daily clinical practice.

Original languageEnglish
Article number58
JournalClinical Epigenetics
Volume9
Issue number1
DOIs
Publication statusPublished - May 30 2017

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Long Interspersed Nucleotide Elements
Squamous Cell Carcinoma
Methylation
Recurrence
Logistic Models
Nucleic Acid Repetitive Sequences
DNA Methylation
Paraffin
Formaldehyde

Keywords

  • DNA methylation
  • HPV
  • LINE-1
  • Oropharyngeal squamous cell carcinoma

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

Cite this

Prognostic significance of LINE-1 hypomethylation in oropharyngeal squamous cell carcinoma. / Furlan, Carlo; Polesel, Jerry; Barzan, Luigi; Franchin, Giovanni; Sulfaro, Sandro; Romeo, Salvatore; Colizzi, Francesca; Rizzo, Aurora; Baggio, Vittorio; Giacomarra, Vittorio; Dei Tos, Angelo Paolo; Boscolo-Rizzo, Paolo; Vaccher, Emanuela; Dolcetti, Riccardo; Sigalotti, Luca; Fratta, Elisabetta.

In: Clinical Epigenetics, Vol. 9, No. 1, 58, 30.05.2017.

Research output: Contribution to journalArticle

Furlan, C, Polesel, J, Barzan, L, Franchin, G, Sulfaro, S, Romeo, S, Colizzi, F, Rizzo, A, Baggio, V, Giacomarra, V, Dei Tos, AP, Boscolo-Rizzo, P, Vaccher, E, Dolcetti, R, Sigalotti, L & Fratta, E 2017, 'Prognostic significance of LINE-1 hypomethylation in oropharyngeal squamous cell carcinoma', Clinical Epigenetics, vol. 9, no. 1, 58. https://doi.org/10.1186/s13148-017-0357-z
Furlan, Carlo ; Polesel, Jerry ; Barzan, Luigi ; Franchin, Giovanni ; Sulfaro, Sandro ; Romeo, Salvatore ; Colizzi, Francesca ; Rizzo, Aurora ; Baggio, Vittorio ; Giacomarra, Vittorio ; Dei Tos, Angelo Paolo ; Boscolo-Rizzo, Paolo ; Vaccher, Emanuela ; Dolcetti, Riccardo ; Sigalotti, Luca ; Fratta, Elisabetta. / Prognostic significance of LINE-1 hypomethylation in oropharyngeal squamous cell carcinoma. In: Clinical Epigenetics. 2017 ; Vol. 9, No. 1.
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abstract = "Background: Inclusion of new biomarkers to improve a personalized treatment approach for oropharyngeal squamous cell carcinoma (OPSCC) is urgently needed. Hypomethylation of the Long interspersed nucleotide element-1 (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was found to be associated with a poor prognosis in several cancers. At present, no studies have investigated the influence of LINE-1 methylation levels on OPSCC relapse. The main goal of this study was the evaluation of the prognostic value of LINE-1 methylation status in predicting early tumor relapse in locally advanced OPSCC. Methods: We retrospectively reviewed a cohort of 77 patients with stage III–IVB OPSCC. Methylation of LINE-1 repetitive sequences was evaluated by real-time quantitative methylation-specific PCR in formalin-fixed paraffin-embedded tissues. The prognostic relevance of LINE-1 methylation was assessed by comparing patients who relapsed within 2 years from the end of treatment (cases) with those who did not (controls). Results were validated in an independent cohort of 33 patients with OPSCC. Results: With respect to early OPSCC relapse, the mean LINE-1 methylation level was significantly lower in relapsed cases than in control group (p < 0.01). Interestingly, LINE-1 methylation was lower in relapsed cases than in controls in both HPV16-negative and HPV16-positive OPSCC patients, even if statistical significance was reached only for the former group (p = 0.01). LINE-1 methylation levels were also significantly reduced in relapsed cases with respect to the controls in OPSCC current smokers (p = 0.02). Consistently, in HPV16-negative current smokers, OPSCC relapse was significantly associated with decreased levels of LINE-1 methylation (p = 0.02). Using logistic regression model, we found that patients with hypomethylated LINE-1 were associated with a 3.5 higher risk of early relapse than hypermethylated ones (OR = 3.51; 95{\%} CI 1.03–12.00). Adjustment for potential confounders did not substantially change the risk magnitude. Results from the validation cohort confirmed the lower LINE-1 methylation in patients who early relapsed compared to relapse-free patients. Conclusions: LINE-1 hypomethylation is associated with higher risk of early relapse in stage III–IVB OPSCC. Further validation in a prospective study is needed for its application in daily clinical practice.",
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T1 - Prognostic significance of LINE-1 hypomethylation in oropharyngeal squamous cell carcinoma

