Abstract
BackgroundStaging and pathological grading systems are convenient but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Identifying biomarkers for HNSCC that will progress and cause death is a critical research area, particularly if the biomarker can be linked to selection of patients. Therefore, to identify potential alternative prognostic markers, we investigated the methylation status of five neuropeptide gene promoters. The promoter methylation status was determined by quantitative methylation-specific PCR in 230 cases of HNSCC; 58 hypopharynx, 45 larynx, 56 oropharynx, and 71 oral cavity tumor samples were studied.ResultsThe somatostatin (SST), tachykinin precursor 1 (TAC1), hypocretin neuropeptide precursor (HCRT), neuropeptide Y (NPY), and galanin (GAL) promoters were methylated in 84.3, 63.5, 32.6, 28.3, and 20.0%, respectively, of the samples. The mean number of methylated genes per sample was 2.29 (range, 0–5). Disease-free survival was lower in patients with 3–5 methylated genes than in those with 0–2 methylated genes (log-rank test, P = 0.007). In multivariate Cox proportional hazards analysis, TAC1 and GAL promoter methylation independently predicted recurrence (odds ratios 1.620, 95% confidence interval [CI] 1.018–2.578, P = 0.042, and odds ratios 1.692, 95% CI 1.063–2.694, P = 0.027, respectively). In patients with oral cancer, TAC1 methylation showed the best correlation with poor survival (odds ratio 4.427, 95% CI 1.634–12.00, P = 0.003). Similar findings were observed for HCRT and GAL in patients with laryngeal cancer and oropharyngeal cancer, respectively.ConclusionIn this study, we demonstrated the methylation status of the neuropeptide-encoding genes SST, TAC1, HCRT, NPY, and GAL and its relationship with recurrence and survival in HNSCC. These methylation changes may serve as potential molecular markers for defining the risk and prognosis of HNSCC.
Highlights
Staging and pathological grading systems are convenient but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC)
Using real-time PCR, we examined the methylation status of these genes, all of which encode neuropeptide genes, in HNSCCs originating in the hypopharynx, larynx, oropharynx, or oral cavity
We found that aberrant methylation of the tachykinin precursor 1 (TAC1) and GAL promoters was positively correlated with recurrence in patients with
Summary
Staging and pathological grading systems are convenient but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). The promoter methylation status was determined by quantitative methylation-specific PCR in 230 cases of HNSCC; 58 hypopharynx, 45 larynx, 56 oropharynx, and 71 oral cavity tumor samples were studied. Neuropeptides and their receptors are important messenger molecules that carry information between neurons; they can act as neurohormones, neurotransmitters, and neuromodulators and maintain physiological homeostasis [1, 2]. Some neuroendocrine peptides such as gastrin, vasoactive intestinal peptide, and neurotensin have been implicated in the modulation of human tumorigenesis [3, 4] Most neuropeptides exert their effect through G protein-coupled receptors (GPCRs), with some exceptions [4]. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated
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