Research Papers:

Genes encoding neuropeptide receptors are epigenetic markers in patients with head and neck cancer: a site-specific analysis

Kiyoshi Misawa _, Atsushi Imai, Daiki Mochizuki, Yuki Misawa, Shiori Endo, Seiji Hosokawa, Ryuji Ishikawa, Masato Mima, Kazuya Shinmura, Takeharu Kanazawa and Hiroyuki Mineta

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Oncotarget. 2017; 8:76318-76328. https://doi.org/10.18632/oncotarget.19356

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Kiyoshi Misawa1, Atsushi Imai1, Daiki Mochizuki1, Yuki Misawa1, Shiori Endo1, Seiji Hosokawa1, Ryuji Ishikawa1, Masato Mima1, Kazuya Shinmura2, Takeharu Kanazawa3 and Hiroyuki Mineta1

1Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan

2Department of Tumour Pathology, Hamamatsu University School of Medicine, Shizuoka, Japan

3Department of Otolaryngology/Head and Neck Surgery, Jichi Medical University, Tochigi, Japan

Correspondence to:

Kiyoshi Misawa, email: [email protected]

Keywords: neuropeptide receptors, GPCR, head and neck cancer, epigenetic markers, metastases

Received: March 15, 2017    Accepted: June 29, 2017    Published: July 18, 2017


Staging and pathological grading systems are useful but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). To identify potential prognostic markers, we examined the methylation status of eight neuropeptide receptor gene promoters in 231 head and neck squamous cell carcinomas. The NPFFR1, NPFFR2, HCRTR1, HCRTR2, NPY1R, NPY2R, NPY4R, and NPY5R promoters were methylated in 80.5%, 79.2%, 67.1%, 73.2%, 35.1%, 36.4%, 38.5%, and 35.9% of the samples, respectively. In a multivariate Cox proportional hazards analysis, the odds ratio for recurrence was 2.044 (95% confidence interval [CI], 1.323–3.156; P = 0.001) when the NPY2R promoter was methylated. In patients without lymph node metastasis (n = 100), methylation of NPY2R (compared with methylation of the other seven genes) best correlated with poor disease-free survival (DFS) (odds ratio, 2.492; 95% CI, 1.190–5.215; P = 0.015). In patients with oral cancer (n = 69), methylated NPY1R and NPY2R were independent prognostic factors for poor DFS, both individually and, even more so, in combination (odds ratio, 3.90; 95% CI, 1.523–9.991; P = 0.005). Similar findings were observed for NPY2R and NPY4R in patients with oropharyngeal cancer (n = 162) (odds ratio, 5.663; 95% CI, 1.507–21.28; P = 0.010).

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