AU - Furlan, Carlo

AU - Polesel, Jerry

AU - Barzan, Luigi

AU - Franchin, Giovanni

AU - Sulfaro, Sandro

AU - Romeo, Salvatore

AU - Colizzi, Francesca

AU - Rizzo, Aurora

AU - Baggio, Vittorio

AU - Giacomarra, Vittorio

AU - Dei Tos, Angelo Paolo

AU - Boscolo-Rizzo, Paolo

AU - Vaccher, Emanuela

AU - Dolcetti, Riccardo

AU - Sigalotti, Luca

AU - Fratta, Elisabetta

PY - 2017/5/30

Y1 - 2017/5/30

N2 - Background: Inclusion of new biomarkers to improve a personalized treatment approach for oropharyngeal squamous cell carcinoma (OPSCC) is urgently needed. Hypomethylation of the Long interspersed nucleotide element-1 (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was found to be associated with a poor prognosis in several cancers. At present, no studies have investigated the influence of LINE-1 methylation levels on OPSCC relapse. The main goal of this study was the evaluation of the prognostic value of LINE-1 methylation status in predicting early tumor relapse in locally advanced OPSCC. Methods: We retrospectively reviewed a cohort of 77 patients with stage III–IVB OPSCC. Methylation of LINE-1 repetitive sequences was evaluated by real-time quantitative methylation-specific PCR in formalin-fixed paraffin-embedded tissues. The prognostic relevance of LINE-1 methylation was assessed by comparing patients who relapsed within 2 years from the end of treatment (cases) with those who did not (controls). Results were validated in an independent cohort of 33 patients with OPSCC. Results: With respect to early OPSCC relapse, the mean LINE-1 methylation level was significantly lower in relapsed cases than in control group (p < 0.01). Interestingly, LINE-1 methylation was lower in relapsed cases than in controls in both HPV16-negative and HPV16-positive OPSCC patients, even if statistical significance was reached only for the former group (p = 0.01). LINE-1 methylation levels were also significantly reduced in relapsed cases with respect to the controls in OPSCC current smokers (p = 0.02). Consistently, in HPV16-negative current smokers, OPSCC relapse was significantly associated with decreased levels of LINE-1 methylation (p = 0.02). Using logistic regression model, we found that patients with hypomethylated LINE-1 were associated with a 3.5 higher risk of early relapse than hypermethylated ones (OR = 3.51; 95% CI 1.03–12.00). Adjustment for potential confounders did not substantially change the risk magnitude. Results from the validation cohort confirmed the lower LINE-1 methylation in patients who early relapsed compared to relapse-free patients. Conclusions: LINE-1 hypomethylation is associated with higher risk of early relapse in stage III–IVB OPSCC. Further validation in a prospective study is needed for its application in daily clinical practice.

AB - Background: Inclusion of new biomarkers to improve a personalized treatment approach for oropharyngeal squamous cell carcinoma (OPSCC) is urgently needed. Hypomethylation of the Long interspersed nucleotide element-1 (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was found to be associated with a poor prognosis in several cancers. At present, no studies have investigated the influence of LINE-1 methylation levels on OPSCC relapse. The main goal of this study was the evaluation of the prognostic value of LINE-1 methylation status in predicting early tumor relapse in locally advanced OPSCC. Methods: We retrospectively reviewed a cohort of 77 patients with stage III–IVB OPSCC. Methylation of LINE-1 repetitive sequences was evaluated by real-time quantitative methylation-specific PCR in formalin-fixed paraffin-embedded tissues. The prognostic relevance of LINE-1 methylation was assessed by comparing patients who relapsed within 2 years from the end of treatment (cases) with those who did not (controls). Results were validated in an independent cohort of 33 patients with OPSCC. Results: With respect to early OPSCC relapse, the mean LINE-1 methylation level was significantly lower in relapsed cases than in control group (p < 0.01). Interestingly, LINE-1 methylation was lower in relapsed cases than in controls in both HPV16-negative and HPV16-positive OPSCC patients, even if statistical significance was reached only for the former group (p = 0.01). LINE-1 methylation levels were also significantly reduced in relapsed cases with respect to the controls in OPSCC current smokers (p = 0.02). Consistently, in HPV16-negative current smokers, OPSCC relapse was significantly associated with decreased levels of LINE-1 methylation (p = 0.02). Using logistic regression model, we found that patients with hypomethylated LINE-1 were associated with a 3.5 higher risk of early relapse than hypermethylated ones (OR = 3.51; 95% CI 1.03–12.00). Adjustment for potential confounders did not substantially change the risk magnitude. Results from the validation cohort confirmed the lower LINE-1 methylation in patients who early relapsed compared to relapse-free patients. Conclusions: LINE-1 hypomethylation is associated with higher risk of early relapse in stage III–IVB OPSCC. Further validation in a prospective study is needed for its application in daily clinical practice.

KW - DNA methylation

KW - HPV

KW - LINE-1

KW - Oropharyngeal squamous cell carcinoma

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