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

• Published in: PloS one 2015-03, Vol.10 (3), p.e0118588-e0118588
• Main Authors: Misawa, Kiyoshi, Misawa, Yuki, Kondo, Haruki, Mochizuki, Daiki, Imai, Atsushi, Fukushima, Hirofumi, Uehara, Takayuki, Kanazawa, Takeharu, Mineta, Hiroyuki
• Format: Article
• Language: English
• Subjects: Aberration; Adult; Aged; Aged, 80 and over; Analysis; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Carcinoma, Squamous Cell - diagnosis; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - mortality; Carcinoma, Squamous Cell - pathology; Correlation; CpG Islands; Deactivation; DNA Methylation; Epidermal growth factor; Epigenetics; Female; Galanin; Galanin - genetics; Galanin - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Head; Head & neck cancer; Head and neck cancer; Head and Neck Neoplasms - diagnosis; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - mortality; Head and Neck Neoplasms - pathology; Humans; Inactivation; Male; Measurement methods; Methylation; Middle Aged; Mouth Neoplasms - diagnosis; Mouth Neoplasms - genetics; Mouth Neoplasms - mortality; Mouth Neoplasms - pathology; Mucosa; Neoplasm Staging; Neuropeptides; Odds Ratio; Oral cavity; Oropharyngeal Neoplasms - diagnosis; Oropharyngeal Neoplasms - genetics; Oropharyngeal Neoplasms - mortality; Oropharyngeal Neoplasms - pathology; Oropharynx; Otolaryngology; Polymerase chain reaction; Promoter Regions, Genetic; Promoters; Receptor, Galanin, Type 2 - genetics; Receptor, Galanin, Type 2 - metabolism; Receptors, Somatostatin - genetics; Receptors, Somatostatin - metabolism; Regression analysis; Retrospective Studies; Risk Factors; Somatostatin; Somatostatin - genetics; Somatostatin - metabolism; Somatostatin receptors; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; Survival; Survival Analysis; Tachykinin; Tachykinin receptors; Tachykinins - genetics; Tachykinins - metabolism; Tissues; Transcription, Genetic; Tumorigenesis; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0118588

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