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Prognostic value of aberrant promoter hypermethylation of tumor-related genes in early-stage head and neck cancer

2016; Impact Journals LLC; Volume: 7; Issue: 18 Linguagem: Inglês

10.18632/oncotarget.8317

1949-2553

Kiyoshi Misawa, Daiki Mochizuki, Atsushi Imai, Shiori Endo, Masato Mima, Yuki Misawa, Takeharu Kanazawa, Thomas E. Carey, Hiroyuki Mineta,

RNA modifications and cancer

// Kiyoshi Misawa 1 , Daiki Mochizuki 1 , Atsushi Imai 1 , Shiori Endo 1 , Masato Mima 1 , Yuki Misawa 1 , Takeharu Kanazawa 2 , Thomas E. Carey 3 , Hiroyuki Mineta 1 1 Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan 2 Department of Otolaryngology/Head and Neck Surgery, Jichi Medical University, Tochigi, Japan 3 Department of Otolaryngology/Head and Neck Surgery, Laboratory of Head and Neck Cancer Biology, University of Michigan, Ann Arbor, MI, USA Correspondence to: Kiyoshi Misawa, e-mail: kiyoshim@hama-med.ac.jp Keywords: tumor-suppressor genes, hypermethylation, head and neck cancer, metastases, biomarker Received: November 03, 2015     Accepted: March 11, 2016     Published: March 24, 2016 ABSTRACT Staging and pathological grading are useful, but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Accordingly, molecular biomarkers that predict the risk of recurrence are necessary to improve clinical outcomes. The methylation statuses of the promoters of 11 tumor-related genes ( p16 , RASSF1A , E-cadherin , H-cadherin , MGMT , DAPK , DCC , COL1A2 , TAC1 , SST , and GALR1 ) were analyzed in 133 HNSCC cases using quantitative methylation-specific PCR. We detected frequent methylation of p16 (44%), RASSF1A (18%), E-cadherin (53%), H-cadherin (35%), MGMT (35%), DAPK (53%), DCC (42%), COL1A2 (44%), TAC1 (61%), SST (64%), and GALR1 (44%) in HNSCC. Disease-free survival was lower in patients with 6–11 methylated genes than in those with 0–5 methylated genes (log-rank test, P = 0.001). In a multivariate Cox proportional hazards analysis, the methylation of E-cadherin, COL1A2, TAC1 , and GALR1 was associated with poor survival, with hazard ratios of 4.474 (95% CI, 1.241–16.124). In a joint analysis of these four genes, patients with 2–4 methylated genes had a significantly lower survival rate than those with 0–1 methylated genes in early-stage HNSCC. Importantly, the methylation of some genes was closely related to poor prognosis in early-stage HNSCC, providing strong evidence that these hypermethylated genes are valuable biomarkers for prognostic evaluation.