Aberrant methylation inactivates somatostatin and somatostatin receptor type 1 in head and neck squamous cell carcinoma

PLoS One. 2015 Mar 3;10(3):e0118588. doi: 10.1371/journal.pone.0118588. eCollection 2015.

Abstract

Purpose: The aim of this study was to define somatostatin (SST) and somatostatin receptor type 1 (SSTR1) methylation profiles for head and neck squamous cell carcinoma (HNSCC) tumors at diagnosis and follow up and to evaluate their prognostic significance and value as a biomarker.

Methods: Gene expression was measured by quantitative RT-PCR. Promoter methylation status was determined by quantitative methylation-specific PCR (Q-MSP) in HNSCC.

Results: Methylation was associated with transcription inhibition. SST methylation in 81% of HNSCC tumor specimens significantly correlated with tumor size (P = 0.043), stage (P = 0.008), galanin receptor type 2 (GALR2) methylation (P = 0.041), and tachykinin-1 (TAC1) (P = 0.040). SSTR1 hypermethylation in 64% of cases was correlated with tumor size (P = 0.037), stage (P = 0.037), SST methylation (P < 0.001), and expression of galanin (P = 0.03), GALR2 (P = 0.014), TAC1 (P = 0.023), and tachykinin receptor type 1 (TACR1) (P = 0.003). SST and SSTR1 promoter hypermethylation showed highly discriminating receiver operator characteristic curve profiles, which clearly distinguished HNSCC from adjacent normal mucosal tissues. Concurrent hypermethylation of galanin and SSTR1 promoters correlated with reduced disease-free survival (log-rank test, P = 0.0001). Among patients with oral cavity and oropharynx cancer, methylation of both SST and SSTR1 promoters correlated with reduced disease-free survival (log-rank test, P = 0.028). In multivariate logistic-regression analysis, concomitant methylation of galanin and SSTR1 was associated with an odds ratio for recurrence of 12.53 (95% CI, 2.62 to 59.8; P = 0.002).

Conclusions: CpG hypermethylation is a likely mechanism of SST and SSTR1 gene inactivation, supporting the hypothesis that SST and SSTR1 play a role in the tumorigenesis of HNSCC and that this hypermethylation may serve as an important biomarker.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Squamous Cell / diagnosis
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / mortality
  • Carcinoma, Squamous Cell / pathology
  • CpG Islands
  • DNA Methylation
  • Female
  • Galanin / genetics
  • Galanin / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Head and Neck Neoplasms / diagnosis
  • Head and Neck Neoplasms / genetics*
  • Head and Neck Neoplasms / mortality
  • Head and Neck Neoplasms / pathology
  • Humans
  • Male
  • Middle Aged
  • Mouth Neoplasms / diagnosis
  • Mouth Neoplasms / genetics*
  • Mouth Neoplasms / mortality
  • Mouth Neoplasms / pathology
  • Neoplasm Staging
  • Odds Ratio
  • Oropharyngeal Neoplasms / diagnosis
  • Oropharyngeal Neoplasms / genetics*
  • Oropharyngeal Neoplasms / mortality
  • Oropharyngeal Neoplasms / pathology
  • Promoter Regions, Genetic
  • Receptor, Galanin, Type 2 / genetics
  • Receptor, Galanin, Type 2 / metabolism
  • Receptors, Somatostatin / genetics*
  • Receptors, Somatostatin / metabolism
  • Retrospective Studies
  • Risk Factors
  • Somatostatin / genetics*
  • Somatostatin / metabolism
  • Squamous Cell Carcinoma of Head and Neck
  • Survival Analysis
  • Tachykinins / genetics
  • Tachykinins / metabolism
  • Transcription, Genetic

Substances

  • Biomarkers, Tumor
  • Receptor, Galanin, Type 2
  • Receptors, Somatostatin
  • Tachykinins
  • somatostatin receptor type 1
  • Somatostatin
  • Galanin

Grants and funding

A Grant-in-Aid for Scientific Research (No. 24592594, 25861485, 26462599, 26462600 and 26861367) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.